Inflammatory signaling induced bone loss Steven R. Goldring PII: DOI: Reference:
S8756-3282(15)00205-7 doi: 10.1016/j.bone.2015.05.024 BON 10741
To appear in:
Bone
Received date: Revised date: Accepted date:
9 January 2015 14 May 2015 20 May 2015
Please cite this article as: Goldring Steven R., Inflammatory signaling induced bone loss, Bone (2015), doi: 10.1016/j.bone.2015.05.024
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ACCEPTED MANUSCRIPT
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Steven R. Goldring, M.D.
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Inflammatory signaling induced bone loss
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York, NY
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Research Division, Hospital for Special Surgery, Weill Cornell Medical College, New
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Steven R. Goldring, M.D. Chief Scientific Officer Hospital for Special Surgery Professor of Medicine Weill Cornell Medical College New York, NY Tel: 212 774-7554 Fax: 212 774-2301 Email: [email protected]
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Corresponding author:
Introduction
ACCEPTED MANUSCRIPT A broad spectrum of inflammatory disorders have the capacity to target the skeleton and to de-regulate the processes of physiological bone remodeling. This review
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will focus on the systemic inflammatory rheumatologic disorders, which target articular
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and periarticular bone tissues. Many of these disorders also affect extra-articular tissues and organs, and in addition, have the capacity to produce systemic bone loss and
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increased risk of osteoporotic fractures. The articular inflammation and joint damage, as
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well as the generalized bone loss and additional systemic extra-articular manifestations, have a profound adverse effect on the quality of life and functional capacity of the
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affected individuals. Attention will focus on rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and the seronegative spondyloarthropathies (SpAs), which include
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ankylosing spondylitis (AS), reactive arthritis (formerly designated as Reiter’s syndrome), and the arthritis of inflammatory bowel disease, juvenile onset-
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spondyloarthropathy and psoriatic arthritis. The discussion will principally focus on RA, which is a prototypical model of an inflammatory disorder that de-regulates bone remodeling, but also will review the other forms of inflammatory joint disease to highlight the differential effects of inflammation on bone remodeling in these conditions.
Structural organization of periarticular bone To understand the articular and periarticular bone pathology in the rheumatic diseases, it is important to appreciate the unique organizational features of the different joints. The joints can be divided into three categories based on their anatomic features 1. They include the highly mobile diarthrodial joints, which are lined by a specialized synovial lining, e.g. the knee, wrist and small joints of the hands and feet; the
ACCEPTED MANUSCRIPT amphiarthroses in which the adjacent bones are separated by articular cartilage or a fibrocartilage disc and are associated with limited mobility, e.g. the intervertebral discs;
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and synarthroses, in which fibrous tissue separates adjoining bones, e.g. the sacroiliac
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joints. The periarticular bone of the diarthrodial joints is separated from the overlying articular cartilage by a zone of calcified cartilage, and the interface between the articular
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and calcified cartilage is demarcated by the “tide-mark”, which can be identified by its
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enhanced metachromatic staining pattern. The bone beneath the calcified cartilage is organized into a plate-like structure of compact cortical bone and below the subchondral
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bone plate, the bone forms a network of cancellous trabecular bone that is surrounded by the bone marrow. The periosteal bone at the joint margins is in immediate contact with
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the joint capsule and synovial lining. The tendons and ligaments insert into the bone
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below the synovial reflection forming the unique structure of the enthesis 2. As will be
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discussed below, in RA and SLE, the synovial lining is the site of an intense immunemediated inflammatory process that results in synovial proliferation and production of potent inflammatory cytokines and soluble mediators that are responsible for the clinical signs of joint inflammation. Synovial inflammation also is present in the SpAs, but unlike the pattern of the joint inflammation in RA and SLE, the entheses are the initial sites of inflammation 3, 4. Subsequently, the inflammatory process extends to the synovial lining, although the distribution and pattern of joint involvement, as well as the response of the periarticular bone to the inflammation differs in RA and the SpAs. 5, 6
Rheumatoid Arthritis RA is a systemic inflammatory disorder that is characterized by a symmetrical
ACCEPTED MANUSCRIPT destructive polyarthritis. The etiology of RA is unknown, but both genetic and environmental factors are involved in its pathogenesis
7, 8
. The hallmark of RA is the
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development of a chronic inflammatory polyarthritis that targets the synovial lining of
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diarthrodial joints. The earliest changes involve the proliferation of the synovial lining cells, consisting of a population of macrophage-like cells (A cells) and synovial
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fibroblasts (B cells). There also is extensive neovascularization and perivascular and
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interstitial infiltration of the synovium with lymphocytes, plasma cells, and activated macrophages. Multiple lines of evidence implicate a pathogenic role for autoantibodies
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and immune complexes in the development of the synovial lesion, which exhibits features consistent with activation of an adaptive immune response in which activated T
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and B cells play a key role as primary effectors of the inflammatory process 7-9. Four distinct patterns of pathologic bone remodeling are observed in RA. These
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include periarticular osteopenia; focal bone erosions that initially are localized to the joint margins; subchondral bone erosions; and systemic osteoporosis. Juxta-articular bone loss at sites removed from the inflamed synovium is a common finding in RA and frequently precedes the development of marginal joint erosions. Histomorphometric analysis of periarticular bone from RA patients undergoing hand arthroplasty procedures for destructive arthritis show evidence of both increased bone resorption and formation. Examination of the bone marrow in these regions reveals the presence of infiltrates with lymphocytes and macrophages, suggesting a potential role for local inflammation
10
.
Immobilization and reduced mechanical loading are additional factors that have been implicated in the pathogenesis of periarticular bone loss. Importantly, the presence of
ACCEPTED MANUSCRIPT periarticular bone loss has been shown to have high predictive value with respect to the subsequent development of marginal joint erosions in the hand 11-13.
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The marginal joint erosions correspond to sites where the inflamed synovium
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comes into contact with the bone surface (Figure 1). At these sites, the bone surface is lined by resorption lacunae containing mono- and multinucleated cells with phenotypic
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features of osteoclasts 14, 15. Similar sites of focal bone resorption can be identified on the
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endosteal surface of the subchondral bone. These regions of bone resorption may extend through the calcified cartilage into the overlying articular cartilage, which is then
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vulnerable to degradation by the invading inflammatory tissue. The initial observations implicating osteoclasts in the pathogenesis of marginal and subchondral bone erosions
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were based on cell morphology and expression of osteoclast associated genes, including
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tartrate resistant acid phosphatase (TRAP), cathepsin K and V3 integrin
14, 15
. Studies
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in mice genetically engineered with an inability to form osteoclasts have more definitively established that osteoclasts are essential for the development of the marginal and subchondral bone erosions in murine models of RA as will be discussed below
16-18
.
These conclusions are supported by studies in patients with RA in whom treatment with antiresorptive agents have been shown to reduce the development of joint erosions 19-21. Studies have helped to establish that the chronic synovial inflammation in RA is dependent on a complex interaction between a network of cytokines and growth factors, and well as direct cell-cell interactions among the cells that populate the inflamed synovium. The development of therapeutic agents that target individual cytokines has revealed the somewhat surprising observation that despite the diversity of these cytokines, targeting of certain key cytokines can produce marked suppression of the
ACCEPTED MANUSCRIPT synovial and systemic inflammation and retard or even prevent the development of joint destruction.
The initial proof of concept studies came from the early clinical trials
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targeting TNF-22, 23. The success of these trials indicated that the cytokine networks
Subsequently, the use of additional therapeutic agents
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involving TNF- signaling 8.
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and related inflammatory mediators and pathways intersected on an “activation node”
targeting alternate cytokines, including IL-6 in RA, as well as IL-23 or IL-17 in the SpAs,
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represent additional “activation nodes” involving these cytokines
24-29
. Therapies
targeting T cell co-stimulatory effector pathways also have been shown to be effective in
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controlling synovial inflammation and joint damage in RA
30
. More recently, therapies
targeting B cells also have shown efficacy, providing evidence of the importance of both
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T and B cells in RA pathogenesis 31.
The capacity of the RA synovium to induce local articular bone resorption can be
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attributed to the production of a broad spectrum of products with the ability to recruit osteoclast precursors and induce their differentiation and activation into bone resorbing osteoclasts. These include a spectrum of proinflammatory cytokines, chemokines and proosteoclastogenic soluble mediators
32-34
, including receptor activator of NF- ligand
(RANKL), which is produced by synovial fibroblasts, T cells and B cells within the synovium
35-38
. Table 1 provides a list of the pro-osteoclastgenic cytokines and growth
factors produced by the RA synovium. Among the T-cell subsets, both Th1 and Th17 (the major source of IL-17) cells have the capacity to produce RANKL, as well as TNF- and multiple additional cytokines and mediators with osteoclastogenic activity
39, 40
. In
addition to the effects of RANKL and TNF-, T cells also have the capacity to enhance osteoclastogenesis via a co-stimulatory pathway involving interaction of paired Ig-like
ACCEPTED MANUSCRIPT receptor-A (PIR-A), which is expressed on the surface of T cells, and its signaling partner Fc receptor-γ (FcRγ) on osteoclast precursors 41.
