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Osteoarthritis year 2012 in review: biology
Osteoarthritis and Cartilage 20 (2012) 1447e1450
Review
Osteoarthritis year 2012 in review: biology P.M. van der Kraan* Department of Rheumatology, Radboud University, Medical Centre, Geert Grooteplein 28, 6525 Nijmegen, The Netherlands
a r t i c l e i n f o
s u m m a r y
Article history: Received 3 May 2012 Accepted 17 July 2012
This review focuses on recent findings in pathobiology of osteoarthritis (OA). The progress in this field will be illustrated based on three questions; 1. What factors maintain or alter the articular chondrocyte phenotype? 2. What is the role of inflammation in OA? 3. Is there a role for aging-related genes in OA? Recent findings make it more and more obvious that OA is not a single tissue disease, but that development and progression of OA is the resulted of an integrated complex of local and systemic factors that contribute to the pathobiology of this widespread disease. Ó 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Keywords: Inflammation Complement SirT1 Lamin A Obesity miRNA FRZB BMP
Introduction Osteoarthritis (OA) is a common and until now untreatable disease, except by total joint replacement, that leads to loss of joint function. The main characteristic of OA is loss of articular cartilage, but also other joint tissues appear to play an important role in the disease process. The biology of OA is very broad and covers several different tissues and a vast number of molecular players. In this review, addressing findings reported in 7 months before the OARSI meeting in Barcelona, it is impossible to deal with all potential processes and an in depth review of all biological actors is therefore unattainable. The focus of this paper will be on a small number of central questions in the biology of OA that are currently attentiongrabbing, but remain a personal selection. Elucidation of these questions is important for our view on the biology of OA and the development of adequate treatments of this widespread disease. This review will focus on the following questions; 1. What factors maintain or alter the articular chondrocyte phenotype? 2. What is the role of inflammation in OA? 3. Is there a role for aging-related genes in OA? A selection of findings concerning these questions will be discussed.
* Address correspondence and reprint requests to: P.M. van der Kraan, Department of Rheumatology, Radboud University, Medical Centre, Geert Grooteplein 28, 6525 Nijmegen, The Netherlands. Tel: 31-24-3616568; Fax: 31-24-3540403. E-mail address: [email protected].
What factors maintain or alter the articular chondrocyte phenotype? OA is characterized by degradation of articular cartilage. The chondrocytes itself contribute to the degradation of articular chondrocytes, by enzymatic degradation of the extracellular matrix (chondrocytic chondrolysis). These cells, that in healthy cartilage maintain the homeostasis of this tissue, are not able to preserve articular cartilage in OA. Since chondrocytes play a crucial role in articular cartilage homeostasis, the regulation of chondrocyte behavior is a central theme in OA research. Healthy articular cartilage is a stable tissue that functions for decades to keep normal joint movement possible. In contrast, growth plate and osteophytic cartilage are temporary and subject to endochondral ossification. Features of this process are thought to occur in OA cartilage at least in a part of the patients. Gelse et al. compared gene expression in intact human articular cartilage with gene expression in the cartilaginous layer of osteophytes1. As expected, osteophytic chondrocytes showed expression of genes involved in endochondral ossification, such as BMP-8B, sclerostin and Runx2. Also enzymes mediating tissue remodeling, like MMP9 and MMP13, were significantly higher expressed in osteophytic chondrocytes. In contrast, articular chondrocytes showed elevated expression of inhibitors for the BMP- and wnt-signaling pathways. The BMP inhibitor gremlin was the gene with the highest expression in articular chondrocytes compared to osteophytic chondrocytes. The high gremlin expression suggests that blocking BMP
1063-4584/$ e see front matter Ó 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.joca.2012.07.010
