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New Thoughts on the Pathophysiology of Osteoarthritis: One More Step Toward New Therapeutic Targets Johanne Martel-Pelletier, PhD, Daniel Lajeunesse, PhD, Hassan Fahmi, PhD, Ginette Tardif, PhD, and Jean-Pierre Pelletier, MD

Corresponding author Johanne Martel-Pelletier, PhD Osteoarthritis Research Unit, University of Montreal Hospital Centre, Notre-Dame Hospital, 1560 Sherbrooke Street East, Montreal, Quebec, Canada, H2L 4M1. E-mail: jm@martelpelletier.ca Current Rheumatology Reports 2006, 8:30 – 36 Current Science Inc. ISSN 1523-3774 Copyright © 2006 by Current Science Inc.

Osteoarthritis is considered an illness in which a complex interaction between the tissues of the joint plays a significant role in the initiation and/or progression of this pathophysiology. We do not yet completely understand all the factors that are responsible for initiating the degradation and loss of the articular tissues. This paper summarizes the novelties of three such mechanisms. The first one points to some factors involved in the regulation of one growth factor family, the bone morphogenetic proteins, the second, the regulation of prostaglandin E2 synthesis, and the third the factors involved in subchondral bone remodeling, all of which could be very significant events for osteoarthritis. This paper should help the reader better understand the most recent advances regarding the roles of these factors in this disease process, and how new therapeutic targets may be identified.

Introduction Research in recent years has shown that osteoarthritis is a disease that is considerably more complex than previously thought. Indeed, it is now accepted that osteoarthritis is not one single disease, but should rather be seen as a common final stage of joint failure, in which the initial stages of the disease can be triggered by many different causes and/or factors. Despite major progress, we still have a great deal to learn about the pathogenesis of this disease. The slowly progressive loss of cartilage, the multifactorial nature of the disease, and the cyclical course with periods of active disease followed-up by remission have limited our comprehension of osteoarthritis. However, several cellular and molecular pathways involved in

this disease have been identified. The present reviews the roles of new classes of molecules that can act on one or more osteoarthritis processes, and how they may be key players in the evolution of the disease. More specifically, novelties in three critical pathways involved in this disease pathogenesis will be addressed. First, we will look at factors that could regulate the activity of one family of growth factors, the bone morphogenetic proteins (BMPs) in the osteoarthritic cells. Second, we will examine a possible new strategy of how prostaglandin E 2 (PGE 2) production may be specifically blocked without interfering with the cyclooxygenase (COX) activity, as the latter enzymes have demonstrated important physiologic functions. Third, as it is now believed that prominent changes in the subchondral bone appear to play a key role in the initiation/progression of osteoarthritic cartilage degradation, factors involved in the altered subchondral bone metabolism will be examined, as they could be of significant importance in osteoarthritis progression. This last topic will be thoroughly reviewed.

Bone Morphogenetic Proteins In contrast to endochondral ossification where chondrocytes mature to terminal hypertrophy leading to mineralization and cellular death, the maturation of articular chondrocytes in cartilage is arrested before this terminal differentiation. In the conditions leading to osteoarthritis, the chondrocytes are allowed to complete the maturation cycle. They proliferate and express genes normally associated with terminal differentiation, possibly as an attempt to stimulate cartilage repair. Recent reports have identified several growth factor genes displaying differential patterns of expression in normal and osteoarthritic human chondrocytes. Growth factors such as the transforming growth factor-β (TGF-β) and insulin-like growth factors (IGFs) have been studied extensively with respect to their expression and roles in osteoarthritis. However, the use of these growth factors in the treatment of osteoarthritis is a challenging avenue, as several problems have yet to be


