J Bone Miner Metab DOI 10.1007/s00774-014-0628-0

REVIEW ARTICLE

MicroRNAs are potential prognostic and therapeutic targets in diabetic osteoarthritis Shi Jingsheng • Wei Yibing • Xia Jun • Wang Siqun • Wu Jianguo • Chen Feiyan Huang Gangyong • Chen Jie

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Received: 4 April 2014 / Accepted: 18 August 2014 Ó The Japanese Society for Bone and Mineral Research and Springer Japan 2014

Abstract Osteoarthritis is an aging-related degenerative disease that severely influences the elders’ life quality. However, there have been few clinical approaches available until now. Currently, more knowledge of the pathology of osteoarthritis has been illustrated. Especially, diabetes can be the only predictor of osteoarthritis. Due to its outstanding characteristics, MicroRNA has been considered as an efficient target in treating diseases. In this review, we will discuss a new insight focusing on the roles of microRNA in the progression of osteoarthritis-induced by diabetes, especially type II diabetes mellitus. Keywords MicroRNA  Type II diabetes  Osteoarthritis chondrocyte

Introduction Osteoarthritis (OA) is the most common degenerative joint disorder, afflicting mainly the weight-bearing joints, such as hips and knees [1]. It is the leading cause of physical disability, and severely influences the quality of life for patients. Articular cartilage maintains joint tissue and the chondrocyte is the only cellular type in articular cartilage [2]. OA occurs when the homeostatic balance between cartilage degradation and its repair mechanism is broken [3–5].

S. Jingsheng  W. Yibing (&)  X. Jun (&)  W. Siqun  W. Jianguo  C. Feiyan  H. Gangyong  C. Jie Department of Orthopedics, Huashan Hospital, Fudan University, 12 Urumqi Road, Shanghai 200040, China e-mail: [email protected] X. Jun e-mail: [email protected]

Previously, risk factors for OA included age, weight, genetics and stimuli such as growth factors and chemokines [6–8]. Nowadays, more research has pointed out that diabetes, especially type II diabetes mellitus (T2DM), can be the only predictor for OA [9–11]. T2DM is characterized by hyperglycemic toxicity, insulin resistance of muscle, adipose, and liver tissue, combined with dysfunction and later failure of insulin-producing pancreatic b cells [12]. Several studies have reported that the involvement of diabetes, especially hyperglycemic toxicity, has great impact on the progression of OA [13]. One of the characterizations of chondrocytes is that they are able to respond to the concentration of glucose present in the cartilage matrix, the synovial fluid and to a less extent, the subchondral bone, and substantially adjust their cellular metabolism by expressing protein of the glucose transporter (GLUT)/SLC2A family [14]. Specifically, hyperglycemia not only reduces dehydroascorbate transport into chondrocytes, which leads to the low synthesis of type II collagen, but also induces the production of reactive oxygen species (ROS), the well-known mediators of cartilage destruction [15, 16]. Hyperglycaemic toxicity also leads to the accumulation of advanced glycation end products (AGEs) in several diabetic target tissues including OA cartilage, which causes matrix stiffness and more sensitivity to mechanical stress [17]. By binding to RAGE, the specific Receptor for Age Glycation End products present on chondrocytes [18], AGEs stimulate the expression of proinflammatory and prodegradative mediators and alter the chondrocyte differentiation phenotype through the activation of several signaling pathways [19–21]. Besides these, exposure of human chondrocytes to high glucose favors the catabolic program and disrupts cartilage matrix homeostasis, which further promote articular cartilage degradation, and facilitate OA development [22]. High