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signaling in articular cartilage inhibits chondrocyte terminal differentiation and that loss of this blockage and elevated BMP signaling might release the brake on chondrocyte endochondral ossification and matrix breakdown. Chondrocyte differentiation is regulated by protein encoding genes, but more and more it becomes clear that additional mechanisms and actors are in play. Small non-coding RNAs (microRNAs, miRs) are important regulators of gene expression and cellular differentiation2. In an experiment with ATDC5 cells stimulated to undergo chondrogenic differentiation, miR-455 and miR-140, increased alongside the chondrogenic differentiation. Expression of miRNA-455 was induced by TGF-b1, TGF-b3 and activin and blocked Smad-dependent signaling3. Three direct targets of miR455 appeared to be Smad2, chordin-like 1 and activin receptor 2B. In an earlier study, the same authors showed that miR-140 targets Smad34. Both miR-140 and miR-455 showed increased expression in OA cartilage compared to controls. The authors suggest that terminal differentiation of chondrocytes is regulated by miRNAs and that elevated expression of miR-140 and miR-455 decreases Smad2/3 signaling and that reduced Smad2/3 signaling leads to OA development, as reported earlier5. Not only BMP and TGF-b signaling appears to play a role in regulation of chondrocyte behavior, also the wnt-signaling pathway is considered to be, as also suggested in the study mentioned above, vital in this process. Glycogen synthase kinase3b (GSK3b) blocks the canonical wnt pathway by promoting degradation of b-catenin. When blocking GSK3b activity by intraarticular injection of the potent and specific inhibitor GIN, b-catenin accumulation was observed in the chondrocytes of rat knee joints6,7. Three intra-articular injections with GIN in rat knee joints led to OA-like features in the articular cartilage after 6 weeks. A limitation of this study is the fact that GSK3b is not only involved in canonical wnt signaling but also in other signaling routes, such as the TGF-b signaling route via modulation of Smad degradation8. Autophagy is an important cell survival mechanism that has drawn great attention lately, also for its role chondrocyte in homeostasis. Autophagy is an evolutionary conserved process that leads to the degradation of “unnecessary” cellular components and has been suggested to play a role in OA9. In a study of Sasaki et al., it was shown that autophagy was up regulated in human OA chondrocytes compared to normal chondrocytes10. Moreover, they showed that cellular stress increased expression of autophagy markers in chondrocytes. Induction of autophagy, using rapamycin, inhibited IL-1-induced gene expression changes while inhibition of autophagy, blocking the autophage essential gene ATG5, exacerbated these effects. This shows that autophagy is a protective mechanism for chondrocytes under stress. The above described observations exemplify that regulation of chondrocyte behavior is a complex process. Apparently, cartilage homeostasis is controlled by a myriad of interacting factors. In addition, aging, genetic make-up, local environmental factors, like inflammation and joint loading, affect the chondrocyte. To develop an adequate treatment for OA, the elucidation of a dominant aberrant process that is abnormal in OA should be very helpful, but until now a single biological pathway that leads to OA appears hard to identify. Moreover, most likely different players and pathways will be prevalent in different OA patient groups. What keeps an articular chondrocyte functioning as an articular chondrocytes is a central question in the structural cartilage changes seen in OA. The chondrocytes have to be in good shape to maintain functioning cartilage. However, since cartilage damage on its own does not immediately lead to clinical symptoms and pain, changes in other joint tissues, such as synovial inflammation, are highly relevant for the treatment of OA symptoms. Moreover, pathological alterations in other joint tissues than cartilage will
have their effects on articular cartilage. The synovial joint has to be considered as an organ with communicating tissues that influence each others behavior. What is more, increasingly it becomes clear that also systemic factors influence OA development11. What is the role of inflammation in OA? Although a large part of OA patients show inflammation in their affected joints, the pathological role of inflammation in OA development and progression is not clarified12. In a study in Nature Medicine by Wang et al., it was reported that proteins of the complement system were differently expressed in OA synovial fluid in comparison with healthy synovial fluid13. Complement activation was apparent both during early and late stages of OA and it was found that the synovium contributed to the elevated complement activation in OA. The authors furthermore investigated the role of complement in an OA mouse model that was induced by medial