Role of inflammation in the aging bones.

LFS-14202; No of Pages 10 Life Sciences xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Life Sciences

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Review Article

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Role of inflammation in the aging bone

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Samir M. Abdelmagid a, Mary F. Barbe c, Fayez F. Safadi a,b,⁎

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Article history: Received 6 June 2014 Accepted 17 November 2014 Available online xxxx

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Keywords: Aging Inflammation Macrophages Osteoblasts Osteoclasts

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Chronic inflammation in aging is characterized by increased inflammatory cytokines, bone loss, decreased adaptation, and defective tissue repair in response to injury. Aging leads to inherent changes in mesenchymal stem cell (MSC) differentiation, resulting in impaired osteoblastogenesis. Also, the pro-inflammatory cytokines increase with aging, leading to enhanced myelopoiesis and osteoclastogenesis. Bone marrow macrophages (BMMs) play pivotal roles in osteoblast differentiation, the maintenance of hematopoietic stem cells (HSCs), and subsequent bone repair. However, during aging, little is known about the role of macrophages in the differentiation and function of MSC and HSC. Aged mammals have higher circulating pro-inflammatory cytokines than young adults, supporting the hypothesis of increased inflammation with aging. This review will aid on the understanding of the potential role of pro-inflammatory (M1) and anti-inflammatory (M2) macrophages in differentiation and function of osteoblasts and osteoclasts. © 2014 Published by Elsevier Inc.

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Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED) School of Medicine, Rootstown, OH 44272, USA School of Biomedical Sciences, Kent State University, Kent, OH 44240, USA Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA

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49 50 Q12 Introduction 51

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Introduction . . . . . . . . . . . . . . . . . . . . . . . Inflammation in aging . . . . . . . . . . . . . . . . . . . Macrophages and aging . . . . . . . . . . . . . . . . . . Macrophage polarization . . . . . . . . . . . . . . . . . . Cumulative trauma disorders . . . . . . . . . . . . . An operant animal model of repetitive strain injury . . . Repetitive strain injury and aging . . . . . . . . . . . Inflammation and bone homeostasis . . . . . . . . . . . . Osteoimmunology . . . . . . . . . . . . . . . . . . . . . Macrophages and tissue regeneration at the site of tissue injury Conclusions and future directions . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . Uncited reference . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .

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journal homepage: www.elsevier.com/locate/lifescie

The population of Americans aged 65 and older is expected to double in the next 25 years due to increased life expectancy. The anticipated growth in the aging population will result in an expected 25% increase in health care costs by 2030 [54]. Aging is associated with chronic inflammation and with the consequent higher risk for diseases, morbidity ⁎ Corresponding author at: Department of Anatomy and Neurobiology, Northeast Ohio Medical University, 4209 State Rt. 44, Rootstown, OH 44224, USA. Tel.: +1 330 325 6596; fax: +1 330 325 5916. E-mail address: [email protected] (F.F. Safadi).

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and perhaps mortality. Chronic systemic inflammation is a common problem associated with aging and is responsible for 7 out of 10 deaths in the elderly, resulting in more than 1.7 million deaths every year and accounting for more than 75% of two trillion dollars spent on health care per year in the U.S. [64,166]. Serum levels of circulating proinflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor (TNF-α) are typically elevated two-to four-fold in the elderly when compared to the young population, even in the absence of chronic disease [41]. These multifunctional cytokines have been associated with morbidity and mortality in the elderly. There is supportive evidence for a direct role of TNF-α in the pathogeneses of atherosclerosis, diabetes mellitus type-2, and Alzheimer's disease in aged individuals

http://dx.doi.org/10.1016/j.lfs.2014.11.011 0024-3205/© 2014 Published by Elsevier Inc.