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glucose exposure increased the matrix metalloproteinase (MMP)-13 in OA chondrocytes. Also, type II collagen increased persistently in OA chondrocytes. More importantly, high glucose exposure impaired the activation of transforming growth factor-beta (TGF-b) signaling, the pro-anabolic stimuli. Although we have uncovered several pathogenesis pathways of OA, there is still no effective clinical approach for prevention and treatment. Until now, pain management has been one of the few treatments and joint replacement surgery is necessary for the late phase of OA. There still remains an urgent need to thoroughly understand the underlying disease mechanisms responsible for diabetes-induced OA, in order to develop new and improved therapeutic strategies for this chronic condition. MicroRNA (miRNA), a class of non-coding small RNAs, is widely accepted as one of the post-transcriptional modifications that influence entire intracellular molecular cascades such as intracellular signaling [23]. The effect of miRNAs is via the incomplete binding of the ‘‘seed sequence’’ at the 50 end of the miRNA to the complementary target site in the 30 untranslated region (UTR) of the messenger RNA. Once bound to the 30 -UTR, this interaction triggers mRNA degradation or repression of translation [24, 25]. One miRNA is able to target multiple genes, and one gene may be the target of multiple miRNAs [26, 27]. For this reason, miRNAs play important and diverse roles in both biological functions such as apoptosis, differentiation, stem cell maintenance and metabolism, and diseases including stress responses, oncogenesis, and diabetes [28–30]. Recently, increasing evidences support the idea that miRNAs are an integral part of the regulatory network in chondrocyte differentiation and cartilage function, indicating a potential role of miRNA in the progression of OA. Specific miRNAs were reported to be involved in chondrogenesis and inflammatory cartilage diseases [31– 33]. A recent work by Kobayashi et al. demonstrated the role of miRNAs in cartilage function. These authors showed that Dicer, a critical enzyme for biogenesis of miRNAs, is essential for normal skeletal development; they generated cartilage-specific Dicer-null mice that showed a greatly decreased chondrocyte proliferation and accelerated hypertrophy, leading to severe growth defects and premature death of mice [34]. In addition, emerging evidence demonstrates that miRNAs play significant roles in glucose and lipid metabolism, as well as in insulin production, secretion, and action [35–37]. Furthermore, many findings have revealed clear links between altered miRNA expression and certain diabetes complications [38]. All these data suggest that these miRNAs may serve as potential biomarkers and/or drug targets in the prevention, treatment, and management of diabetes and its complications, especially OA. In this article, we will firstly summarize an overview of altered microRNAs in the

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progression of OA. Secondly, we will review the roles of several well-known microRNAs in the development and progression of diabetic-related complications, especially OA. Finally, we will uncover the potential clinical applications of microRNAs.

An overview of microRNAs in the development of OA In general, systemic microRNA profiling arrays have exhibited a number of miRNAs whose expression differs dramatically in human OA chondrocytes compared to their healthy counterparts [39–41]. Quantitative real-time PCR confirmed these expressions and further functional target analysis revealed several regulatory pairs involved in cartilage homeostasis, in biomechanics, and in lipid metabolism. For example, microRNA-93 (miR-93) has been identified as a signature microRNA in hyperglycemic conditions, and it regulates VEGF-A expression by directly targeting its 30 -untranslated region (UTR) both in vitro and in vivo, indicating that miR-93 might prevent the progression of diabetic nephropathy by modulating the VEGF signaling pathway [42]. On the other hand, angiogenesis is increased during osteoarthritis, leading to ossification in osteophytes and the deep layers of articular cartilage. In addition, blood vessel growth is increased at and disrupts the osteochondral junction. Other research has focused on the alterations occurring in the synovial fluids adjacent to articular cartilage, which also contribute to the progression of OA [43]. The levels of miR-132, miR-223, and miR-16 are decreased in the synovial fluid of patients with OA compared to their normal subjects [44].

Loss of MiR-140 disrupts the cartilage homeostasis and promotes the progression of OA Previously, microRNA-140 (MiR-140) was identified to be specifically expressed in cartilage tissues in mouse embryo during both long and flat bone development [45], which exhibit a similar pattern in human cartilage tissue. The miR-140 (-/-) mouse model showed age-related osteorarthritis (OA)-like phenotypes, such as proteoglycan loss and fibrillation of articular cartilage. After overexpression of miR-140 in cartilage, the transgenic mice were resistant to antigen-induced OA [46]. Similarly, miR-140 is highly expressed in normal human articular cartilage, whereas this expression is dramatically reduced in OA patients [47]. All these findings indicate the role of miR-140 in tissue development and homeostasis, and its loss would induce the occurrence of OA. Afterwards, many researches were carried out to characterize the specific targets of miR-140 and the potential pathways it might be involved in. It has