meniscectomy, comparing C5-deficient and wild type mice. The effector C5 is central in the complement cascade14. The C5-deficient mice were protected against OA and showed 16 weeks after surgery less cartilage damage, synovitis and osteophyte formation than controls. In contrast, mice deficient for CD59a, an inhibitor of the complement cascade effector machinery (Membrane Attack Complex, MAC), developed more severe OA and synovitis. Moreover, CD59b deficiency worsened the spontaneous OA both in old mice and in mice with surgically (DMM)-induced OA. Extensive deposition of MAC can lead to cell death while moderate MAC deposition can activate pro-inflammatory signaling pathways. The authors demonstrated that in human OA cartilage MAC co-localized with MMP13. In C5-deficient mice, that were also deficient in MAC, lower expression of inflammatory and degradative mediators was observed. These data point toward a significant role for complement activation in the pathogenesis of OA. Inflammation can be a local process but it has its systemic counterpart. Obesity is considered to be a form of systemic lowgrade inflammation and highly-associated with OA15. A mouse strain that is both obese and shows spontaneous OA development at a young age is the STR/ort strain. Kyostio-Moore et al. found that this mouse strain showed both a local and systemic proinflammatory state compared to the control CBA strain16. Serum analysis showed elevated levels of several inflammatory cytokines, such as IL-1b, and serum cytokine concentrations correlated with joint pathology. Tissue markers of inflammation, AGE and HMBG1, were strongly elevated in cartilage, meniscus, ligaments and hyperplastic synovium. In this obese mouse strain both local and systemic and inflammatory mediators go hand in hand with increased susceptibility for OA and the authors consider this model therefore a clinically relevant OA model. In humans the metabolic syndrome is associated with OA17. Recently Griffin et al. showed that also in mice diet-induced obesity was related to OA development and that OA development went hand in hand with expression of behavioral, biomechanical, and molecular risk factors17,18. In a follow-up study, these authors showed that short-term wheel running protected against obesityinduced OA in fat mice by modulating systemic inflammation19. Obesity induced by a very high-fat diet caused OA and systemic inflammation was proportional to body fat. Short-term running did not result in reduced body weight or body fat but partially elevated glucose clearance. Remarkably, wheel running partly prevented the fat-induced OA in the medial femur. A high-fat diet led to significant increased leptin and adiponectin levels as expected, but also in an increase in KC and MIG and a decrease in the anti-inflammatory cytokine IL-4. Exercise increased IL-10 fifteenfold in the high-fat diet mice. The concentration of KC, leptin and IL-1Ra were positively associated with the
P.M. van der Kraan / Osteoarthritis and Cartilage 20 (2012) 1447e1450
knee OA score. The independent contribution of systemic inflammation to knee OA was not obvious; inflammation was related to increased adiposity and not to knee OA. However, exercise improved glucose clearance and interrupted the co-expression of pro-inflammatory cytokines. Moreover, since the running mice did not loose weight but were partly protected against OA this study indicates that increased joint loading is not the major factor in obesity-induced OA in mice. Another study examined the effect of a high-fat diet on OA development in human CRP-transgenic mice20. Part of the animals on a high-fat diet was treated with a statin (rosuvastatin) or a PPARg inhibitor (rosiglitazone). The switch to a high-fat diet resulted in increased expression of human CRP that was prevented by both drugs. After 42 weeks male mice showed significantly more severe OA than mice on chow but there was no association between body weight and OA. Remarkably, both drug treatments resulted in OA grades comparable to those in control animals. Apparently, high-fat diet-induced OA can be modulated with drugs with antiinflammatory properties in mice. Systemic inflammation appears to be associated with OA development. This appears to be not only the case for OA but also for other age-related diseases such as Alzheimer’s Disease (AD)21. An association between OA and AD in a mouse model has been recently suggested22. Local over expression of human IL-1b in murine knee joints resulted in fibrillation and erosions after 8 weeks. Surprisingly, 2 months after the induction of OA, in the brain of these mice astrocyte and microglia activation was observed. Moreover, a