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The critical role of RANKL in the pathogenesis of joint erosions is provided by the observation that blocking RANKL in animal models of RA with osteoprotegerin
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42-44
(OPG), the RANKL antagonist, results in marked attenuation of joint erosions
.
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in animal models of RA protects animals from both articular and
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its receptor RANK
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Additional evidence is provided by studies showing that genetic deletion of RANKL 17 or
systemic bone loss. More recently, studies in human subjects with RA have shown that
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blockade of RANKL with Denosumab, a monoclonal antibody that blocks RANKL activity, significantly reduces bone erosions 19, 20. These results provide further evidence
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that RANKL and osteoclasts play a critical role in articular bone destruction in RA. The RA synovium also is a source of inhibitors of osteoclastogenesis
32-34
. A list of
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several of these factors is included in Table 1. Many of the inhibitors are products of T cells, which have the capacity to produce both inhibitory and stimulatory factors. For example, Th1 and Th17 cells produce both TNF- and RANKL, but they also have the capacity to produce interferons, which are inhibitors of osteoclastogenesis
38, 45
.
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regulatory cells (Tregs) represent an additional T cell subset that exhibit antiosteoclastogenic activity 46-48. This has been attributed to effects mediated by direct cellcontact via CTLA-4 interactions with CD80/CD86 on myeloid osteoclast precursors and also to their capacity to produce IL-4 and-10, which are inhibitors of osteoclastogenesis. Of interest, Komatsu et al. recently demonstrated that Tregs in inflamed synovial tissues in an RA animal model have the capacity to undergo transdifferentiation into Th17 cells that exhibit potent pro-osteoclastogenic activity
49
. The shift in the balance of bone
ACCEPTED MANUSCRIPT remodeling towards bone resorption in the RA joint, indicates that despite these differential capacities among the T cell subsets, the environment in the RA synovium As discussed below, this
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strongly favors the activity of pro-osteoclastogenic factors.
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contrasts with the synovial tissue in lupus in which the anti-osteoclastogenic factors, including the interferons may predominate, limiting the capacity of the synovial tissue to
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produce bone erosions.
50
.
In these studies, the authors investigated the role of
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enhances bone resorption
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Recent studies have suggested an additional mechanism by which the RA synovium
autoantibodies directed against citrullinated proteins, so called anti-citrullinated protein
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antibodies, ACPAs, which have been shown to be an independent predictor of the 7, 51
. They first showed that human
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development of bone erosions in patients with RA
osteoclasts expressed enzymes that specifically induced N-terminal citrullination of
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vimentin during osteoclast differentiation, and then demonstrated that binding of the antibodies to osteoclast precursors enhanced osteoclast differentiation. This effect was attributed to up-regulation of TNF- production by the osteoclast precursors that then synergized with RANKL and M-CSF to enhance osteoclast formation. A recent study by Hecht et al. demonstrates that rheumatoid factors may cooperate with ACPAs to enhance osteoclastogenesis 52. Of importance, these observations provide a novel link between autoimmunity and osteoclastogenesis. A unique feature of the articular bone erosions in RA is the virtual absence of bone repair. Studies by Diarra et al.
53
demonstrated that cells in the inflamed RA
synovial tissue produce dickkopf-1 (DKK-1), the inhibitor of the wingless (Wnt)signaling pathway that plays a critical role in osteoblast-mediated bone formation. These
ACCEPTED MANUSCRIPT results provide insights into the mechanism involved in the uncoupling of bone resorption and formation in RA. Studies by Walsh et al.
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confirmed these observations and
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identified additional Wnt family antagonists, including members of the DKK and
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secreted Frizzled related protein families in RA synovium. Multiple cell types within the RA synovium have the capacity to produce these Wnt pathway inhibitors, including
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synovial fibroblasts, endothelial cells and chondrocytes.
In the Diarra studies, they
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showed that TNF- was a potent inducer of DKK-1 in RA synovial fibroblasts, thus implicating TNF in both the enhanced resorption and suppressed bone formation in RA.
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They then showed that inhibition of DKK-1 with blocking antibodies partially restored bone formation. An unexpected finding was the inhibition of bone resorption by DKK-1
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blockade. These effects were attributed to the reversal of Wnt pathway inhibition and upregulation of OPG, the potent inhibitor of osteoclastogenesis. These observations have
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clear implications with respect to future therapeutic strategies in RA patients
55
. The
differential effects of the RA synovial inflammation on bone resorption and formation are depicted in Figure 2.
It is well established that patients with RA have reduced bone mineral density (BMD) and are at risk for an increased risk of fracture 56-59. These findings highlight the importance of monitoring patients with RA for evidence of systemic bone loss and for the institution of early therapeutic interventions to reduce the long-term risks of fracture and disability. In general, authors have identified an association between the presence of increased disease activity and reduced bone mass, but the interpretation of the findings has been challenging because of the presence of multiple confounding factors that affect bone remodeling, including the influence of sex, age, nutritional state, level of physical
ACCEPTED MANUSCRIPT activity, disease duration and severity and the use of medications such as glucocorticoids that adversely affect bone remodeling but also can suppress joint and systemic 60
.
Several approaches have been utilized to gain insights into the
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inflammation
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mechanism involved in the pathogenesis of the systemic bone loss in RA, including histomorphometric analysis of bone biopsies, assessment of urinary and serum
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biomarkers of bone remodeling and the measurement of serum cytokine levels. In
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general, results are consistent with the presence of reduced bone formation as well as increased bone resorption, but the findings in these studies vary depending on the patient
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characteristics, including the level and duration of the disease 61-63. The disturbance in systemic bone remodeling in RA has been attributed to the
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release into the circulation of proinflammatory cytokines from sites of synovial inflammation. These products then act systemically in a manner similar to endocrine
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hormones to regulate bone remodeling. The serum levels of several osteoclastogenic cytokines have been assessed in patients with RA, but particular attention has focused on the levels of RANKL and OPG 64-67. For example, Geusens and colleagues observed that the presence of low circulating OPG/RANKL ratios in a cohort of patients with early RA predicted the subsequent risk for bone loss 68. Other studies have examined the effects of RA therapy on systemic bone loss and shown that anti-TNF therapy is accompanied by a fall in serum RANKL levels and decreased systemic bone loss
64, 65, 67
. There also is
evidence that products released from inflamed joints can adversely affect bone formation. Diarra et al.
53
and more recently other authors have detected elevated levels of the Wnt
pathway inhibitor DKK-1 in the sera of patients with RA
69, 70
. Of interest, as will be
discussed below, the levels of DKK-1 have not been shown to be increased in patients
ACCEPTED MANUSCRIPT with AS, and this may play a role in the tendency of these patients to exhibit increased
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periarticular bone formation at sites of joint inflammation.
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Systemic Lupus Erythematosus
SLE is a systemic autoimmune disease characterized by loss of tolerance to self
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antigens that results in aberrant T and B cell activation and the generation of high affinity 71
.
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autoantibodies directed against host tissues leading to organ damage and dysfunction
Symmetrical polyarthritis affecting diarthrodial joints is a characteristic feature of SLE,
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and the arthritis may be a significant contributor to the disease morbidity. Similar to RA the synovial lining undergoes proliferation and infiltration with inflammatory cells,
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including T and B cells, plasma cells and macrophages. However, unlike the synovial lesion in RA there characteristically is an absence of extensive joint erosions and articular
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cartilage destruction. The joint inflammation may be associated with deformities and subluxation, but these changes have been attributed primarily to ligamentous laxity resulting from persistent periarticular inflammation rather than presence of extensive bone erosions and cartilage loss. A characteristic feature of this form of arthritis, referred to as Jaccoud’s arthritis, is the presence of “hook” erosions that occur on the radial aspect of metacarpal bones
72
. These regions of bone loss are distinct from the marginal joint
erosions seen in RA and have been attributed to the effects of tensile forces on bone remodeling at the entheseal insertion sites of tendons and ligaments. As will be discussed below, a similar effect of tensile forces at the entheseal sites of tendon and ligament attachment have been implicated in the pathogenesis of bone erosions in the SpAs. Molecular profiling of synovial tissue from patients with SLE has provided
ACCEPTED MANUSCRIPT insights into the differential capacities of the inflamed synovial tissues in lupus and RA to produce bone erosions and cartilage destruction 73. The synovial tissue in SLE, unlike the
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RA tissue, reveals the marked up-regulation of interferon inducible genes. Patients with
74-76
.