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been demonstrated that miR-140 directly regulated the expression of matrix metalloproteinase-13 (MMP-13) [48], a major enzyme in cartilage degradation, whose overexpression is closely associated with OA [49]. In another work, miR-140 is reported to directly target Smad3, a key transcription factor in the transforming growth factor b (TGFb) signaling pathway, which plays an important role in the development, growth, maintenance and repair of articular cartilage. The authors speculate a double negative feedback loop, in which miR-140 suppresses the TGFb pathway through repression of Smad3, and TGFb suppresses the accumulation of miR-140 [50]. Sox9 plays a critical role in early chondrocyte initiation and promotion, as well as repression of later maturation, and its loss accelerates the progression of OA [51]. In sox9a mutant (sox9a-/-) and sox9b mutant (sox9b-/-) zebrafish and SOX9 small interfering RNA in human chondrocytes, the expression of miR-140 was decreased, suggesting that SOX9 might function as the upstream regulator of miR-140 [52]. Furthermore, two recent studies identified that Sox9 directly regulates miR-140 expression by binding to the upstream region of miR-140 and enhances its expression together with L-Sox and Sox [53, 54]. Another microRNA, miR-145, repressed the expression of SOX9 by directly binding to its 30 -UTR. Moreover, increased miR-145 expression led to several signatures of changes in OA, such as reduced expression of critical cartilage extracellular matrix genes (COLA and aggrecan) and tissue-specific microRNAs (miR-140), and increased levels of the hypertrophic markers (RUN and MPM), strongly indicating a crosstalk between genetic and epigenetic modifications [55].

The roles of MiR-146a in balancing cartilage homeostasis Clinically, it has been demonstrated that miR-146a is highly expressed in grade I cartilage samples that represent mild OA, when compared with grade II or grade III samples, which represent moderate or severe OA, respectively. In addition, the expression of COL2A1 is in parallel with miR-146, while the expression of MMP-13 is increased in grade II OA samples. Tissue section in situ hybridization of primary miR-146a (pri-miR-146a) revealed that pri-miR146a was expressed in chondrocytes residing in all tissue layers, especially in the superficial layer, where it was intensely expressed. All these data suggested that miR146a is closely associated with the progression of OA [56]. In contrast, from the plasma samples of new-T2DM patients, the circulating miR-146 levels were remarkably higher than the healthy controls [57]. This differential expression of miR-146 put forward more investigations regarding theelucidation of its specific functions.

Functional analysis of the role of miR-146 in OA uncovered that miR-146a significantly suppresses extracellular matrix-associated proteins (e.g., Aggrecan, MMP13, ADAMTS-5, collagen II) in human knee joint chondrocytes, suggesting that miR-146 plays key roles in balancing the cartilage matrix homeostasis by means of inhibiting the catabolic phase (Fig. 1). OA has been considered as an inflammatory process for the detection of interleukin-1 beta (IL-1b) in synovial fluid [58]. However, the mechanisms of inflammation in OA are uncertain. Overexpression of miR-146 in isolated human chondrocytes reduced IL-1b-induced tumor necrosis factor-alpha (TNF-a) [41]. Similarly, exogenous supplementation of synthetic miR-146a significantly modulates the expression of TNF-a [59], indicating that miR-146 mediates inflammatory functions and pathways. Conversely, when treatment with pro-inflammatory cytokines such as IL-1b, the expression of both miR-146a and miR-146b is stimulated, which in turn represses the nuclear factor kappa-B (NF-jB) pathway, as well as the MAP kinase pathway, indicating a negative regulator of miR-146 on inflammation and a negative feedback loop [57]. Despite this, miR-146 has also been demonstrated to be regulated by NF-jB through binding to the promoter of miR-146, which subsequently inhibits the IKK/IjB/p65 signaling cascade and interleukin-6 (IL-6) secretion [60]. One feature of microRNAs is that they cooperate with each other in response to environmental stimuli. With exposure to microbial lipopolysaccharide (LPS), both miR-146 and miR-155, two conserved immunomodulatory miRNAs, were induced. However, under this induction, they dramatically differ in their induction behavior. MiR-146 was in charge of regulating LPS signaling transduction, which in turn reduced cellular LPS sensitivity, whereas miR-155 was mainly involved in the pro-inflammatory transcriptional programs [61]. Similarly, a phenomenon has been found in peripheral blood mononuclear cells (PBMCs) from patients with T2DM. Both miR-146 and miR-155 levels were decreased in patients with T2DM when compared with normal subjects. However, they differed in their distributions that were closely related to glucose, BMI and HbA1c [62]. One of the most common features of OA is chronic pain, which is correlated with pathological changes in the joint tissues. Aberrant inflammatory responses, normally dependent on NF-jB, are the major cause of chronic pain in OA [63]. Besides this, changes in miRNAs expression are closely relevant to pain sensation through modulating pain-related pathways [64]. Li et al. found that in the mono-iodoacetate (MIA)-induced OA model, the expression of miR146 is dramatically reduced in both the dorsal root ganglion (DRG) and dorsal horn of the spinal cords. Furthermore, the overexpression of miR-146 in human glial cells, which is demonstrated to play major roles in the