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addressed; among them, the formation of osteophytes, the non-responsiveness of older cells to these growth factors, and their inability to counteract many catabolic actions of pro-inflammatory molecules. Recently, other growth factors, such as the BMPs and activin, have received more attention as to their possible implication in osteoarthritis. BMPs belong to the TGF-β super-family of secreted signaling molecules. They were initially identified for their ability to induce bone formation; they are now recognized for their role in the maintenance and repair of bone, cartilage, and other tissues in adults. Some BMP genes are re-expressed during osteoarthritis. For example, BMP-2 and BMP-4 are up-regulated in osteoarthritic cartilage and are present in the osteophytes, but are scarce in normal adult articular cartilage [1]. Transmission of the BMP-generated signals from the cell surface to the nucleus is mediated by proteins termed Smad. These proteins can be divided into three classes according to their functions: receptor regulated (Smads 1, 2, 3, 5, and 8), common Smad (Smad 4), and inhibitory Smads (Smads 6 and 7). Although Smads 1, 5, and 8 are specific to the BMP pathway, they do not seem to be upor down-regulated in osteoarthritic cartilage as compared with normal [2]. However, a Smad-interacting molecule, Tob1, has recently been implicated in the osteoarthritis process. This protein, first found to be a cell cycle regulator acting as an anti-proliferative protein [3], has also been shown to function as a negative regulator of BMP signaling by sequestering Smad 1 and 5 [4] and enhancing the interaction of Smad 6 with the activated BMP receptor [5]. The expression of Tob1 was recently reported to be down-regulated in osteoarthritis [6], which could likely result in an increase in cellular proliferation as well as an increase in BMP activity. Recent studies have shown that BMP activity/availability can be controlled by specific antagonists. These comprise a family of structurally unrelated extracellular proteins that prevent proper binding of the BMPs to their receptors. Each antagonist differs in its specificity and affinity for a specific BMP, and they likely play different roles depending on cell and tissue types in spatial and temporal regulation of BMP activity. Recent reports have demonstrated a possible role for some BMP antagonists in osteoarthritis. Indeed, follistatin, gremlin, chordin, and a chordin-like 2 (CHL2) were up-regulated in osteoarthritic cartilage [7•,8,9]. Moreover, a differential topographic distribution and regulation was found in osteoarthritic chondrocytes between follistatin and gremlin, suggesting their appearance at different stages during the disease process and/or that they play different roles [7•]. Data suggested that gremlin may appear at the hypertrophic stage of osteoarthritic cartilage, thus at an early stage, and that follistatin, in contrast to gremlin, may have a strong link to the inflammatory aspect of osteoarthritis and appear later in the disease process. The role played by BMP antagonists in osteoarthritis is likely complex, as each antagonist binds preferentially to different BMPs and is dif-

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ferently regulated in osteoarthritis. As their major function is to bind BMPs and activin, they may help to keep in check the increased BMP activity triggered in osteoarthritis at different stages of the disease. However, and addressing the multifaceted role of BMPs in joint tissue metabolism, it was recently shown, in a mouse model of arthritis, that in vivo treatment with a follistatin-related protein ameliorates the joint inflammation [10]. In this respect, it is interesting to note that BMPs could also promote catabolic processes. Indeed, it was recently shown that BMP-2 induces a DNA damage inducible protein, GADD45β, which in turn up-regulates the metalloprotease MMP-13 (collagenase-3) [11], a key protease involved in osteoarthritic cartilage degradation. Interestingly and also recently shown, another DNA damage protein, the DDB1, appears to be associated with a human MMP-13 promoter binding site named AGRE [12], whose regulation appears to be involved in the MMP-13 basal production. Whether DNA damage proteins are target proteins in osteoarthritis remains, however, to be determined. Understanding the role of BMPs and their associated molecules represents a challenging avenue of research that may open up new directions in the treatment of osteoarthritis.

Prostaglandin E Synthase It is well established that PGE 2 plays a crucial role in the pathogenesis of arthritis. Increased levels of PGE 2 have been reported in serum and synovial fluids of patients with rheumatoid arthritis (RA) and osteoarthritis. PGE 2 contributes to the pathogenesis of arthritis by inducing pain and increasing the production of catabolic molecules including pro-inflammatory cytokines, matrix metalloproteases, and reactive oxygen species, which in turn contribute to cartilage, synovial membrane, and bone alterations. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed drugs, with arthritis as the main indication. The clinical efficacy of NSAIDs is related to PGE2 production inhibition through the inhibition of COX-1 and COX-2 activities. However, these drugs, including the recently developed generation of COX-2 selective inhibitors (COXIBs), have shown serious adverse effects. Hence, a selective inhibitor of PGE2 production targeting only PGE2 could be of major significance. In this respect, targeting the terminal enzyme responsible for PGE 2 synthesis may prove to be an interesting approach for osteoarthritis therapeutic development. One such enzyme was recently identified and named prostaglandin E synthase (PGES). The latter catalyzes the conversion of PGH2 to PGE 2. At least three distinct PGES isoforms have been identified; these being the cytosolic PGES (cPGES), which is identical to the heat shock protein 90-associated protein p23, the microsomal PGES-1 (mPGES-1), originally designated microsomal glutathione S-transferase 1-like 1 (MGST1-L1), and the mPGES-2.