Of importance, in vitro studies have shown that both
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activity and severity
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SLE show elevated levels of serum IFN-, which correlates with both lupus disease
interferon- and -inhibit osteoclastogenesis, and this may account for the limited
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capacity of the synovial lesion in lupus to produce osteoclast-mediated bone erosions 77. This speculation is supported by the studies of Mensah et al
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using the serum transfer
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K/BxN model of RA, which recapitulates the erosive bone disease seen in RA patients.
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The authors first showed that systemic overexpression of INF- using an adenoviral
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delivery system induced an osteopetrotic bone phenotype in normal mice consistent with an inhibition of osteoclast-mediated bone resorption. They then overexpressed IFN- in
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the serum transfer K/BxN model of RA and showed that the mice were protected from the development of bone erosions. These findings provide additional support for the concept that the reduced capacity of synovium in SLE to produce bone erosions may at least in part be attributable to the production of type 1 interferons. Patients with SLE, similar to RA patients also are at risk for the development of systemic osteoporosis and associated osteoporotic fractures
79, 80
. The bone loss has been
attributed to the effects of chronic inflammation, but similar to RA patients there are multiple other factors that may contribute to the bone loss, including glucocorticoid therapy and renal insufficiency that may accompany lupus nephritis.
Seronegative Spondyloarthropathies
ACCEPTED MANUSCRIPT As described in the introduction, the SpAs are a heterogeneous group of inflammatory disorders that exhibit articular and periarticular features that differ from
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RA. They are classified as seronegative forms of arthritis based on the absence of The genetic factors,
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rheumatoid factors and ACPAs that are associated with RA.
particularly involvement of the HLA-B27 class I major histocompatibility (MHC) gene,
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differ from the genetic associations in RA, and in general, the SpAs do not exhibit
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features of an autoimmune disease. Instead the clinical features and contributory role of bacterial and mechanical danger signals suggest an autoinflammatory origin with
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involvement of the IL-23 and IL-17 cytokine pathways in addition to TNF-
29, 81, 82
.
Unlike RA, the SpAs tend to involve the axial skeleton in addition to the diarthrodial , and there is prominent involvement of the entheses, which are not common
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6, 83
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joints
sites of primary pathology in RA.
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Syndesmophytes are one of the anatomic and radiographic hallmarks of the SpAs. They represent examples of new bone formation that is initially localized to the region of the annulus fibrosis of the intervertebral discs. These bony outgrowths may eventually lead to bony bridging of the adjacent vertebral bodies
84
. The regions of new bone
formation may be associated with bone erosions, which are localized to the margins of the discovertebral junctions. The local production of bone growth factors, including TGF- and BMPs, has been implicated in the bone formation, which is primarily via a process of endochondral ossification
84-88
. Appel and co-workers
89
have shown that
serum sclerostin levels correlate with the tendency to form syndesmophytes and that low serum sclerostin levels are associated with an increase in the incidence of new syndesmophyte formation.
ACCEPTED MANUSCRIPT Syndesmophytes are an example of a general feature of the articular bone pathology in the SpAs, which is the enhanced tendency to form bone at sites of 6, 83
. Analysis of tissues from inflamed sacroiliac joints
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inflammation and tissue injury
from patients with AS reveals the presence of infiltrates of CD14 positive macrophages
85, 90
. In the studies by Braun and co-workers they observed that many of the
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ossification
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and CD4+ and CD8T+ lymphocytes associated with localized nodules of endochondral
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inflammatory cells in the entheseal and synovial tissues expressed messenger RNA for TNF-, but not interleukin IL-1 (IL-1) 85. They also noted TGF-2 mRNA expression
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in cells in close proximity to the regions of new bone formation.
Lories et al.
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examined synovial biopsies from patients with AS and RA and detected elevated levels
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of BMP-2 and -6 expression in synovial fibroblasts and macrophages. The presence of these bone growth factors in the RA synovium was surprising given the general absence
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of bone repair in RA. They speculated that in RA the effects of the growth factors could be overridden by the production of Wnt pathway inhibitors such as DKK-1 as demonstrated by the studies of Diarra and Walsh 53, 54. Recent studies by Sherlock et al. provide insights into the role of IL-23 and T cells in the pathogenesis of AS
91
.
They demonstrated the presence of a unique
population IL-23 receptor T cells in entheseal sites, and using an ex vivo organ culture model of entheseal tissues showed that IL-23 induced the expression of IL-17a, IL-17f, IL-22 and BMP-6. They next showed that overexpression of IL-23 in vivo was sufficient to induce a destructive enthesitis that pheno-copied the pathological features of AS. Although IL-23 induced the expression of IL-17, they found that depletion of Th17 T cells in mice did not abrogate the capacity of IL-23 to induce inflammatory arthritis,
ACCEPTED MANUSCRIPT indicating that IL-17 was not essential for induction of the joint disease.
However,
inhibition of IL-17 and IL-22 using blocking antibodies in a murine AS model synergized
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to reduce joint inflammation, suggesting that both IL-17 and IL-22 contributed to the
effector molecule.
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inflammatory disease, although their results indicated that IL-22 was the predominant In additional studies they showed that IL-22 induced osteoblast
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differentiation via effects on the Wnt and BMP pathways, providing a link between the
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proinflammatory activities of IL-22 and its capacity to enhance bone formation. A proposed model of the mechanisms involved in the de-regulated periarticular bone
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remodeling in AS is shown in Figure 3.
In recent studies, Jacques et al. employed a mouse model of inflammatory arthritis
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that recapitulates many of the articular and skeletal features of the SpAs to investigate the role of mechanical factors in the pathogenesis of the entheseal inflammation and de-
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regulated bone remodeling 92. In this model, the initial site of inflammation localized to the entheses. They exposed the animals to hind limb unloading, which protects the mice from mechanical loading, and showed that this markedly reduced the local inflammation and the formation of new bone at the Achilles tendon insertion site. These findings provide evidence that mechanical strains and local tissue injury can initiate and drive both entheseal inflammation as well as new bone formation in a model of inflammatory arthritis. Epidemiological studies have shown that despite the propensity of patients with SpAs to exhibit enhanced bone formation at sites of joint and spinal inflammation, many patients show signs of spinal osteopenia. The osteoporosis and osteopenia correlate with the disease burden and importantly are associated with an increased risk of fracture
93-95
.
ACCEPTED MANUSCRIPT The demonstration that spinal osteopenia may occur even in the absence of bony ankylosis suggests that factors other than the loss of spinal mobility contribute to the 96, 97
. The adverse effects of local inflammatory mediators released from the
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bone loss
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sites of joint pathology, as well as the effects of systemic inflammation likely play a contributory role. In support of this concept, studies by Marzo-Ortega et al.
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have
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shown that in patients with SpA, increases in spinal BMD are associated with clinical
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responses to anti-TNF- therapy. Conclusion
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In conclusion, the rheumatic joint diseases share in common the capacity to produce a chronic synovial inflammatory reaction that can lead to disabling joint pain and
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disruption of the integrity and functional properties of joint tissues. These conditions also can affect systemic bone remodeling leading to progressive bone loss and increased risk The de-regulated periarticular and systemic bone remodeling can be
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of fracture.
attributed to the capacity of the inflamed synovial, and in the case of the SpAs, entheseal tissues to produce a broad spectrum of mediators that in addition to their immunoregulatory functions also have the capacity to affect osteoclast-mediated bone resorption and osteoblast–mediated bone formation.
The differential patterns of
periarticular bone remodeling in each of the joint diseases is related to the unique cellular and immunological mechanisms involved in the initiation and pathogenesis the inflammatory reactions that target the synovium and the entheseal tissues.
An
understanding of differential pathophysiological processes involved in the pathogenesis of the joint inflammation and alterations in bone remodeling in the rheumatic joint
ACCEPTED MANUSCRIPT disorders will lead to more specific and effective therapies to prevent joint destruction and disability in these conditions.