Please cite this article as: S.M. Abdelmagid, et al., Role of inflammation in the aging bone..., Life Sci (2014), http://dx.doi.org/10.1016/ j.lfs.2014.11.011

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Although, it is well studied that the adaptive immune system including both B and T lymphocytes deteriorate with advancing age [46,119], the effects of the innate immune response mediated by macrophages have been under-investigated. One aspect that has not been explored is the effect of aging on macrophage polarization. Macrophages isolated from aged humans and mice display reduced functions, ranging from a defective response in the early immune defense to decreased efficiency in the development of specific immune reactions [116,117,151,168]. Macrophages can be classified into classically activated M1 cells, or, alternatively, as activated M2 macrophages, based on their polarization status. M1 macrophages can be induced by lipopolysaccharide derived from bacteria (LPS) or a combination of T helper cell (Th1) cytokines, such as IFN-γ and TNF-α. Inflammatory M1 macrophages also up-regulate pro-inflammatory mediators, including IL-1β, TNF-α, IL-6, IL-12, and their receptors (Table 1). Moreover, M1 macrophages increase the production of reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS) and other nitrogen intermediates [83,167]. In contrast, M2 macrophages can be induced by Th2 cytokines, such as M-CSF and IL-4 [82]. Anti-inflammatory M2 macrophages upregulate the expression of arginase-1 (Arg-1), scavenger and mannose

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Aging results from the accumulation of detrimental changes at the cellular and molecular levels in all organs and tissues, changes that ulti76 mately lead to increased risk for several diseases [164]. Young adult 77 mammals are able to survive their reproductive years because of strong 78 immune and inflammation responses. However, the same immune 79 mechanisms can lead to deleterious effects in humans that survive to 80 older ages [137]. Aging is a complex process in which body organs and 81 tissues lose their structural integrity leading to increased prevalence 82 for age-related diseases, such as osteoporosis, osteoarthritis, dementia 83 and cancer. Although the etiology of the aging process is not fully under84 stood [164], altered inflammatory processes play a major role in aging 85 [56]. 86 Inflammation occurs subsequent to trauma or infection at the cellu87 lar level [22,29,30]. As a result, inflammatory cells, e.g. macrophages and 88 monocytes, are activated and release several inflammatory cytokines 89 into the systemic circulation, including IL-1β, IL-6 and TNF-α. These cy90 tokines in return are responsible for the humoral immune responses 91 [28,29,52]. The aim of inflammation is to initiate the repair processes 92 that restore the tissue to its physiological condition [75] (Fig. 1). 93 Inflammatory cascade can also induce tissue catabolism if not regulated 94 properly. Several epidemiological studies have characterized the im95 mune response in aged individuals. Levels of inflammatory cytokines 96 and mediators increase with aging even in the absence of acute 97 infections or other physiologic stressors [164]. Chronic increases of in98 flammatory mediators underlie many aging-related conditions, such 99 Q13 as autoimmune diseases and malignancies [56,171]. For example, rheu100 matoid arthritis is characterized by high levels of pro-inflammatory cy101 tokines not only in the patient serum, but also in their affected joints 102 [81]. Similarly, in multiple myeloma, a neoplasm of B-cell origin [15], 103 the cancer cells secrete numerous pro-inflammatory cytokine-induced 104 chemotaxis of osteoclasts, resulting in profound bone resorption and 105 enhanced tumor growth [128,182].

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Studies from other groups have shown that anti-inflammatory macrophages (M2) regulate MSC differentiation needed for tissue repair [120]. Based on our previously published reports and generated preliminary data, we suggest that macrophage polarization is shifted towards the pro-inflammatory macrophages (M1) as a consequence of aging. This phenotypic change is exacerbated with chronic inflammation or injury, due to the steady release of inflammatory cytokines from injured cells and tissues, compared with the acute increases of the same cytokines [181]. Combined, this results in reduced bone quality in aged populations (Fig. 2). However, the role of macrophage polarization in bone homeostasis has not been previously studied. We hypothesize that age, injury and chronic inflammation alter macrophage polarization in a manner that negatively influences the bone homeostasis. In this review, we propose to discuss the role of macrophage polarization in the recruitment and differentiation of MSC and HSC into osteoblasts and osteoclasts in young adults and aged mammals, respectively.

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[73,100,123]. High levels of circulating IL-6 may also be a risk factor for thromboembolic complications [131]. Furthermore, even in healthy, elderly populations, high circulating levels of inflammatory cytokines are predictive of mortality [41]. The objective of this review is to characterize the potential role(s) of macrophages in age-related bone loss.