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The cPGES is ubiquitously and constitutively expressed, and displays functional coupling with COX-1 [13]. The mPGES-1 is an inducible enzyme that exhibits preferential functional coupling with COX-2 [14]. mPGES-2, as with the cPGES, is ubiquitously expressed in diverse tissues, but its function and regulation still remain to be determined. mPGES-1 is expressed in human cartilage, and its level up-regulated in osteoarthritis [15–17]. In cartilage, this enzyme is located mainly in chondrocytes at the superficial layers. Increased expression of mPGES1 was also reported in synovial tissues from RA patients [18]. In this tissue, the mPGES-1 was produced in synovial lining cells, in scattered mononuclear and fibroblast-like cells in the sublining layer, in mononuclear infiltrates, and in endothelial cells. Although cPGES was found in normal and osteoarthritic cartilage, its production was similar in both tissues. Unstimulated human articular chondrocytes express low or trace amounts of mPGES-1, and its expression was up-regulated by interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-17 [15]. Other cytokines including IL-4, IL-6, IL-8, IL-10, and interferon-γ (IFNγ) have no effect. Combinations of IL-1β, TNF-α, and IL-17 were synergistic upon the induction of mPGES-1 protein production [15], suggesting that the combination of pro-inflammatory cytokines may be of importance in the increased expression of mPGES-1. In chondrocytes, mPGES-1 expression induced by IL-1β involved the mitogen-activated protein (MAP) kinases ERK1/2, and p38β signaling pathways [16]. In synovial fibroblasts mPGES is also up-regulated by the pro-inflammatory cytokines, IL-1β and TNF-α [19,20], an effect that was inhibited by the NSAID indomethacin, and by the selective COX-2 inhibitors NS-398 and rofecoxib. PGE 2 also contributes to the induction of mPGES-1, since it prevents the inhibitory effect of NSAIDs on IL–1β-induced mPGES-1 expression [19]. The induction of mPGES-1 expression is also prevented by dexamethasone and activators of the peroxisome proliferator-activated receptor-γ (PPARγ) [15,20] suggesting that inhibition of mPGES-1 expression may be part of the mechanism by which these molecules exert their antiinflammatory and anti-arthritic effects. Several studies using animal models of arthritis and mPGES-1 deficient mice strongly support the crucial role of mPGES-1 in the induction of PGE2 in arthritis. For instance, the expression of mPGES-1 was significantly up-regulated in the treated paw of a rat model of adjuvantinduced arthritis [18]. In this model, the up-regulation of mPGES-1 expression coincides with increased PGE2 synthesis [21•]. However, the most persuasive evidence derives from studies using mPGES-1 -/- deficient mice in which LPS-induced PGE2 production was almost completely abrogated [22,23]. Importantly, in two animal models of inflammatory arthritis (collagen-induced and collagen antibody-induced arthritis), mPGES -/- mice

exhibited reduced inflammatory responses and histopathologic changes (cartilage and bone erosion) associated with arthritis, did not develop fever, and exhibited reduced pain response [23,24••,25]. Altogether these data suggest that mPGES-1 is responsible for the increased PGE2 production observed in arthritic tissues. Hence, mPGES-1 appears to be an excellent candidate to control PGE 2 synthesis in arthritis, as inhibiting its production/activity will specifically block PGE 2 synthesis without interfering with the synthesis of other COX-derived eicosanoids that may have important physiologic (PGI 2, tromboxane) or anti-inflammatory (PGD2 and its metabolites) functions.