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Fig. 1 The roles of miR-146 in balancing the cartilage homeostasis and OA-related pain symptoms. Chondrocytes can respond to high glucose of type II diabetes mellitus, inducing high expression of MMP-13 and destroying the balance of cartilage matrix homeostasis to facilitate OA development (presented in green lines). Highly expressed miR-146 by chondrocytes in OA reduced expression of ECM-associated proteins, balancing cartilage matrix homeostasis (shown in black lines), and also modulating TNF-a expression.

Overexpression of miR-146 by glial cells in OA reduced expression of pain-related proteins, decreasing chronic pain (shown in orange lines). Treatment with IL-1b activated miR-146, which repressed NFjB and MAPK signaling pathways, acted as a negative regulator of inflammation (showed in blue lines). Red arrow represents overexpression. OA osteoarthritis; IL-1 interleukin-1 beta; TNF-a tumor necrosis factor-alpha; NF-jB nuclear factor kappa-B; ECM extracellular matrix (color figure online)

development and maintenance of persistent chronic pain [65], significantly reduced the expression of several painrelated factors, including TNF-a, COX-2, iNOS, IL-6, IL8, RANTS and ion channels, and TRPV1 [66]. Moreover, the expression of miR-146 and the miR-183 cluster are dramatically decreased in the DRG and spinal cord from animals experiencing knee joint OA pain. Also this downregulation is closely correlated with the upregulation of inflammatory pain mediators [67]. All these data suggest that specific microRNAs and their interactions may facilitate cartilage homeostasis and OA-related pain symptoms by modulating the inflammatory response and pain-relevant mediators in glial cells (Fig. 1), which may be a potential therapeutic strategy for the treatment of both cartilage regeneration and OA-related pain management.

farnesoid X receptor (FXR) suppressed the expression of miR-34a in the liver, leading to an upregulation of Sirtuin 1 (SIRT1), an NAD-dependent deacetylase involved in metabolic diseases [69]. Further research pointed out that an miR34a functional binding site presented on the 30 -UTR of NAMPT mRNA, the rate-limiting enzyme for NAD? biosynthesis [70], which mediated the downregulation of NAD? levels and SIRT1 activity [69]. Hepatic overexpression of miR-34a decreased NAMPT/NAD? levels, and increased acetylation of the SIRT1-targeted transcriptional regulators, such as NF-jB, PGC-1a, and SREBP-1c, ultimately leading to obesity-mimetic outcomes [69]. In another study, miR-34a was reported to bind to the 30 -UTR of betaKlotho (b-KL), a co-receptor of the hepatic membrane receptor complex that also contains FGF19 receptor 4. Overexpression of miR-34a in mice reduced the hepatic bKL level, inhibited FGF19-activated ERK and glycogen synthase kinase signaling, and altered expression of FGF19 target genes. Similar outcomes were observed in dietary obese mice in which the miR34a level was dramatically elevated [71]. These novel findings of the miR-34a/NAMPT axis and miR-34a/b-KL/FGF19 cohort have presented enormous potential targets for treating metabolic disorders.