significant up regulation of IL-1b and TNF-a was demonstrated. Both cell activation and cytokine up regulation returned to base line after 6 months. No evidence for IL-1b in the serum of OA mice was found. In a mouse model of AD, APP/PS1 mice, IL-1b-induced OA-like pathology was associated with accelerated and enhanced AD pathology. These and above data indicate that systemic inflammation is a risk factor for both OA and AD, and that peripheral inflammation is associated with AD. Circulating cytokines, triggered by the OA process in the joint, might influence the central nervous system. Since OA is a very prevalent disease in the elderly such a relationship could have a large impact on the overall mental health. In this respect it is interesting to point to the relationship between OA and depression, and the association between depression and circulating cytokines23,24. Fascinatingly, although it is obvious that mouse OA is not a precise copy of human OA, it appears that these complex associations between inflammation, pathology and behavior can be reproduced in a small animal model. Is there a role for aging-related genes in OA? Like depression and AD, development of OA is highly agerelated, and age is the risk factor most strongly correlated to OA25. This strong association has triggered the research in the role of aging in OA for several decades26,27. The protein deacetylase SirT1 has an important role in life span determination and regulates fat and glucose metabolism28. It has been reported that chondrocyte survival is increased by full-length SirT129. A decrease of full-length SirT1 levels in aging mice was recently described by Gabay et al.30. Comparing wild type mice with SirT1 heterozygous mice showed no significant differences in cartilage morphology at an age of 1 month, but loss of aggrecan and increased OA severity were seen in 9 month old heterozygous mice. Moreover, 9 month old heterozygous mice showed a marked increase in chondrocyte apoptosis compared to wild type mice. The authors suggest that a cathepsin B cleavage product of SirT1, 75SirT1, that was only found in 9 month old wild type mice protects chondrocytes against apoptosis. The investigators conclude that loss of full-length SirT1
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Fig. 1. Local and systemic interactions that are involved in OA pathophysiology and symptoms.
inhibits the expression of type II collagen and aggrecan but that the 75SirT1 variant protects chondrocytes against apoptosis. A disease showing accelerated aging is the HutchinsoneGilford progeria syndrome. This syndrome is associated with a mutation that leads to accumulation of a truncated, farnesylated lamin A form. Patients with this mutation show bone and joint abnormalities at a young age31. In OA cartilage, lamin A appears to be up regulated both on mRNA and protein level32. In addition, over expression of lamin A in chondrocytes resulted in a decreased cell proliferation and viability. This was accompanied by increased expression of cellular senescence markers, caspase-3 activation and apoptosis. These findings indicate that alterations in lamin A function are related to chondrocyte senescence and apoptosis. However, although both aging-related molecules show a relationship between alterations in these molecules and chondrocyte apoptosis, the specific contribution of apoptosis to OA development and progression is not settled yet. Concluding remarks This review focuses on a number of biological findings in the field of OA research reported in the last year. These findings illustrate that although articular cartilage is the tissue considered to be mainly affected by OA, and that chondrocytes are the major players in cartilage degradation, other joint tissue as well as systemic metabolic processes determine the development and progression of OA (Fig. 1). This in combination with the genetic background, the structure of the extracellular matrix, effect of joint loading, joint shape and the unpreventable aging process determine the initiation and progression of OA. This view of OA, that has changed form a single tissue disease to a “complex, multisystem disease”, has the major advantage that it has provided several new levels that can be targeted for the treatment of OA patients. That OA can be successfully targeted, at least in animal models, was shown in a study by Johnson et al.33. The small molecule kartogenin that was identified in a high trough-put screen from 22.000 candidates showed significant OA protective effects in two OA animal models. Author contribution PM van der Kraan analyzed and interpreted the reported data and drafted the article.