Subchondral Bone The degeneration and erosion of cartilage as a primary pathologic mechanism for osteoarthritis has recently been challenged, and prominent changes in the subchondral bone provide evidence suggesting that this tissue plays a key role in osteoarthritis. It is common knowledge that, in animal models of osteoarthritis, increased bone density, osteoid volume, and an age-dependent higher subchondral bone thickness are often more severe than cartilage changes [26,27]. Moreover, the severity of cartilage fibrillation and loss generally exceeds bone changes only in advanced osteoarthritis in primate animal models. The enhanced uptake of technetium labeled diphosphonate, which is an indicator of increased subchondral bone activity, was reported to predict cartilage loss in osteoarthritis patients [28], while cartilage lesions do not progress in the absence of significant subchondral activity. The scintigraphic evidence of increased bone activity appears to switch on and off in a phasic manner and precede episodes of progression of radiographic changes [28]. These changes are associated with intensified subchondral bone remodeling and increased bone stiffness. A stiffening bone would no longer be an effective shock absorber after healing of trabecular micro-fractures in osteoarthritic subchondral bone. Progressive joint space narrowing correlates positively with bone mineral density (BMD) of the subchondral tibial bone in knee osteoarthritis [29]. However, BMD in osteoarthritis appears to be a result of an increase in material density, not an increase in mineral density. Indeed, osteoarthritic subchondral bone demonstrates an increased osteoid collagen matrix and an abnormal mineralization resulting in a hypomineralization of this tissue [30,31]. A more compliant bone due to inhomogeneities in density or stiffness will deform the articular cartilage. Such a deformation can then stretch the articular cartilage at the edge of the joint contact area, generating tensile and shear stresses. Although the subchondral bone tissue is hypomineralized in osteoarthritis, the increase in trabecular number and volume


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compensates for this situation, thus providing an apparent stiffer structure. Therefore, evidence suggests that the subchondral bone sclerosis in osteoarthritis results from an increased stiffness, and not an actual increase in BMD. Of note, BMD measures may not be sensitive enough to detect changes in trabecular organization as can be detected by fractal analysis at subchondral and subarticular sites [32•]. For all of these reasons BMD may likely not represent the measure of choice for following osteoarthritis progression. In addition to physical cartilage alteration due to subchondral bone changes, data strongly support the hypothesis that subchondral bone cells release factors that influence cartilage metabolism. The nature of these factors is still elusive, although IGF-1, TGF-β, hepatocyte growth factor (HGF), and proteases may all be involved. However, when considering the role of subchondral bone in osteoarthritis progression or initiation, a number of mechanisms might be modified. These include the recruitment of mesenchymal stem cells, the cellular function (or dysfunction) of these cells, abnormal local or humoral regulation, the alteration in blood supply to the tissue, and so on. It also cannot be overlooked that osteoarthritis is linked with aging and obesity, both conditions associated with changes in vascular function, and that these changes are associated with the pathology of the disease [33••]. Recent data [34•] has shown that bone resorption pits in subchondral bone may be an important factor in cartilage destruction through the release of metalloproteases by cells derived from the bone marrow, thereby establishing a clear link between subchondral bone activity and altered metabolism, and cartilage loss. This would prompt the recognition that, not only osteoblasts, but other cells present in bone tissue and bone marrow, may be involved in cartilage destruction. This clearly supports a concept put forth by Aspden et al. [35] that osteoarthritis is a metabolic disease in which systemic and/or local factors induce changes in skeletal tissues by modifying the formation and activity of mesenchymal precursor cells. This hypothesis is also supported by the observation that osteoblast maturation from bone marrow stromal cells in osteoarthritis patients is enhanced, while that of adipocytes and chondrocytes is blunted [36]. It therefore suggests a possible link between abnormal lipid metabolism and connective tissues in osteoarthritis. In this line of thought, leptin acts as an afferent signal to influence energy homeostasis through effects on energy intake and expenditure, and also through high affinity leptin receptors on cells in peripheral tissues. Of interest, within the bone marrow, leptin favors the differentiation of mesenchymal stromal cells into osteoblasts while impeding the maturation of adipocytes [37], a situation that is also observed in osteoarthritis [36]. Leptin is now considered an important player in osteoarthritis. Its level is increased in human osteoarthritic