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Fig. 1. Proposed model for the effects of M1/M2 polarization on osteoblast differentiation. M1 macrophages (macs) decrease the differentiation of MSC into osteoblasts (OB) in young adults. However, with aging, M1 macs are inherently increased, leading to further reduction in MSC into OB. M2 macs are increased with inflammation in young adults, a change that will result in increased MSC differentiation and OB function. The latter will decrease with aging, due to reduced M2 cells.


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Cumulative trauma disorders

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The term Work-related Musculoskeletal Disorders (WMSDs) represents a model of chronic inflammation, and encompasses neuromusculoskeletal disorders arising from repeated task performance with submaximal levels of physical exertion, or work in awkward postures [27]. WMSDs are a leading cause of long-term pain and physical disability world-wide [39,43,91,93,179], with diagnostic signs of tendinopathies, neuritis, myositis, bursitis, osteoarthritis and bone stress fractures [44,84]. In 2011, WMSDs accounted for 33% of all lost work time, workplace injuries and illnesses in the U.S. and a median of 11 days absence from work [43]. Work-related MSDs in the U.S. are associated with 130 million health care encounters and are estimated to cost over $50 billion annually [138]. In 2011, the number of occupational injuries involving days away from work due to hand and wrist injuries was 140,460 and 47,550, respectively, and their incidence rates were 13.9 and 4.7 per 10,00 workers [43]. Work-related MSDs often

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Table 1

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M1 markers

M2 markers

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CD 68 (ED1) IL-1β (cytokine) IL-6 (cytokine) TNF-α (cytokine) CCL8 (chemokine) CXCL9 (chemokine)

CD163 (ED2) IL-10 (cytokine) TGF-β IL21R (cytokine-R) CCL18 (chemokine) CXCL1 (chemokine)

result from physical demands placed upon the musculoskeletal system in the workplace [36,139]. Several risk factors of occupationally related MSDs have been identified, including forceful exertions, repetitive motion, and non-neutral body postures [154]. Repetitive trauma, especially in aged individuals, results in structural damage of tissues and cell membranes. Part of the etiology of repeated trauma is that intracellular factors, including inflammatory cytokines, diffuse out through disrupted plasma membranes of damaged cells into the extracellular matrix [28,29,121]. These fragmented plasma membranes are chemotactic stimulants and induce lymphocyte and macrophage infiltration into the site of injury, as do inflammatory cytokines released from damaged cells. Tissue fibroblasts, satellite, endothelial cells and infiltrating macrophages also release cytokines in response to tissue damage [13,48,49,77,110]. The released cytokines further stimulate cell proliferation and macrophage infiltration, leading to edema, inflammation and pain [48], although some cytokines stimulate proliferation and differentiation of stem cells instead, which can lead to tissue regeneration [47,77,109,110]. Inflammatory cytokines released during the acute inflammatory phase, such as IL-1α, IL-1β and TNF-α, are known to stimulate proliferation and maturation of macrophages and other mononuclear cells [47,77,109,110] that in turn further activate macrophages and the production of additional inflammatory cytokines [13,14,88,136]. With regard to tissue catabolism, IL-1α, for example, serves as a potent stimulator of bone resorption [110,126]. Its increase can lead to activation of macrophages and osteoclasts in bone, enhancing their phagocytic function (and therefore bone resorption) as well as the release of additional cytokines. These events combined will initiate a vicious cycle of tissue damage and chronic inflammation, as described in detail previously [20,28,29,32]. In support of this, other findings have detected inflammation biomarkers in serum of patients with upper extremity WMSDs, including IL-6, TNFα, and members of the IL-1 family [50,158,160]. These increases correlated with symptom severity in patients with upper extremity WMSDs [50,160]. Also, increased serum levels of carboxyterminal collagen type I peptide (CTX-1), a serum biomarker of bone resorption, have been identified in workers involved in heavy manual lifting [105–107]. For example, increased CTX-1 has been associated with spinal shrinkage (assayed as stature loss) in healthy young nurses performing patient handling activities [105]. Since serum CTX-1 is released by activated osteoclasts, these studies suggest that bone resorptive events are occurring with WMSDs, although a causal relationship has yet to be established in this patient population.