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42. Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature. 1999; 402(6759): 304-9. 43. Redlich K, Hayer S, Maier A, Dunstan C, Tohidast-Akrad M, Lang S, et al. Tumor necrosis factor--mediated joint destruction is inhibited by targeting osteoclasts with osteoprotegerin. Arthritis and rheumatism. 2002; 46: 785-92. 44. Romas E, Sims NA, Hards DK, Lindsay M, Quinn JW, Ryan PF, et al. Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collageninduced arthritis. The American journal of pathology. 2002; 161(4): 1419-27. 45. Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, et al. T-cellmediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature. 2000; 408(6812): 600-5. 46. Kim YG, Lee CK, Nah SS, Mun SH, Yoo B, Moon HB. Human CD4+CD25+ regulatory T cells inhibit the differentiation of osteoclasts from peripheral blood mononuclear cells. Biochemical and biophysical research communications. 2007; 357(4): 1046-52. 47. Zaiss MM, Axmann R, Zwerina J, Polzer K, Guckel E, Skapenko A, et al. Treg cells suppress osteoclast formation: a new link between the immune system and bone. Arthritis and rheumatism. 2007; 56(12): 4104-12. 48. Zaiss MM, Frey B, Hess A, Zwerina J, Luther J, Nimmerjahn F, et al. Regulatory T cells protect from local and systemic bone destruction in arthritis. J Immunol. 2010; 184(12): 7238-46. 49. Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nature medicine. 2014; 20(1): 62-8. 50. Harre U, Georgess D, Bang H, Bozec A, Axmann R, Ossipova E, et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. The Journal of clinical investigation. 2012; 122(5): 1791-802. 51. Meyer O, Labarre C, Dougados M, Goupille P, Cantagrel A, Dubois A, et al. Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damage. Annals of the rheumatic diseases. 2003; 62(2): 120-6. 52. Hecht C, Englbrecht M, Rech J, Schmidt S, Araujo E, Engelke K, et al. Additive effect of anti-citrullinated protein antibodies and rheumatoid factor on bone erosions in patients with RA. Annals of the rheumatic diseases. 2014. 53. Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, et al. Dickkopf-1 is a master regulator of joint remodeling. Nature medicine. 2007; 13(2): 15663. 54. Walsh NC, Reinwald S, Manning CA, Condon KW, Iwata K, Burr DB, et al. Osteoblast function is compromised at sites of focal bone erosion in inflammatory arthritis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2009; 24(9): 1572-85. 55. Goldring SR, Goldring MB. Eating bone or adding it: the Wnt pathway decides. Nature medicine. 2007; 13(2): 133-4. 56. Haugeberg G, Orstavik RE, Kvien TK. Effects of rheumatoid arthritis on bone. Current opinion in rheumatology. 2003; 15(4): 469-75.
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57. Lodder MC, de Jong Z, Kostense PJ, Molenaar ET, Staal K, Voskuyl AE, et al. Bone mineral density in patients with rheumatoid arthritis: relation between disease severity and low bone mineral density. Annals of the rheumatic diseases. 2004; 63(12): 1576-80. 58. van Staa TP, Geusens P, Bijlsma JW, Leufkens HG, Cooper C. Clinical assessment of the long-term risk of fracture in patients with rheumatoid arthritis. Arthritis and rheumatism. 2006; 54(10): 3104-12. 59. Vis M, Haavardsholm EA, Boyesen P, Haugeberg G, Uhlig T, Hoff M, et al. High incidence of vertebral and non-vertebral fractures in the OSTRA cohort study: a 5-year follow-up study in postmenopausal women with rheumatoid arthritis. Osteoporos Int. 2011. 60. Solomon DH, Finkelstein JS, Shadick N, LeBoff MS, Winalski CS, Stedman M, et al. The relationship between focal erosions and generalized osteoporosis in postmenopausal women with rheumatoid arthritis. Arthritis and rheumatism. 2009; 60(6): 1624-31. 61. Compston JE, Vedi S, Croucher PI, Garrahan NJ, O'Sullivan MM. Bone turnover in non-steroid treated rheumatoid arthritis. Annals of the rheumatic diseases. 1994; 53(3): 163-6. 62. Garnero P, Landewe R, Boers M, Verhoeven A, Van Der Linden S, Christgau S, et al. Association of baseline levels of markers of bone and cartilage degradation with long-term progression of joint damage in patients with early rheumatoid arthritis: the COBRA study. Arthritis and rheumatism. 2002; 46(11): 2847-56. 63. Gough A, Sambrook P, Devlin J, Huissoon A, Njeh C, Robbins S, et al. Osteoclastic activation is the principal mechanism leading to secondary osteoporosis in rheumatoid arthritis. The Journal of rheumatology. 1998; 25(7): 1282-9. 64. Barnabe C, Hanley DA. Effect of tumor necrosis factor alpha inhibition on bone density and turnover markers in patients with rheumatoid arthritis and spondyloarthropathy. Semin Arthritis Rheum. 2009; 39(2): 116-22. 65. Seriolo B, Paolino S, Sulli A, Ferretti V, Cutolo M. Bone metabolism changes during anti-TNF-alpha therapy in patients with active rheumatoid arthritis. Annals of the New York Academy of Sciences. 2006; 1069: 420-7. 66. Syversen SW, Haavardsholm EA, Boyesen P, Goll GL, Okkenhaug C, Gaarder PI, et al. Biomarkers in early rheumatoid arthritis: longitudinal associations with inflammation and joint destruction measured by magnetic resonance imaging and conventional radiographs. Annals of the rheumatic diseases. 2011; 69(5): 845-50. 67. Vis M, Havaardsholm EA, Haugeberg G, Uhlig T, Voskuyl AE, van de Stadt RJ, et al. Evaluation of bone mineral density, bone metabolism, osteoprotegerin and receptor activator of the NFkappaB ligand serum levels during treatment with infliximab in patients with rheumatoid arthritis. Annals of the rheumatic diseases. 2006; 65(11): 14959. 68. Geusens PP, Landewe RB, Garnero P, Chen D, Dunstan CR, Lems WF, et al. The ratio of circulating osteoprotegerin to RANKL in early rheumatoid arthritis predicts later joint destruction. Arthritis and rheumatism. 2006; 54(6): 1772-7. 69. Garnero P, Tabassi NC, Voorzanger-Rousselot N. Circulating dickkopf-1 and radiological progression in patients with early rheumatoid arthritis treated with etanercept. The Journal of rheumatology. 2008; 35(12): 2313-5.
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70. Wang SY, Liu YY, Ye H, Guo JP, Li R, Liu X, et al. Circulating Dickkopf-1 is correlated with bone erosion and inflammation in rheumatoid arthritis. The Journal of rheumatology. 2011; 38(5): 821-7. 71. Schwartz N, Goilav B, Putterman C. The pathogenesis, diagnosis and treatment of lupus nephritis. Current opinion in rheumatology. 2014; 26(5): 502-9. 72. Ostendorf B, Scherer A, Specker C, Modder U, Schneider M. Jaccoud's arthropathy in systemic lupus erythematosus: differentiation of deforming and erosive patterns by magnetic resonance imaging. Arthritis and rheumatism. 2003; 48(1): 157-65. 73. Nzeusseu Toukap A, Galant C, Theate I, Maudoux AL, Lories RJ, Houssiau FA, et al. Identification of distinct gene expression profiles in the synovium of patients with systemic lupus erythematosus. Arthritis and rheumatism. 2007; 56(5): 1579-88. 74. Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J, et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003; 197(6): 711-23. 75. Crow MK. Type I interferon in systemic lupus erythematosus. Curr Top Microbiol Immunol. 2007; 316: 359-86. 76. Crow MK. Type I interferon in the pathogenesis of lupus. J Immunol. 2014; 192(12): 5459-68. 77. Coelho LF, Magno de Freitas Almeida G, Mennechet FJ, Blangy A, Uze G. Interferon-alpha and -beta differentially regulate osteoclastogenesis: role of differential induction of chemokine CXCL11 expression. Proceedings of the National Academy of Sciences of the United States of America. 2005; 102(33): 11917-22. 78. Mensah KA, Mathian A, Ma L, Xing L, Ritchlin CT, Schwarz EM. Mediation of nonerosive arthritis in a mouse model of lupus by interferon-alpha-stimulated monocyte differentiation that is nonpermissive of osteoclastogenesis. Arthritis and rheumatism. 2011; 62(4): 1127-37. 79. Almehed K, Hetenyi S, Ohlsson C, Carlsten H, Forsblad-d'Elia H. Prevalence and risk factors of vertebral compression fractures in female SLE patients. Arthritis research & therapy. 2010; 12(4): R153. 80. Bultink IE, Lems WF, Kostense PJ, Dijkmans BA, Voskuyl AE. Prevalence of and risk factors for low bone mineral density and vertebral fractures in patients with systemic lupus erythematosus. Arthritis and rheumatism. 2005; 52(7): 2044-50. 81. Colbert RA, Tran TM, Layh-Schmitt G. HLA-B27 misfolding and ankylosing spondylitis. Mol Immunol. 2014; 57(1): 44-51. 82. Tsui FW, Tsui HW, Akram A, Haroon N, Inman RD. The genetic basis of ankylosing spondylitis: new insights into disease pathogenesis. Appl Clin Genet. 2014; 7: 105-15. 83. Goldring SR. Osteoimmunology and bone homeostasis: relevance to spondyloarthritis. Current rheumatology reports. 2013; 15(7): 342. 84. Lories RJ, Luyten FP, de Vlam K. Progress in spondylarthritis. Mechanisms of new bone formation in spondyloarthritis. Arthritis research & therapy. 2009; 11(2): 221. 85. Braun J, Bollow M, Neure L, Seipelt E, Seyrekbasan F, Herbst H, et al. Use of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum. 1995; 4: 499-505.