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cartilage, and its expression/synthesis is also increased in osteoarthritic subchondral osteoblasts compared with normal [38,39]. Moreover, it is noteworthy that leptin injections in rats stimulate the expression of IGF-1 and TGF-β1 [38], two factors found at higher levels in osteoarthritic subchondral bone tissue and osteoblasts than in normal. As TGF-β1 stimulates osteophyte formation, a hallmark feature of osteoarthritis, this could suggest a link between leptin and osteophyte formation. Abnormal leptin levels in osteoarthritis patients could also explain the abnormally high levels of fat and (n-6) fatty acids in osteoarthritic bone tissue [40•]. However, a clear link between circulating leptin levels and osteoarthritis has not been reported, and local leptin levels in the joint may be more important than circulating leptin for osteoarthritis progression. Nonetheless, as factors produced by isolated osteoarthritic osteoblasts influence cartilage, local leptin synthesis would be a more likely explanation. In vitro and in vivo studies will definitely be needed to clarify this situation. Leptin can control the synthesis of endothelin-1 [41–43], trigger nitric oxide production, and p38 MAP kinase [44]. As all of these activities are elevated in osteoarthritis tissues, this would also suggest leptin and its signaling pathways as new potential targets for osteoarthritis treatment, although the local versus the systemic role of leptin would have to be taken into account. The subchondral bone is richly vascularized whereas the hyalin cartilage is not, hence the nutrition of the articular cartilage is in part provided by the vascular bed of the subchondral bone and by the synovial fluid. Therefore, any loss of vascular tone in the subchondral bone could potentially affect the cartilage. In this respect, the observation of early microvascular damage affecting the venous circulation in the bony tissue in osteoarthritis is important to consider. Whether these vascular changes are secondary to bony changes or whether they prompt them, remains an open question. However, a clear association is observed between osteoarthritis and cardiovascular disease risk factors [45–47]. The hypothesis that osteoarthritis may then be viewed as an atheromatous vascular disease has recently been proposed [33••]. Clearly, this hypothesis raises an important question for which we have little experimental evidence, but that should be considered a priority to investigate. Furthermore, abnormal vascular function in osteoarthritis could be linked with elevated leptin levels, since leptin is associated with arterial wall thickness, decreased vessel distensibility, and elevated C reactive protein levels [48•]. Lastly, as the “gene” responsible for osteoarthritis is still sought after and must explain, at least, abnormal bone tissue metabolism, recent genome-wide scans have revealed an osteoarthritis susceptibility locus on chromosome 11q, in close proximity to the low-


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density lipoprotein receptor-related protein 5 (LRP5). This gene product controls bone mass and therefore could explain the abnormal bone tissue mineralization and remodeling observed in osteoarthritis patients. Although no individual polymorphisms were observed in a study of 187 individuals, an altered haplotype (C-G-C-C-A) of LRP5 was observed conferring a 1.6-fold increased risk for osteoarthritis [49•]. This would then suggest that LRP5, and its associated Wnt signaling pathway, could also be key targets to investigate in the pathology of osteoarthritis.