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receptors, as well as several intracellular proteins, such as Found in Inflammatory Zone 1 (FIZZ-1), T-lymphocyte-derived eosinophil chemotactic factor (ECF-L) and Ym-1. Arginine is metabolized by Arg-1 to ornithine and polyamines in M2 macrophages, thus, decreasing substrate availability for M1 macrophages to produce nitric oxide (NO). FIZZ-1 and Ym1 are produced in large amounts during allergic inflammation and other pathological states in which a highly polarized Th2 response is prevalent [130,132,133] (Fig. 3). It has been well reported that Th1 cells are increased with age, unlike Th2 cells, and that the ratio of Th1/Th2 increases with aging [162,173] (Fig. 4). The altered percentage of Th1 to Th2 cells with aging contributes to the polarization shift of macrophages towards the classically activated M1 phenotype, which in turn explains, at least in part, the chronic inflammatory events observed with aging [40,117,176] (Fig. 2).

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Fig. 2. Proposed model for the effects of M1/M2 polarization on osteoclast differentiation. In contrast to MSC, M1 macs increase HSC differentiation and therefore osteoclast (OC) function. However, with aging, M1 macs further stimulate HSC differentiation with enhanced OC differentiation, resulting in bone loss. M2 macs are increased with inflammation in young adults, but to a lower extent with aging resulting in a reduced HSC differentiation into OC.


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An operant animal model of repetitive strain injury

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Fig. 3. Proposed model for M1/M2 polarization in young adults. M1 macs differentiate in response to INF-γ from Th1 cells. M2 macs differentiate in response to IL-4 from Th2 cells. Chronic inflammation in young adults, stimulates production of pro-inflammatory cytokines in M1 macs, followed by production of anti-inflammatory cytokines in M2 macs, with resultant net tissue adaptation (increased bone).

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The laboratory of Dr. Mary Barbe has developed a unique repetitive 218 and forceful reaching rat model in which rats tolerantly perform 219 upper extremity repetitive reaching tasks [4,22,58,59,66,155,157]. The 220 reach rates and force levels used in this model were determined from 221 epidemiological and clinical studies as risks for WMSDs in humans 222 [11,19,21,23,24,26,28,31–33,51,52,58,60,69,71,72,156]. In this review, 223 we focus on the effects of performance of a high repetition low force 224 task as a model of chronic inflammation, it is as described next. Rats per225 form the HRLF task regimens for 2 h/day, 3 days/week for 12 weeks, 226 while daily task sessions are divided into 4, half-hour sessions separated 227 by 1.5 h in order to avoid satiation. For high repetition tasks, rats are 228 cued to reach at target rates of 4 reaches/min. Task rats reach forward 229 into a portal, extend their forearm, grab a lever and then exerted a target 230 isometric pull for at least 50 ms at a force effort of either 15% (0.23 N) of 231 their average maximum pulling force (±5%) for low force tasks. Signs 232 and symptoms indicative of the development of carpal tunnel syn233 drome, a known type of WMSD, have been observed in this model, 234 including forepaw hypersensitivity, declines in grip strength and reach 235 performance, as well as degraded myelin and decreased conduction 236 Q19 velocity in the median nerve at the level of the wrist [58,59,61,68–71, 237 96,97]. The sensorimotor declines correlated with increased tissue in238 flammation (macrophages and cytokines) and increased levels of 239 Q20 serum inflammatory cytokines [4,58,61,70,96]. Performance of repeti240 tive reaching also induced exposure-dependent changes in inflammato241 ry cytokines, osteoclast and osteoblast numbers in involved forelimb 242 bones [25,33,67,155,157]. Rats performing a low demand reaching

task for 12 weeks, had a transient increase in osteoclasts in forelimb bones in weeks 4–6 that resolved by week 12, a time point associated with bone adaptation [25,33]. In contrast, performance of high force tasks for 12 weeks resulted in prolonged increases in bone inflammatory cytokines, degradation in radiocarpal joints, metaphyseal cortical bone thinning, and increased serum biomarkers of bone and cartilage degradation (TRAP5b and C1,2C) [67,155,157]. Radio-carpal joint degradation was attenuated with oral ibuprofen treatment, indicating that joint degeneration is linked to inflammation in this model. Interestingly, aging increased the serum and tissue inflammatory cytokines and tissue macrophages in this WMSD rat model. In addition, there was also increased nerve and tendon degradative changes in aged rats performing a moderate demand task for 12 weeks, changes that correlated with increased tissue macrophages and inflammatory cytokines [70,96,181].