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86. Lories RJ, Derese I, Ceuppens JL, Luyten FP. Bone morphogenetic proteins 2 and 6, expressed in arthritic synovium, are regulated by proinflammatory cytokines and differentially modulate fibroblast-like synoviocyte apoptosis. Arthritis and rheumatism. 2003; 48(10): 2807-18. 87. Lories RJ, Derese I, Luyten FP. Modulation of bone morphogenetic protein signaling inhibits the onset and progression of ankylosing enthesitis. The Journal of clinical investigation. 2005; 115(6): 1571-9. 88. Lories RJ, Schett G. Pathophysiology of new bone formation and ankylosis in spondyloarthritis. Rheumatic diseases clinics of North America. 2012; 38(3): 555-67. 89. Appel H, Ruiz-Heiland G, Listing J, Zwerina J, Herrmann M, Mueller R, et al. Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis. Arthritis and rheumatism. 2009; 60(11): 3257-62. 90. Bollow M, Fischer T, Reisshauer H, Backhaus M, Sieper J, Hamm B, et al. Quantitative analyses of sacroiliac biopsies in spondyloarthropathies: T cells and macrophages predominate in early and active sacroiliitis- cellularity correlates with the degree of enhancement detected by magnetic resonance imaging. Annals of the rheumatic diseases. 2000; 59(2): 135-40. 91. Sherlock JP, Joyce-Shaikh B, Turner SP, Chao CC, Sathe M, Grein J, et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nature medicine. 2012; 18(7): 1069-76. 92. Jacques P, Lambrecht S, Verheugen E, Pauwels E, Kollias G, Armaka M, et al. Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells. Annals of the rheumatic diseases. 2014; 73(2): 43745. 93. Klingberg E, Geijer M, Gothlin J, Mellstrom D, Lorentzon M, Hilme E, et al. Vertebral fractures in ankylosing spondylitis are associated with lower bone mineral density in both central and peripheral skeleton. The Journal of rheumatology. 2012; 39(10): 1987-95. 94. Klingberg E, Lorentzon M, Mellstrom D, Geijer M, Gothlin J, Hilme E, et al. Osteoporosis in ankylosing spondylitis - prevalence, risk factors and methods of assessment. Arthritis research & therapy. 2012; 14(3): R108. 95. Ralston SH, Urquhart GD, Brzeski M, Sturrock RD. Prevalence of vertebral compression fractures due to osteoporosis in ankylosing spondylitis. Bmj. 1990; 300(6724): 563-5. 96. Frediani B, Allegri A, Falsetti P, Storri L, Bisogno S, Baldi F, et al. Bone mineral density in patients with psoriatic arthritis. The Journal of rheumatology. 2001; 28(1): 138-43. 97. Will R, Bhalla A, Palmer R, Ring F, Calin A. Osteoporosis in early ankylosing spondylitis; a primary pathological event? Lancet. 1989; 23: 1483-5. 98. Marzo-Ortega H, McGonagle D, Haugeberg G, Green MJ, Stewart SP, Emery P. Bone mineral density improvement in spondyloarthropathy after treatment with etanercept. Annals of the rheumatic diseases. 2003; 62(10): 1020-1.
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Figure 1. Normal and RA diarthrodial joint. Destruction of articular cartilage and erosion of periarticular bone by proliferative RA synovial tissue. A histological section of the interface between the periarticular bone and RA synovium demonstrating the presence of osteoclasts eroding the bone surface.
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Figure 2. Model of de-regulated bone remodeling in RA. The RA synovium produces a broad spectrum of osteoclastogenic factors including RANKL and TNF-. These factors recruit and induce osteoclast-mediated bone resorption. Under physiological conditions the release of bone growth factors such as BMPs and TGF- from the bone matrix and products derived from resorbing osteoclasts, including sphingosine-1phosphate (S-1-P) and Wnt 10B, provide a mechanism for coupling bone resorption and formation to maintain bone homeostasis. The production of the Wnt pathway inhibitors DKK-1 and sclerostin by the RA synovium inhibit bone formation and block bone repair.
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Figure 3. Model of de-regulated bone remodeling in AS. The sites of entheseal and synovium inflammation in AS are a source of pro-osteoclastogenic factors, including RANKL and TNF-, which contribute to focal bone resorption. In contrast to the RA synovium, the inflamed tissues in AS produce bone growth factors including BMPs and IL-22 that enhance bone formation at the sites of inflammation. These local bone anabolic effects are not offset by the production of the Wnt pathway inhibitors DKK-1 and sclerostin.
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of pro- and anti-osteoclastogenic cytokines, chemokines and growth factors produced by
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the inflamed synovium and entheseal tissues. The table provides a partial list of pro- and anti-osteoclastogenic cytokines and growth factors produced by these tissues. Some of
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the cytokines act directly on osteoclast lineage cells and others work indirectly via effects
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Cytokines/Growth Factors Pro-osteoclastogenic RANKL M-CSF TNF- IL-1 IL-11 Oncostatin M (IL-6) (IL-15) (IL-17) (IL-23)
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(Indirect via RANKLInduction)
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on synovial fibroblasts or other cell types.
Anti-osteoclastogenic GM-CSF IFN- IFN- IL-4 IL-10 IL-12 IL-18 IL-27 IL-33
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Inflammatory joint diseases de-regulate articular bone remodeling Products from the inflamed joint tissues mediate the de-regulated bone remodeling Osteoclasts mediate the articular bone resorption in inflammatory arthritis The pattern of articular bone repair differs in the inflammatory joint diseases Differential immune mechanisms account for the different patterns of bone repair
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Graphical Abstract
S8756-3282(15)00205-7 doi: 10.1016/j.bone.2015.05.024 BON 10741
To appear in:
Bone
Received date: Revised date: Accepted date:
9 January 2015 14 May 2015 20 May 2015
Please cite this article as: Goldring Steven R., Inflammatory signaling induced bone loss, Bone (2015), doi: 10.1016/j.bone.2015.05.024
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Steven R. Goldring, M.D.
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Inflammatory signaling induced bone loss
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York, NY
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Research Division, Hospital for Special Surgery, Weill Cornell Medical College, New
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Steven R. Goldring, M.D. Chief Scientific Officer Hospital for Special Surgery Professor of Medicine Weill Cornell Medical College New York, NY Tel: 212 774-7554 Fax: 212 774-2301 Email: [email protected]
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Corresponding author:
Introduction
ACCEPTED MANUSCRIPT A broad spectrum of inflammatory disorders have the capacity to target the skeleton and to de-regulate the processes of physiological bone remodeling. This review
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will focus on the systemic inflammatory rheumatologic disorders, which target articular
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and periarticular bone tissues. Many of these disorders also affect extra-articular tissues and organs, and in addition, have the capacity to produce systemic bone loss and
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increased risk of osteoporotic fractures. The articular inflammation and joint damage, as
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well as the generalized bone loss and additional systemic extra-articular manifestations, have a profound adverse effect on the quality of life and functional capacity of the
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affected individuals. Attention will focus on rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and the seronegative spondyloarthropathies (SpAs), which include
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ankylosing spondylitis (AS), reactive arthritis (formerly designated as Reiter’s syndrome), and the arthritis of inflammatory bowel disease, juvenile onset-
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spondyloarthropathy and psoriatic arthritis. The discussion will principally focus on RA, which is a prototypical model of an inflammatory disorder that de-regulates bone remodeling, but also will review the other forms of inflammatory joint disease to highlight the differential effects of inflammation on bone remodeling in these conditions.