Conclusions Osteoarthritis is the most common disabling condition of humans in the western world. It is not a single disease entity, but represents a disease group with rather different underlying pathophysiologic mechanisms. Osteoarthritis is a disease of a whole organ system, in which structural and metabolic changes in the articular tissues play roles. The concepts discussed herein address the complex pathophysiologic mechanisms involved. Elucidation of the critical pathways in this disease pathogenesis involves discrimination of the different facets of osteoarthritis. To achieve such a screening, the disease should be investigated at its beginning stages. Until now, osteoarthritis studies have focused only on symptomatic patients showing clinical parameters such as pain and joint function disability. At this stage, the structural articular changes have already reached the moderate-to-severe range of the disease. Sensitive and accurate methods for the assessment of osteoarthritis at its onset are crucial requirements in research efforts to find the key players in the initiation and progression of this disease, to differentiate between the subgroups and to assess the therapeutic efficacy of new treatments. To this end, the use of biomarkers is still unsatisfactory. A recently described new application of MRI allows precise visualization of joint structures such as cartilage, bone, synovium, ligaments, and meniscus, and their pathologic changes. In recent years, there has been a series of advances in the use of optimized MRI acquisition sequences to precisely quantify changes in cartilage volume and thickness in individuals, and to discriminate subgroups of patients, those with slow progression and those with fast progression [50,51••]. The new MRI system allows highly reliable quantification of cartilage volume, enabling assessment of the intra-individual variability of cartilage volume. This technology will be critical for analysis of osteoarthritis at the beginning of the disease process and of its progression over time, thus enabling us to discriminate between osteoarthritis subgroups, which could better correlate to specific markers.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance Nakase T, Miyaji T, Tomita T, et al.: Localization of bone morphogenetic protein-2 in human osteoarthritic cartilage and osteophyte. Osteoarthritis Cartilage 2003, 11:278–284. 2. Bau B, Haag J, Schmid E, et al.: Bone morphogenetic proteinmediating receptor-associated Smads as well as common Smad are expressed in human articular chondrocytes but not up-regulated or down-regulated in osteoarthritic cartilage. J Bone Miner Res 2002, 17:2141–2150. 3. Matsuda S, Rouault J, Magaud J, et al.: In search of a function for the TIS21/PC3/BTG1/TOB family. FEBS Lett 2001, 497:67–72. 4. Yoshida Y, Tanaka S, Umemori H, et al.: Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Cell 2000, 103:1085–1097. 5. Yoshida Y, von Bubnoff A, Ikematsu N, et al.: Tob proteins enhance inhibitory Smad-receptor interactions to repress BMP signaling. Mech Dev 2003, 120:629–637. 6. Gebauer M, Saas J, Haag J, et al.: Repression of anti-proliferative factor Tob1 in osteoarthritic cartilage. Arthritis Res Ther 2005, 7:R274–R284. 7.• Tardif G, Hum D, Pelletier JP, et al.: Differential gene expression and regulation of the bone morphogenetic protein antagonists follistatin and gremlin in normal and osteoarthritic human chondrocytes and synovial fibroblasts. Arthritis Rheum 2004, 50:2521–2530. This is the first report on the involvement of bone morphogenetic protein antagonists in osteoarthritis. 8. Tardif G, Pelletier JP, Hum D, et al.: Differential regulation of the BMP antagonist chordin in human normal and osteoarthritic chondrocytes. Ann Rheum Dis 2005, In press. 9. Nakayama N, Han CY, Cam L, et al.: A novel chordinlike BMP inhibitor, CHL2, expressed preferentially in chondrocytes of developing cartilage and osteoarthritic joint cartilage. Development 2004, 131:229–240. 10. Kawabata D, Tanaka M, Fujii T, et al.: Ameliorative effects of follistatin-related protein/TSC-36/FSTL1 on joint inflammation in a mouse model of arthritis. Arthritis Rheum 2004, 50:660–668. 11. Ijiri K, Zerbini LF, Peng H, et al.: A novel role for GADD45beta as a mediator of MMP-13 gene expression during chondrocyte terminal differentiation. J Biol Chem 2005, (online). 12. Fan Z, Tardif G, Boileau C, et al.: Identification in osteoarthritic chondrocytes of proteins binding to the novel regulatory site AGRE in the human MMP-13 proximal promoter [abstract]. Arthritis Rheum 2005, 52:S58. 13. Tanioka T, Nakatani Y, Semmyo N, et al.: Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis. J Biol Chem 2000, 275:32775–32782. 14. Murakami M, Naraba H, Tanioka T, et al.: Regulation of prostaglandin E2 biosynthesis by inducible membraneassociated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2. J Biol Chem 2000, 275:32783–32792. 15. Li X, Afif H, Cheng S, et al.: Expression and regulation of microsomal prostaglandin E synthase-1 in human osteoarthritic cartilage and chondrocytes. J Rheumatol 2005, 32:887–895. 16. Masuko-Hongo K, Berenbaum F, Humbert L, et al.: Upregulation of microsomal prostaglandin E synthase 1 in osteoarthritic human cartilage: critical roles of the ERK-1/2 and p38 signaling pathways. Arthritis Rheum 2004, 50:2829–2838. 1.