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Repetitive strain injury and aging

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As mentioned above, performance of upper extremity high repetition low force (HRLF) tasks for prolonged periods results in increased sera and tissue levels of pro-inflammatory cytokines and chemokines. This response was exacerbated with aging [70,96,181], supporting a hypothesis of both age- and repetitive task-induced increases in these cytokines. Dr. Barbe's group also observed a transient increase in serum proinflammatory cytokines mediated by M1 (pro-inflammatory) macrophages, such as, IFNγ, in young adult rats at week 6 of the HRLF task. However, this serum inflammatory cytokine response was resolved by week 12, coincident with increased serum IL-10, an M2- (anti-inflammatory) mediated cytokine. The latter is indicative of an M2 macrophage

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Fig. 4. Proposed model for M1/M2 polarization in aged mammals. In contrast to young adults, in aged mammals, M1 pro-inflammatory cytokines are inherently increased due to reversal of Th1/Th2 ratio; the tissue injury progressively increases M1 and decreases M2 responses, with a net loss of an adaptive response resulting in bone resorption and erosions. The combination of age and tissue injury shifts the mac polarization towards the M1 phenotype.

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mediated resolution of the systemic cytokine response in young adult rats, despite continued task performance. This resolution was absent in aged rats that performed the 12-week HRLF, suggestive of a loss of tissue 272 Q25 repair or adaptation in the aged rats [70,96,181]. Although this loss of 273 tissue adaptation and repair with aging is apparent in the literature, the 274 underlying mechanisms are not fully understood.

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Inflammation and bone homeostasis

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Osteoporosis is a growing public health problem, in part because of the increasing numbers of people living beyond 65 years of age [127,169]. The National Osteoporosis Foundation estimates that there are 29.5 million women and 11.7 million men in the U.S. with osteoporosis. It is characterized by low bone mass, significant destruction of trabecular architecture and loss of connectivity between plates of trabecular bone, leading to increased bone fragility and fracture risk [127,169]. The estimated cost of treating patients hospitalized with a diagnosis of osteoporosis is $19.1 billion per year [65]. Eighty percent of patients with osteoporosis are women, largely due to the marked reduction in bone density associated with estrogen withdrawal during menopause. Bone resorption has been associated with a significant increase of pro-inflammatory cytokines in patients with inflammatory diseases. For example, chronic gingivitis; a periodontal disease is associated with increased pro-inflammatory cytokines and osteoclastmediated destruction of alveolar bone in the jaw. Also, rheumatoid arthritis is associated with increased pro-inflammatory cytokines in the affected joints, as well as osteoclast-mediated bone erosion on the margins of these joints [81]. A long list of pro-inflammatory cytokines is capable of stimulating osteoclastic bone resorption, including IL-1, TNF-α, IL-6, IL-11, IL-15 and IL-17 [34,103,125,178].

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Osteoimmunology

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Several bone diseases have been linked to the immune cell activity, such as the release of -pro-inflammatory cytokines with subsequent production of receptor activator of nuclear factor kappa-B ligand (RANKL) by osteoblasts [174]. RANKL stimulates osteoclast formation and bone erosions resulting in the development of osteolytic lesions in patients with rheumatoid arthritis [63]. The mechanism of rheumatoid arthritis-induced bone loss is explained by the infiltration of synovium and surrounding tissues of the affected joints with inflammatory cells, such as T lymphocytes and macrophages. T lymphocytes stimulate osteolysis, an event mediated by osteoclast differentiation and activation. Initial studies showed that activated T lymphocytes, or their culture supernatants, stimulate osteoclastogenesis in vitro [101]. Activated macrophages also secret pro-inflammatory cytokines such as TNF-α, IL-1 and IL-6 that have a synergistic effect on RANKL release by osteoblasts [8,9,86]. These inflammatory cytokines also direct osteoclast formation through a RANKL/RANK-independent mechanism, as previously reported [92,99,170]. In addition, activated macrophages and T lymphocytes produce macrophage migration inhibitory factor (MIF) [35], a chemokine that stimulates expression of matrix metalloproteinase (MMP)-9 and -13 by osteoblasts [143] and that supports RANKL-stimulated osteoclastogenesis in vitro [98]. Previous studies reported the osteoporotic phenotype with high bone turnover in mice overexpressing MIF [144], while mice lacking MIF do not exhibit bone loss [146]. Other devastating disease with high incidence in the elderly is multiple myeloma; a plasma B-cell tumor that arises in the bone marrow and quickly metastasizes to the skeleton. The tumor cells start and maintain a chronic inflammatory cascade and produce a chemokine called macrophage inflammatory protein (MIP)-1α and β. This