Structural organization of periarticular bone To understand the articular and periarticular bone pathology in the rheumatic diseases, it is important to appreciate the unique organizational features of the different joints. The joints can be divided into three categories based on their anatomic features 1. They include the highly mobile diarthrodial joints, which are lined by a specialized synovial lining, e.g. the knee, wrist and small joints of the hands and feet; the
ACCEPTED MANUSCRIPT amphiarthroses in which the adjacent bones are separated by articular cartilage or a fibrocartilage disc and are associated with limited mobility, e.g. the intervertebral discs;
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and synarthroses, in which fibrous tissue separates adjoining bones, e.g. the sacroiliac
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joints. The periarticular bone of the diarthrodial joints is separated from the overlying articular cartilage by a zone of calcified cartilage, and the interface between the articular
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and calcified cartilage is demarcated by the “tide-mark”, which can be identified by its
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enhanced metachromatic staining pattern. The bone beneath the calcified cartilage is organized into a plate-like structure of compact cortical bone and below the subchondral
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bone plate, the bone forms a network of cancellous trabecular bone that is surrounded by the bone marrow. The periosteal bone at the joint margins is in immediate contact with
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the joint capsule and synovial lining. The tendons and ligaments insert into the bone
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below the synovial reflection forming the unique structure of the enthesis 2. As will be
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discussed below, in RA and SLE, the synovial lining is the site of an intense immunemediated inflammatory process that results in synovial proliferation and production of potent inflammatory cytokines and soluble mediators that are responsible for the clinical signs of joint inflammation. Synovial inflammation also is present in the SpAs, but unlike the pattern of the joint inflammation in RA and SLE, the entheses are the initial sites of inflammation 3, 4. Subsequently, the inflammatory process extends to the synovial lining, although the distribution and pattern of joint involvement, as well as the response of the periarticular bone to the inflammation differs in RA and the SpAs. 5, 6
Rheumatoid Arthritis RA is a systemic inflammatory disorder that is characterized by a symmetrical
ACCEPTED MANUSCRIPT destructive polyarthritis. The etiology of RA is unknown, but both genetic and environmental factors are involved in its pathogenesis
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. The hallmark of RA is the
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development of a chronic inflammatory polyarthritis that targets the synovial lining of
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diarthrodial joints. The earliest changes involve the proliferation of the synovial lining cells, consisting of a population of macrophage-like cells (A cells) and synovial
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fibroblasts (B cells). There also is extensive neovascularization and perivascular and
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interstitial infiltration of the synovium with lymphocytes, plasma cells, and activated macrophages. Multiple lines of evidence implicate a pathogenic role for autoantibodies
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and immune complexes in the development of the synovial lesion, which exhibits features consistent with activation of an adaptive immune response in which activated T
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and B cells play a key role as primary effectors of the inflammatory process 7-9. Four distinct patterns of pathologic bone remodeling are observed in RA. These
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include periarticular osteopenia; focal bone erosions that initially are localized to the joint margins; subchondral bone erosions; and systemic osteoporosis. Juxta-articular bone loss at sites removed from the inflamed synovium is a common finding in RA and frequently precedes the development of marginal joint erosions. Histomorphometric analysis of periarticular bone from RA patients undergoing hand arthroplasty procedures for destructive arthritis show evidence of both increased bone resorption and formation. Examination of the bone marrow in these regions reveals the presence of infiltrates with lymphocytes and macrophages, suggesting a potential role for local inflammation
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Immobilization and reduced mechanical loading are additional factors that have been implicated in the pathogenesis of periarticular bone loss. Importantly, the presence of
ACCEPTED MANUSCRIPT periarticular bone loss has been shown to have high predictive value with respect to the subsequent development of marginal joint erosions in the hand 11-13.
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The marginal joint erosions correspond to sites where the inflamed synovium
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comes into contact with the bone surface (Figure 1). At these sites, the bone surface is lined by resorption lacunae containing mono- and multinucleated cells with phenotypic
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features of osteoclasts 14, 15. Similar sites of focal bone resorption can be identified on the
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endosteal surface of the subchondral bone. These regions of bone resorption may extend through the calcified cartilage into the overlying articular cartilage, which is then
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vulnerable to degradation by the invading inflammatory tissue. The initial observations implicating osteoclasts in the pathogenesis of marginal and subchondral bone erosions
D
were based on cell morphology and expression of osteoclast associated genes, including
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tartrate resistant acid phosphatase (TRAP), cathepsin K and V3 integrin
14, 15
. Studies
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in mice genetically engineered with an inability to form osteoclasts have more definitively established that osteoclasts are essential for the development of the marginal and subchondral bone erosions in murine models of RA as will be discussed below
16-18
.
These conclusions are supported by studies in patients with RA in whom treatment with antiresorptive agents have been shown to reduce the development of joint erosions 19-21. Studies have helped to establish that the chronic synovial inflammation in RA is dependent on a complex interaction between a network of cytokines and growth factors, and well as direct cell-cell interactions among the cells that populate the inflamed synovium. The development of therapeutic agents that target individual cytokines has revealed the somewhat surprising observation that despite the diversity of these cytokines, targeting of certain key cytokines can produce marked suppression of the
ACCEPTED MANUSCRIPT synovial and systemic inflammation and retard or even prevent the development of joint destruction.
The initial proof of concept studies came from the early clinical trials
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targeting TNF-22, 23. The success of these trials indicated that the cytokine networks
Subsequently, the use of additional therapeutic agents
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involving TNF- signaling 8.
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and related inflammatory mediators and pathways intersected on an “activation node”
targeting alternate cytokines, including IL-6 in RA, as well as IL-23 or IL-17 in the SpAs,
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represent additional “activation nodes” involving these cytokines
24-29
. Therapies
targeting T cell co-stimulatory effector pathways also have been shown to be effective in
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controlling synovial inflammation and joint damage in RA
30
. More recently, therapies
targeting B cells also have shown efficacy, providing evidence of the importance of both
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T and B cells in RA pathogenesis 31.
The capacity of the RA synovium to induce local articular bone resorption can be
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attributed to the production of a broad spectrum of products with the ability to recruit osteoclast precursors and induce their differentiation and activation into bone resorbing osteoclasts. These include a spectrum of proinflammatory cytokines, chemokines and proosteoclastogenic soluble mediators
32-34
, including receptor activator of NF- ligand
(RANKL), which is produced by synovial fibroblasts, T cells and B cells within the synovium
35-38
. Table 1 provides a list of the pro-osteoclastgenic cytokines and growth
factors produced by the RA synovium. Among the T-cell subsets, both Th1 and Th17 (the major source of IL-17) cells have the capacity to produce RANKL, as well as TNF- and multiple additional cytokines and mediators with osteoclastogenic activity
39, 40
. In
addition to the effects of RANKL and TNF-, T cells also have the capacity to enhance osteoclastogenesis via a co-stimulatory pathway involving interaction of paired Ig-like
ACCEPTED MANUSCRIPT receptor-A (PIR-A), which is expressed on the surface of T cells, and its signaling partner Fc receptor-γ (FcRγ) on osteoclast precursors 41.
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The critical role of RANKL in the pathogenesis of joint erosions is provided by the observation that blocking RANKL in animal models of RA with osteoprotegerin
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42-44
(OPG), the RANKL antagonist, results in marked attenuation of joint erosions
.
17
in animal models of RA protects animals from both articular and
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its receptor RANK
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Additional evidence is provided by studies showing that genetic deletion of RANKL 17 or
systemic bone loss. More recently, studies in human subjects with RA have shown that
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blockade of RANKL with Denosumab, a monoclonal antibody that blocks RANKL activity, significantly reduces bone erosions 19, 20. These results provide further evidence
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that RANKL and osteoclasts play a critical role in articular bone destruction in RA. The RA synovium also is a source of inhibitors of osteoclastogenesis
32-34
. A list of
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several of these factors is included in Table 1. Many of the inhibitors are products of T cells, which have the capacity to produce both inhibitory and stimulatory factors. For example, Th1 and Th17 cells produce both TNF- and RANKL, but they also have the capacity to produce interferons, which are inhibitors of osteoclastogenesis
38, 45
.
T
regulatory cells (Tregs) represent an additional T cell subset that exhibit antiosteoclastogenic activity 46-48. This has been attributed to effects mediated by direct cellcontact via CTLA-4 interactions with CD80/CD86 on myeloid osteoclast precursors and also to their capacity to produce IL-4 and-10, which are inhibitors of osteoclastogenesis. Of interest, Komatsu et al. recently demonstrated that Tregs in inflamed synovial tissues in an RA animal model have the capacity to undergo transdifferentiation into Th17 cells that exhibit potent pro-osteoclastogenic activity
49
. The shift in the balance of bone
ACCEPTED MANUSCRIPT remodeling towards bone resorption in the RA joint, indicates that despite these differential capacities among the T cell subsets, the environment in the RA synovium As discussed below, this
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strongly favors the activity of pro-osteoclastogenic factors.
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contrasts with the synovial tissue in lupus in which the anti-osteoclastogenic factors, including the interferons may predominate, limiting the capacity of the synovial tissue to
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produce bone erosions.
50
.
In these studies, the authors investigated the role of
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enhances bone resorption
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Recent studies have suggested an additional mechanism by which the RA synovium
autoantibodies directed against citrullinated proteins, so called anti-citrullinated protein
D
antibodies, ACPAs, which have been shown to be an independent predictor of the 7, 51
. They first showed that human
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development of bone erosions in patients with RA
osteoclasts expressed enzymes that specifically induced N-terminal citrullination of
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vimentin during osteoclast differentiation, and then demonstrated that binding of the antibodies to osteoclast precursors enhanced osteoclast differentiation. This effect was attributed to up-regulation of TNF- production by the osteoclast precursors that then synergized with RANKL and M-CSF to enhance osteoclast formation. A recent study by Hecht et al. demonstrates that rheumatoid factors may cooperate with ACPAs to enhance osteoclastogenesis 52. Of importance, these observations provide a novel link between autoimmunity and osteoclastogenesis. A unique feature of the articular bone erosions in RA is the virtual absence of bone repair. Studies by Diarra et al.
53
demonstrated that cells in the inflamed RA
synovial tissue produce dickkopf-1 (DKK-1), the inhibitor of the wingless (Wnt)signaling pathway that plays a critical role in osteoblast-mediated bone formation. These
ACCEPTED MANUSCRIPT results provide insights into the mechanism involved in the uncoupling of bone resorption and formation in RA. Studies by Walsh et al.