New Thoughts on the Pathophysiology of Osteoarthritis Martel-Pelletier et al. Kojima F, Naraba H, Miyamoto S, et al.: Membraneassociated prostaglandin E synthase-1 is upregulated by proinflammatory cytokines in chondrocytes from patients with osteoarthritis. Arthritis Res Ther 2004, 6: R355–R365. 18. Westman M, Korotkova M, af Klint E, et al.: Expression of microsomal prostaglandin E synthase 1 in rheumatoid arthritis synovium. Arthritis Rheum 2004, 50:1774–1780. 19. Kojima F, Naraba H, Sasaki Y, et al.: Prostaglandin E2 is an enhancer of interleukin-1beta-induced expression of membrane-associated prostaglandin E synthase in rheumatoid synovial fibroblasts. Arthritis Rheum 2003, 48:2819–2828. 20. Cheng S, Afif H, Martel-Pelletier J, et al.: Activation of peroxisome proliferator-activated receptor γ inhibits interleukin-1β-induced mPGES-1 expression in human synovial fibroblasts by interfering with Egr-1. J Biol Chem 2004, 279:22057–22065. 21.• Claveau D, Sirinyan M, Guay J, et al.: Microsomal prostaglandin E synthase-1 is a major terminal synthase that is selectively up-regulated during cyclooxygenase-2-dependent prostaglandin E2 production in the rat adjuvant-induced arthritis model. J Immunol 2003, 170:4738–4744. This is an elegant study demonstrating, among others, that increased expression of mPGES-1 correlates with enhanced PGE2 synthesis in a rat model of adjuvant-induced arthritis. 22. Uematsu S, Matsumoto M, Takeda K, et al.: Lipopolysaccharide-dependent prostaglandin E(2) production is regulated by the glutathione-dependent prostaglandin E(2) synthase gene induced by the Toll-like receptor 4/MyD88/NF-IL6 pathway. J Immunol 2002, 168:5811–5816. 23. Trebino CE, Stock JL, Gibbons CP, et al.: Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase. Proc Natl Acad Sci U S A 2003, 100:9044–9049. 24.•• Kamei D, Yamakawa K, Takegoshi Y, et al.: Reduced pain hypersensitivity and inflammation in mice lacking microsomal prostaglandin e synthase-1. J Biol Chem 2004, 279:33684–33695. An important study supporting the role of mPGES-1 in mediating pain and inflammation. Moreover, this study confirms a critical role of mPGES-1 in the pathogenesis of arthritis. 25. Engblom D, Saha S, Engstrom L, et al.: Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis. Nat Neurosci 2003, 6:1137–1138. 26. Carlson CS, Loeser RF, Purser CB, et al.: Osteoarthritis in cynomolgus macaques. III: effects of age, gender, and subchondral bone thickness on the severity of disease. J Bone Miner Res 1996, 11:1209–1217. 27. Huebner JL, Hanes MA, Beekman B, et al.: A comparative analysis of bone and cartilage metabolism in two strains of guinea-pig with varying degrees of naturally occurring osteoarthritis. Osteoarthritis Cartilage 2002, 10:758–767. 28. Dieppe P, Cushnaghan J, Young P, et al.: Prediction of the progression of joint space narrowing in osteoarthritis of the knee by bone scintigraphy. Ann Rheum Dis 1993, 52:557–563. 29. Ferguson VL, Bushby AJ, Boyde A: Nanomechanical properties and mineral concentration in articular calcified cartilage and subchondral bone. J Anat 2003, 203:191–202. 30. Bailey AJ, Sims TJ, Knott L: Phenotypic expression of osteoblast collagen in osteoarthritic bone: production of type I homotrimer. Int J Biochem Cell Biol 2002, 34:176–182. 31. Li B, Aspden RM: Mechanical and material properties of the subchondral bone plate from the femoral head of patients with osteoarthritis or osteoporosis. Ann Rheum Dis 1997, 56:247–254. 32.• Messent EA, Buckland-Wright JC, Blake GM: Fractal analysis of trabecular bone in knee osteoarthritis (OA) is a more sensitive marker of disease status than bone mineral density (BMD). Calcif Tissue Int 2005, 76:419–425. 17.