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not well understood. Our group has previously reported early tissue injury marked by a transient increase in serum and tissue inflammatory cytokines and a decrease in grip strength in young adults performing repetitive strain tasks [20,25,33]. Recent studies showed an induction of M1 polarization and a persistent increase of M1 cytokines (IFN-γ) in aged versus young adults indicating a chronic inflammation. This response was even greater in aged versus young adults performing the repetitive strain task [70,96,180]. We have preliminary data showing that serum from aged HRLF rats (model of repetitive strain injury) inhibits MSC proliferation, compared to serum from young HRLF rats. In addition, we have preliminary evidence that serum from aged HRLF rats increased HSC proliferation, compared to serum from young HRLF rats. These findings suggest that serum anti-inflammatory cytokines in young rats are preferentially contributed by alternatively activated M2 macrophages that likely have a reparative role mediated by MSC proliferation and then differentiation into osteoblasts at the site of injury, a response that should lead to adaptive bone formation. Conversely, serum cytokines in aged rats that are preferentially contributed by classically activated M1 macrophages have a pathological role in mediating HSC proliferation and differentiation into osteoclasts, a response that should lead to enhanced bone resorption. Studies confirming these hypotheses are currently underway in our laboratories.

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Macrophages and tissue regeneration at the site of tissue injury

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The site of a tissue injury is largely associated with a dense population of infiltrated macrophages with heterogeneous phenotypes and 379 an inflammatory response that is mediated by these cells [12]. Thus, 380 macrophages modulate the microenvironment at the site of injuries 381 Q28 [12]. Macrophage polarization (M1 versus M2) differentially regulates 382 MSC and HSC differentiation in bone tissue. This regulatory mechanism 383 mediates either a regenerative or pathological response based on M1/ 384 M2 shift mediating MSC and HSC differentiation, respectively [55,74]. 385 Recent studies show that macrophage polarization regulates certain 386 physiological, metabolic conditions and regenerative functions [37,38]. 387 The nature of the complex interplay between the M1 and M2 macro388 phages and how these interactions influence the ability of MSC389 mediated tissue regeneration or HSC-mediated tissue pathology are

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Conclusions and future directions

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The role of inflammatory macrophages in age-associated bone loss is under investigated. Elucidation of the complex interplay between chronic inflammation and altered bone homeostasis is a subject of intense clinical interest. Treatment of aged patients with generalized bone loss, such as osteoporosis and/or chronic inflammation is a health challenge. Since bone homeostasis in aged patients is likely altered due to chronic inflammation, future studies should focus on new strategies to reduce age-related inflammation for improved quality of life in the elderly. This information will help in developing new therapeutic strategies to selectively enhance bone formation in aged patients suffering from chronic inflammation and significant bone loss. For example, stem cell therapy is a hot topic for treatment of several other pathological bone diseases. One suggested intervention is the treatment of aged osteoporotic patients with bone marrow derived-mesenchymal stem cells and/or anti-inflammatory repair macrophages isolated from their young siblings [118]. We also need to improve our understanding of the regulatory mechanisms of inflammation in skeletal tissues of aged mammals at rest and following injury that will help develop novel and specific anti-inflammatory medications. In addition, we need to explore the advantages of dietary modifications and regular exercise training to subside inflammation in skeletal tissues of aged mammals. Moderate exercise, in particular resistance training, is effective in maintaining the skeletal mass in aged mammals [102,149]. Moreover, moderate exercise is also effective in decreasing systemic inflammation [42,62]. Reducing inflammation in skeletal tissues will help to restrict muscle atrophy and bone loss, enhance muscular strength, and reduce the incidence of osteoporosis and fracture risk in aged mammals [78,89,124]. More research is required to establish the potential mechanisms of macrophages and inflammatory cytokines in regulating bone homeostasis and that will be critical over the course of the next 30 years, during which the world's aged population is expected to grow exponentially.