54
confirmed these observations and
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identified additional Wnt family antagonists, including members of the DKK and
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secreted Frizzled related protein families in RA synovium. Multiple cell types within the RA synovium have the capacity to produce these Wnt pathway inhibitors, including
SC
synovial fibroblasts, endothelial cells and chondrocytes.
In the Diarra studies, they
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showed that TNF- was a potent inducer of DKK-1 in RA synovial fibroblasts, thus implicating TNF in both the enhanced resorption and suppressed bone formation in RA.
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They then showed that inhibition of DKK-1 with blocking antibodies partially restored bone formation. An unexpected finding was the inhibition of bone resorption by DKK-1
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D
blockade. These effects were attributed to the reversal of Wnt pathway inhibition and upregulation of OPG, the potent inhibitor of osteoclastogenesis. These observations have
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clear implications with respect to future therapeutic strategies in RA patients
55
. The
differential effects of the RA synovial inflammation on bone resorption and formation are depicted in Figure 2.
It is well established that patients with RA have reduced bone mineral density (BMD) and are at risk for an increased risk of fracture 56-59. These findings highlight the importance of monitoring patients with RA for evidence of systemic bone loss and for the institution of early therapeutic interventions to reduce the long-term risks of fracture and disability. In general, authors have identified an association between the presence of increased disease activity and reduced bone mass, but the interpretation of the findings has been challenging because of the presence of multiple confounding factors that affect bone remodeling, including the influence of sex, age, nutritional state, level of physical
ACCEPTED MANUSCRIPT activity, disease duration and severity and the use of medications such as glucocorticoids that adversely affect bone remodeling but also can suppress joint and systemic 60
.
Several approaches have been utilized to gain insights into the
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inflammation
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mechanism involved in the pathogenesis of the systemic bone loss in RA, including histomorphometric analysis of bone biopsies, assessment of urinary and serum
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biomarkers of bone remodeling and the measurement of serum cytokine levels. In
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general, results are consistent with the presence of reduced bone formation as well as increased bone resorption, but the findings in these studies vary depending on the patient
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characteristics, including the level and duration of the disease 61-63. The disturbance in systemic bone remodeling in RA has been attributed to the
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D
release into the circulation of proinflammatory cytokines from sites of synovial inflammation. These products then act systemically in a manner similar to endocrine
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hormones to regulate bone remodeling. The serum levels of several osteoclastogenic cytokines have been assessed in patients with RA, but particular attention has focused on the levels of RANKL and OPG 64-67. For example, Geusens and colleagues observed that the presence of low circulating OPG/RANKL ratios in a cohort of patients with early RA predicted the subsequent risk for bone loss 68. Other studies have examined the effects of RA therapy on systemic bone loss and shown that anti-TNF therapy is accompanied by a fall in serum RANKL levels and decreased systemic bone loss
64, 65, 67
. There also is
evidence that products released from inflamed joints can adversely affect bone formation. Diarra et al.
53
and more recently other authors have detected elevated levels of the Wnt
pathway inhibitor DKK-1 in the sera of patients with RA
69, 70
. Of interest, as will be
discussed below, the levels of DKK-1 have not been shown to be increased in patients
ACCEPTED MANUSCRIPT with AS, and this may play a role in the tendency of these patients to exhibit increased
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periarticular bone formation at sites of joint inflammation.
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Systemic Lupus Erythematosus
SLE is a systemic autoimmune disease characterized by loss of tolerance to self
SC
antigens that results in aberrant T and B cell activation and the generation of high affinity 71
.
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autoantibodies directed against host tissues leading to organ damage and dysfunction
Symmetrical polyarthritis affecting diarthrodial joints is a characteristic feature of SLE,
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and the arthritis may be a significant contributor to the disease morbidity. Similar to RA the synovial lining undergoes proliferation and infiltration with inflammatory cells,
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D
including T and B cells, plasma cells and macrophages. However, unlike the synovial lesion in RA there characteristically is an absence of extensive joint erosions and articular
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cartilage destruction. The joint inflammation may be associated with deformities and subluxation, but these changes have been attributed primarily to ligamentous laxity resulting from persistent periarticular inflammation rather than presence of extensive bone erosions and cartilage loss. A characteristic feature of this form of arthritis, referred to as Jaccoud’s arthritis, is the presence of “hook” erosions that occur on the radial aspect of metacarpal bones
72
. These regions of bone loss are distinct from the marginal joint
erosions seen in RA and have been attributed to the effects of tensile forces on bone remodeling at the entheseal insertion sites of tendons and ligaments. As will be discussed below, a similar effect of tensile forces at the entheseal sites of tendon and ligament attachment have been implicated in the pathogenesis of bone erosions in the SpAs. Molecular profiling of synovial tissue from patients with SLE has provided
ACCEPTED MANUSCRIPT insights into the differential capacities of the inflamed synovial tissues in lupus and RA to produce bone erosions and cartilage destruction 73. The synovial tissue in SLE, unlike the
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RA tissue, reveals the marked up-regulation of interferon inducible genes. Patients with
74-76
.
Of importance, in vitro studies have shown that both
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activity and severity
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SLE show elevated levels of serum IFN-, which correlates with both lupus disease
interferon- and -inhibit osteoclastogenesis, and this may account for the limited
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capacity of the synovial lesion in lupus to produce osteoclast-mediated bone erosions 77. This speculation is supported by the studies of Mensah et al
78
using the serum transfer
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K/BxN model of RA, which recapitulates the erosive bone disease seen in RA patients.
D
The authors first showed that systemic overexpression of INF- using an adenoviral
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delivery system induced an osteopetrotic bone phenotype in normal mice consistent with an inhibition of osteoclast-mediated bone resorption. They then overexpressed IFN- in
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the serum transfer K/BxN model of RA and showed that the mice were protected from the development of bone erosions. These findings provide additional support for the concept that the reduced capacity of synovium in SLE to produce bone erosions may at least in part be attributable to the production of type 1 interferons. Patients with SLE, similar to RA patients also are at risk for the development of systemic osteoporosis and associated osteoporotic fractures
79, 80
. The bone loss has been
attributed to the effects of chronic inflammation, but similar to RA patients there are multiple other factors that may contribute to the bone loss, including glucocorticoid therapy and renal insufficiency that may accompany lupus nephritis.
Seronegative Spondyloarthropathies
ACCEPTED MANUSCRIPT As described in the introduction, the SpAs are a heterogeneous group of inflammatory disorders that exhibit articular and periarticular features that differ from
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RA. They are classified as seronegative forms of arthritis based on the absence of The genetic factors,
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rheumatoid factors and ACPAs that are associated with RA.
particularly involvement of the HLA-B27 class I major histocompatibility (MHC) gene,
SC
differ from the genetic associations in RA, and in general, the SpAs do not exhibit
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features of an autoimmune disease. Instead the clinical features and contributory role of bacterial and mechanical danger signals suggest an autoinflammatory origin with
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involvement of the IL-23 and IL-17 cytokine pathways in addition to TNF-
29, 81, 82
.
Unlike RA, the SpAs tend to involve the axial skeleton in addition to the diarthrodial , and there is prominent involvement of the entheses, which are not common
D
6, 83
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joints
sites of primary pathology in RA.
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Syndesmophytes are one of the anatomic and radiographic hallmarks of the SpAs. They represent examples of new bone formation that is initially localized to the region of the annulus fibrosis of the intervertebral discs. These bony outgrowths may eventually lead to bony bridging of the adjacent vertebral bodies
84
. The regions of new bone
formation may be associated with bone erosions, which are localized to the margins of the discovertebral junctions. The local production of bone growth factors, including TGF- and BMPs, has been implicated in the bone formation, which is primarily via a process of endochondral ossification
84-88
. Appel and co-workers
89
have shown that
serum sclerostin levels correlate with the tendency to form syndesmophytes and that low serum sclerostin levels are associated with an increase in the incidence of new syndesmophyte formation.
ACCEPTED MANUSCRIPT Syndesmophytes are an example of a general feature of the articular bone pathology in the SpAs, which is the enhanced tendency to form bone at sites of 6, 83
. Analysis of tissues from inflamed sacroiliac joints
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inflammation and tissue injury
from patients with AS reveals the presence of infiltrates of CD14 positive macrophages
85, 90
. In the studies by Braun and co-workers they observed that many of the
SC
ossification
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and CD4+ and CD8T+ lymphocytes associated with localized nodules of endochondral
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inflammatory cells in the entheseal and synovial tissues expressed messenger RNA for TNF-, but not interleukin IL-1 (IL-1) 85. They also noted TGF-2 mRNA expression
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in cells in close proximity to the regions of new bone formation.
Lories et al.
86
examined synovial biopsies from patients with AS and RA and detected elevated levels
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D
of BMP-2 and -6 expression in synovial fibroblasts and macrophages. The presence of these bone growth factors in the RA synovium was surprising given the general absence
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of bone repair in RA. They speculated that in RA the effects of the growth factors could be overridden by the production of Wnt pathway inhibitors such as DKK-1 as demonstrated by the studies of Diarra and Walsh 53, 54. Recent studies by Sherlock et al. provide insights into the role of IL-23 and T cells in the pathogenesis of AS
91
.