MiR-34a participates in the regulation of metabolic disorders Obesity is a common risk factor of T2DM and osteoarthritis. MiR-34a expression is significantly elevated in hepatic cells of diet-induced obese mice [68]. It has been reported that

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Clinical applications of targeting microRNAs in treating OA Given that microRNAs play pivotal roles in maintaining the homeostasis of articular cartilage and contribute to the progression of the joint disorders including OA, the development of therapeutic strategies focusing on microRNAs have attracted much attention [40]. Exogenous injection of mesenchymal stem cells (MSCs) is currently one of the most premier approaches in treating knee joint injury [72–76]. Moreover, several studies have reported that microRNAs are also responsible for the process of MSCs’ commitment to the chondrocytes [77–79]. Adult MSCs are undifferentiated multi-potent cells ubiquitously residing in bone marrow (BM), connective tissues and notably, adipose tissue (AT), placenta, umbilical cord, dental pulp, tendon, trabecular bone and synovium [80, 81]. It has been identified that MSCs are primarily located in the superficial and middle layers of the articular cartilage [82–85]. By FACS and in vitro differentiation assay, these isolated MSCs commit to chondrogenic, adipogenic and osteogenic potentials [86, 87]. Besides this, a subgroup of highly migratory cells expressing MSC markers has been identified in the calcified zone in the late stage of OA [88]. These migratory progenitor cells are endowed with enhanced in vitro chondrogenic commitment. These cells reside in non-cartilage tissue in the joint, such as the synovium, exhibiting greater chondrogenic differentiation potential [80]. Ironically, these endogenous MSCs by themselves are unable to halt the pathogenesis of OA [89]. One explanation for this may be that the local microenvironment niche, including high levels of inflammatory cytokines, impairs their in vitro chondrogenic differentiation commitment [90–93]. Based on this, strategies may move to the modification of exogenous MSCs. Recently, intense research has proven that MSCs are capable of suppressing local inflammation and tissue damage in a variety of inflammatory autoimmune diseases, in particular, in rheumatoid arthritis. Moreover, MSCs may have influences on the course of degenerative disorders and prevent cartilage degradation in osteoarthritis. All these data suggest the great potential of MSCs for the treatment of rheumatic diseases. However, the underlying molecular mechanisms have not been well documented. Only few evidences associated with microRNAs have been reported. MiR-140, mentioned above, also plays pivotal roles during chondrogenic differentiation. It has been demonstrated in equine cord blood-derived MSCs (eCB-MSCs) that miRNA-140 is highly expressed in both normal equine articular cartilage and eCB-MSCs [94]. Furthermore, the expression of the chemokine (CXC motif) ligand 12 (CXCL12) and a disintegrin and metalloproteinase with

trombospoin motifs (ADAMTS)-5 was decreased while miR-140 was upregulated [94]. Exogenous injection of MSCs to diabetic mice can improve healing in diabetic murine wounds [95]. In this process, miR-146 expression was dramatically enhanced; otherwise, it was downregulated. The upregulation of miR-146 resulted in a decrease of the expression of its pro-inflammatory targets, further enhancing the wound healing [96–98]. The function of miR-34 has been investigated in chick limb MSCs during chondrogenesis. This study reported that miR-34 is a negative regulator of chondrogenesis, evidenced by increasing migration of chondrogenic progenitors and formation of precartilage condensation when there is a blockade of miR-34a [99]. Also, miR-34 plays key roles in the reorganization of the actin cytoskeleton, an important step for chondrocyte differentiation. After treatment with JNK inhibitor, the suppressor of chondrogenic differentiation, the expression of miR-34a was increased in parallel with the upregulation of RhoA1, a modulator of stress fiber expression. A blockade of miR-34a expression caused a decrease in the level of RhoA and a resultant upregulation of Rac1 and type II collagen, which ultimately inhibited reorganization of the actin cytoskeleton [100].

Conclusions Owing to this research, we have obtained a large number of candidates for the diagnosis or prognosis of OA. Two major characteristics of microRNAs,,easy manipulation and endogenous sources, give microRNAs overwhelming advantages to exploit the specific inhibitors. However, there still remains much controversy on microRNAs’ functions during chondrogenic differentiation and OA progression. More research is needed to systematically figure out the roles of microRNAs and the crosstalk between them, or with other signaling pathways. In addition, future work calls for more attention on elucidating whether diabetes (including insulin tolerance) induces OA and the underlying molecular mechanisms. Acknowledgments The authors appreciate the research funds from the Ministry of Health on Research for special purpose-biomarkers for diagnosing and monitoring autoimmune diseases (201202008). Conflict of interest

None.

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