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Bone mineral density has long been described as elevated in osteoarthritic patients, but we now know that this may be misleading as the tissue is sclerotic yet undermineralized. The proposed approach evaluates the bone tissue quality, which provides much better information on the tissue and its spatial variation than the overall evaluation of BMD. 33.•• Conaghan PG, Vanharanta H, Dieppe PA: Is progressive osteoarthritis an atheromatous vascular disease? Ann Rheum Dis 2005, 64:1539–1541. This is the first comprehensive overview of the hypothesis that osteoarthritis may be a vascular disease. The comments focus on different key data of the literature demonstrating that abnormal vascular functions are observed in osteoarthritic and may be more than circumstantial. 34.• Shibakawa A, Yudoh K, Masuko-Hongo K, et al.: The role of subchondral bone resorption pits in osteoarthritis: MMP production by cells derived from bone marrow. Osteoarthritis Cartilage 2005, 13:679–687. This manuscript offers an explanation of the possible cross-talk between the subchondral bone plate and the articular cartilage. It suggests what could be the biologic information between the two tissues and how it is carried over between them. 35. Aspden RM, Scheven BA, Hutchison JD: Osteoarthritis as a systemic disorder including stromal cell differentiation and lipid metabolism. Lancet 2001, 357:1118–1120. 36. Murphy JM, Dixon K, Beck S, et al.: Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis. Arthritis Rheum 2002, 46:704–713. 37. Thomas T, Gori F, Khosla S, et al.: Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. Endocrinology 1999, 140:1630–1638. 38. Dumond H, Presle N, Terlain B, et al.: Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum 2003, 48:3118–3129. 39. Lajeunesse D, Delalandre A, Fernandes J: Subchondral osteoblasts from osteoarthritic patients show abnormal expression and production of leptin: possible role in cartilage degradation [abstract]. J Bone Miner Res 2004, 19:S149. 40.• Plumb MS, Aspden RM: High levels of fat and (n-6) fatty acids in cancellous bone in osteoarthritis. Lipids Health Dis 2004, 3:12 (online). It was a well-known fact, yet unpublished, that bone marrow and bone tissue of osteoarthritic patients was “fatty.” This study evaluated the amount of lipids in cancellous bone tissue of osteoarthritic patients and shows that it is clearly elevated in (n-6) fatty acids leading to arachidonic acid. This could then explain the elevated amounts of prostaglandins observed in osteoarthritic joint tissues. 41. Barton M, Carmona R, Ortmann J, et al.: Obesity-associated activation of angiotensin and endothelin in the cardiovascular system. Int J Biochem Cell Biol 2003, 35:826–837. 42. Quehenberger P, Exner M, Sunder-Plassmann R, et al.: Leptin induces endothelin-1 in endothelial cells in vitro. Circ Res 2002, 90:711–718. 43. Xu FP, Chen MS, Wang YZ, et al.: Leptin induces hypertrophy via endothelin-1-reactive oxygen species pathway in cultured neonatal rat cardiomyocytes. Circulation 2004, 110:1269–1275. 44. van den Brink GR, O’Toole T, Hardwick JC, et al.: Leptin signaling in human peripheral blood mononuclear cells, activation of p38 and p42/44 mitogen-activated protein (MAP) kinase and p70 S6 kinase. Mol Cell Biol Res Commun 2000, 4:144–150. 45. Kadam UT, Jordan K, Croft PR: Clinical comorbidity in patients with osteoarthritis: a case-control study of general practice consulters in England and Wales. Ann Rheum Dis 2004, 63:408–414. 46. Marks R, Allegrante JP: Comorbid disease profiles of adults with end-stage hip osteoarthritis. Med Sci Monit 2002, 8:CR305–309.


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Singh G, Miller JD, Lee FH, et al.: Prevalence of cardiovascular disease risk factors among US adults with self-reported osteoarthritis: data from the Third National Health and Nutrition Examination Survey. Am J Manag Care 2002, 8:S383–391. 48.• Kougias P, Chai H, Lin PH, et al.: Effects of adipocytederived cytokines on endothelial functions: implication of vascular disease. J Surg Res 2005, 126:121–129. Since osteoarthritis may be considered a vascular disease, this study shows that adipocyte-derived cytokines such as leptin may be involved in this abnormal function. In addition to the potential direct effect of these adipocytes on joint tissues, it offers a new perspective to evaluate or follow osteoarthritis. 49.• Smith AJ, Gidley J, Sandy JR, et al.: Haplotypes of the low-density lipoprotein receptor-related protein 5 (LRP5) gene: are they a risk factor in osteoarthritis? Osteoarthritis Cartilage 2005, 13:608–613. Since we now believe that bone tissue is a key factor in the onset of osteoarthritis, this study illustrates that bone-specific genes are altered in osteoarthritic bone tissue. Hence, the LRP5 gene may be a potential target for future research on the cause of osteoarthritis through the bone hypothesis. The paper also offers other potential key target bone genes involved in the disease.

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Raynauld JP, Kauffmann C, Beaudoin G, et al.: Reliability of a quantification imaging system using magnetic resonance images to measure cartilage thickness and volume in human normal and osteoarthritic knees. Osteoarthritis Cartilage 2003, 11:351–360. 51.•• Raynauld JP, Martel-Pelletier J, Berthiaume MJ, et al.: Quantitative magnetic resonance imaging evaluation of knee osteoarthritis progression over two years and correlation with clinical symptoms and radiologic changes. Arthritis Rheum 2004, 50:476–487. This is the first longitudinal study in a large cohort of knee osteoarthritic patients that provides major insight into the predominant risk factors associated with disease progression. 50.

New Thoughts on the Pathophysiology of Osteoarthritis- One More Step Toward New Therapeutic Targets  

Introduction Corresponding author Johanne Martel-Pelletier, PhD Osteoarthritis Research Unit, University of Montreal Hospital Centre, Notre-...

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