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Conflict of interest statement

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chemokine not only triggers proliferation and survival of tumor cells, but also enhances osteoclast formation-mediated bone resorption 328 resulting in osteolytic lesions and leading to increased morbidity and 329 mortality [7,87,112]. 330 In MSC and osteoblasts, numerous cytokines are reported to regulate 331 their proliferation, survival and differentiation. TNF-α is a pro-apoptotic 332 for osteoblasts [94], possibly through induction of Fas–FasL interaction 333 [95]. TNF-α is also reported to inhibit osteoblast differentiation [79,80, 334 108,135]. IFN-γ, IL-1 and TNF-α inhibit collagen synthesis by osteo335 blasts [45,53,165]. Several anti-inflammatory cytokines counteract the 336 effects of pro-inflammatory ones at the site of injury that is necessary 337 to start tissue repair and bone regeneration. IL-4 has been reported to 338 stimulate proliferation and inhibit differentiation of osteoblastic cell 339 line [175]. Moreover, IL-4 overexpressing mice showed decreased 340 total bone mass and bone formation associated with decreased numbers 341 of differentiated osteoblasts [113]. IL-4 and IL-13 have also been report342 ed to inhibit prostaglandin synthesis in bone and stimulate migration of 343 osteoblasts [115,145]. Also, it has been shown that TGF-β and IL-10, 344 secreted by M2 macrophages, inhibit osteoclast formation and subse345 quent bone resorption [90,150]. 346 Generally, cytokines are not the only mediators of the inflammatory 347 response in bone tissue, other factors are also released in response to 348 inflammation. One important factor is osteoactivin (OA) that have 349 been discovered in our laboratory and was reported to stimulate MSC 350 differentiation into osteoblasts with increased mineralization of 351 the extracellular matrix (ECM), leading to significant bone growth 352 [1–3,5,147,161]. In addition, our lab also shows that OA works as a neg353 ative regulator of osteoclastogenesis. 354 Other groups have designated different names to OA in different 355 species, such as glycoprotein nmb (Gpnmb) in melanoma cell lines 356 [104,141,152,172,177], and melanocytes [16,17], dendritic cell heparan 357 sulfate proteoglycan integrin dependent ligand (DC-HIL) in dendritic 358 and T-cells [57,163] and human hematopoietic growth factor inducible 359 neurokinin (HGFIN) in tumor cells [18]. 360 Previous studies reported on the several functions of osteoactivin 361 (OA) in regulating cell proliferation, adhesion, differentiation and 362 synthesis of ECM proteins in normal and pathological conditions 363 Q26 [1,6,10,16,17,57,85,104,111,122,134,140,142,147,152,159,161,163,172]. 364 Interestingly, OA is produced by inflammatory macrophages recruited to 365 the site of injury in several diseases. Previous studies showed that OA is 366 not only produced by macrophages surrounding non-viable adipocyes 367 in obese individuals [76], but also by tumor-associated macrophages in 368 a combination with other bio-active extracelllular matrix proteins 369 (ECM) [114]. Moreover, OA expression was increased in heart infilatrated 370 macrophages in a mouse model of dilated cardiomyopathy [153]. In a 371 separate study, OA upregulation in uremic macrophages was reported 372 in patients with chronic nephritis; an end-stage renal disease [148]. 373 Furthermore, patients with acute liver injury showed a high levels of OA 374 in inflammatory liver macrophages, suggesting a significant role of OA 375 Q27 in regulating the immune response [85].

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The role of oxidative stress and inflammation in cardiovascular aging.

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Role of glycation in aging.

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The role of inflammation in suicidal behaviour.

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X-ray imaging characterization of femoral bones in aging mice with osteopetrotic disorder.

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