They demonstrated the presence of a unique
population IL-23 receptor T cells in entheseal sites, and using an ex vivo organ culture model of entheseal tissues showed that IL-23 induced the expression of IL-17a, IL-17f, IL-22 and BMP-6. They next showed that overexpression of IL-23 in vivo was sufficient to induce a destructive enthesitis that pheno-copied the pathological features of AS. Although IL-23 induced the expression of IL-17, they found that depletion of Th17 T cells in mice did not abrogate the capacity of IL-23 to induce inflammatory arthritis,
ACCEPTED MANUSCRIPT indicating that IL-17 was not essential for induction of the joint disease.
However,
inhibition of IL-17 and IL-22 using blocking antibodies in a murine AS model synergized
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to reduce joint inflammation, suggesting that both IL-17 and IL-22 contributed to the
effector molecule.
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inflammatory disease, although their results indicated that IL-22 was the predominant In additional studies they showed that IL-22 induced osteoblast
SC
differentiation via effects on the Wnt and BMP pathways, providing a link between the
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proinflammatory activities of IL-22 and its capacity to enhance bone formation. A proposed model of the mechanisms involved in the de-regulated periarticular bone
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remodeling in AS is shown in Figure 3.
In recent studies, Jacques et al. employed a mouse model of inflammatory arthritis
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D
that recapitulates many of the articular and skeletal features of the SpAs to investigate the role of mechanical factors in the pathogenesis of the entheseal inflammation and de-
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regulated bone remodeling 92. In this model, the initial site of inflammation localized to the entheses. They exposed the animals to hind limb unloading, which protects the mice from mechanical loading, and showed that this markedly reduced the local inflammation and the formation of new bone at the Achilles tendon insertion site. These findings provide evidence that mechanical strains and local tissue injury can initiate and drive both entheseal inflammation as well as new bone formation in a model of inflammatory arthritis. Epidemiological studies have shown that despite the propensity of patients with SpAs to exhibit enhanced bone formation at sites of joint and spinal inflammation, many patients show signs of spinal osteopenia. The osteoporosis and osteopenia correlate with the disease burden and importantly are associated with an increased risk of fracture
93-95
.
ACCEPTED MANUSCRIPT The demonstration that spinal osteopenia may occur even in the absence of bony ankylosis suggests that factors other than the loss of spinal mobility contribute to the 96, 97
. The adverse effects of local inflammatory mediators released from the
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bone loss
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sites of joint pathology, as well as the effects of systemic inflammation likely play a contributory role. In support of this concept, studies by Marzo-Ortega et al.
98
have
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shown that in patients with SpA, increases in spinal BMD are associated with clinical
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responses to anti-TNF- therapy. Conclusion
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In conclusion, the rheumatic joint diseases share in common the capacity to produce a chronic synovial inflammatory reaction that can lead to disabling joint pain and
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disruption of the integrity and functional properties of joint tissues. These conditions also can affect systemic bone remodeling leading to progressive bone loss and increased risk The de-regulated periarticular and systemic bone remodeling can be
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of fracture.
attributed to the capacity of the inflamed synovial, and in the case of the SpAs, entheseal tissues to produce a broad spectrum of mediators that in addition to their immunoregulatory functions also have the capacity to affect osteoclast-mediated bone resorption and osteoblast–mediated bone formation.
The differential patterns of
periarticular bone remodeling in each of the joint diseases is related to the unique cellular and immunological mechanisms involved in the initiation and pathogenesis the inflammatory reactions that target the synovium and the entheseal tissues.
An
understanding of differential pathophysiological processes involved in the pathogenesis of the joint inflammation and alterations in bone remodeling in the rheumatic joint
ACCEPTED MANUSCRIPT disorders will lead to more specific and effective therapies to prevent joint destruction and disability in these conditions.
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27. Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Annals of the rheumatic diseases. 2014; 73(3): 492-509. 28. Smolen JS, Schoels MM, Nishimoto N, Breedveld FC, Burmester GR, Dougados M, et al. Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions. Annals of the rheumatic diseases. 2013; 72(4): 482-92. 29. Yeremenko N, Paramarta JE, Baeten D. The interleukin-23/interleukin-17 immune axis as a promising new target in the treatment of spondyloarthritis. Current opinion in rheumatology. 2014; 26(4): 361-70. 30. Guyot P, Taylor P, Christensen R, Pericleous L, Poncet C, Lebmeier M, et al. Abatacept with methotrexate versus other biologic agents in treatment of patients with active rheumatoid arthritis despite methotrexate: a network meta-analysis. Arthritis research & therapy. 2011; 13(6): R204. 31. Buch MH, Smolen JS, Betteridge N, Breedveld FC, Burmester G, Dorner T, et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Annals of the rheumatic diseases. 2011; 70(6): 909-20. 32. Schett G. Effects of inflammatory and anti-inflammatory cytokines on the bone. Eur J Clin Invest. 2011; 10: 1-6. 33. Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol. 2012; 8(11): 656-64. 34. Takayanagi H. New immune connections in osteoclast formation. Annals of the New York Academy of Sciences. 2010; 1192: 117-23. 35. Gravallese EM, Goldring SR. Cellular mechanisms and the role of cytokines in bone erosions in rheumatoid arthritis. Arthritis and rheumatism. 2000; 43(10): 2143-51. 36. Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999; 397(6717): 315-23. 37. Romas E, Bakharevski O, Hards DK, Kartsogiannis V, Quinn JM, Ryan PF, et al. Expression of osteoclast differentiation factor at sites of bone erosion in collagen-induced arthritis. Arthritis and rheumatism. 2000; 43(4): 821-6. 38. Takayanagi H, Iizuka H, Juji T, Nakagawa T, Yamamoto A, Miyazaki T, et al. Involvement of receptor activator of nuclear factor kappaB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis and rheumatism. 2000; 43(2): 259-69. 39. Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17 helper T cells. N Engl J Med. 2009; 361(9): 888-98. 40. Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006; 203(12): 2673-82. 41. Ochi S, Shinohara M, Sato K, Gober HJ, Koga T, Kodama T, et al. Pathological role of osteoclast costimulation in arthritis-induced bone loss. Proceedings of the National Academy of Sciences of the United States of America. 2007; 104(27): 11394-9.
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Figure 1. Normal and RA diarthrodial joint. Destruction of articular cartilage and erosion of periarticular bone by proliferative RA synovial tissue. A histological section of the interface between the periarticular bone and RA synovium demonstrating the presence of osteoclasts eroding the bone surface.
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Figure 2. Model of de-regulated bone remodeling in RA. The RA synovium produces a broad spectrum of osteoclastogenic factors including RANKL and TNF-. These factors recruit and induce osteoclast-mediated bone resorption. Under physiological conditions the release of bone growth factors such as BMPs and TGF- from the bone matrix and products derived from resorbing osteoclasts, including sphingosine-1phosphate (S-1-P) and Wnt 10B, provide a mechanism for coupling bone resorption and formation to maintain bone homeostasis. The production of the Wnt pathway inhibitors DKK-1 and sclerostin by the RA synovium inhibit bone formation and block bone repair.
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Figure 3. Model of de-regulated bone remodeling in AS. The sites of entheseal and synovium inflammation in AS are a source of pro-osteoclastogenic factors, including RANKL and TNF-, which contribute to focal bone resorption. In contrast to the RA synovium, the inflamed tissues in AS produce bone growth factors including BMPs and IL-22 that enhance bone formation at the sites of inflammation. These local bone anabolic effects are not offset by the production of the Wnt pathway inhibitors DKK-1 and sclerostin.
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of pro- and anti-osteoclastogenic cytokines, chemokines and growth factors produced by
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the inflamed synovium and entheseal tissues. The table provides a partial list of pro- and anti-osteoclastogenic cytokines and growth factors produced by these tissues. Some of
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the cytokines act directly on osteoclast lineage cells and others work indirectly via effects
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Cytokines/Growth Factors Pro-osteoclastogenic RANKL M-CSF TNF- IL-1 IL-11 Oncostatin M (IL-6) (IL-15) (IL-17) (IL-23)
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(Indirect via RANKLInduction)
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on synovial fibroblasts or other cell types.
Anti-osteoclastogenic GM-CSF IFN- IFN- IL-4 IL-10 IL-12 IL-18 IL-27 IL-33
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Inflammatory joint diseases de-regulate articular bone remodeling Products from the inflamed joint tissues mediate the de-regulated bone remodeling Osteoclasts mediate the articular bone resorption in inflammatory arthritis The pattern of articular bone repair differs in the inflammatory joint diseases Differential immune mechanisms account for the different patterns of bone repair
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Graphical Abstract