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Conflict of interest The author has no competing interests. References 1. Gelse K, Ekici AB, Cipa F, Swoboda B, Carl HD, Olk A, et al. Molecular differentiation between osteophytic and articular cartilage e clues for a transient and permanent chondrocyte phenotype. Osteoarthritis Cartilage 2012;20(2):162e71. 2. Huang Y, Shen XJ, Zou Q, Wang SP, Tang SM, Zhang GZ. Biological functions of microRNAs: a review. J Physiol Biochem 2011;67(1):129e39. 3. Swingler TE, Wheeler G, Carmont V, Elliott HR, Barter MJ, buElmagd M, et al. The expression and function of microRNAs in chondrogenesis and osteoarthritis. Arthritis Rheum 2011. 4. Pais H, Nicolas FE, Soond SM, Swingler TE, Clark IM, Chantry A, et al. Analyzing mRNA expression identifies Smad3 as a microRNA-140 target regulated only at protein level. RNA 2010;16(3):489e94. 5. Blaney Davidson EN, Remst DF, Vitters EL, van Beuningen HM, Blom AB, Goumans MJ, et al. Increase in ALK1/ALK5 ratio as a cause for elevated MMP-13 expression in osteoarthritis in humans and mice. J Immunol 2009;182(12):7937e45. 6. Engler TA, Henry JR, Malhotra S, Cunningham B, Furness K, Brozinick J, et al. Substituted 3-imidazo[1,2-a]pyridin-3-yl- 4(1,2,3,4-tetrahydro-[1,4]diazepino-[6,7,1-hi]indol-7-yl) pyrrole-2,5-diones as highly selective and potent inhibitors of glycogen synthase kinase-3. J Med Chem 2004;47(16):3934e7. 7. Miclea RL, Siebelt M, Finos L, Goeman JJ, Lowik CW, Oostdijk W, et al. Inhibition of Gsk3beta in cartilage induces osteoarthritic features through activation of the canonical Wnt signaling pathway. Osteoarthritis Cartilage 2011;19(11):1363e72. 8. Aragon E, Goerner N, Zaromytidou AI, Xi Q, Escobedo A, Massague J, et al. A Smad action turnover switch operated by WW domain readers of a phosphoserine code. Genes Dev 2011;25(12):1275e88. 9. Lotz MK, Carames B. Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA. Nat Rev Rheumatol 2011;7(10):579e87. 10. Sasaki H, Takayama K, Matsushita T, Ishida K, Kubo S, Matsumoto T, et al. Autophagy modulates osteoarthritis-related gene expressions in human chondrocytes. Arthritis Rheum 2011. 11. Bijsterbosch J, van Bemmel JM, Watt I, Meulenbelt I, Rosendaal FR, Huizinga TW, et al. Systemic and local factors are involved in the evolution of erosions in hand osteoarthritis. Ann Rheum Dis 2011;70(2):326e30. 12. Goldring MB, Otero M. Inflammation in osteoarthritis. Curr Opin Rheumatol 2011;23(5):471e8. 13. Wang Q, Rozelle AL, Lepus CM, Scanzello CR, Song JJ, Larsen DM, et al. Identification of a central role for complement in osteoarthritis. Nat Med 2011;17(12):1674e9. 14. Kirschfink M. Controlling the complement system in inflammation. Immunopharmacology 1997;38(1e2):51e62. 15. Rai MF, Sandell LJ. Inflammatory mediators: tracing links between obesity and osteoarthritis. Crit Rev Eukaryot Gene Expr 2011;21(2):131e42. 16. Kyostio-Moore S, Nambiar B, Hutto E, Ewing PJ, Piraino S, Berthelette P, et al. STR/ort mice, a model for spontaneous
17.
18.
19.
20.
21.
22.
23.
24. 25. 26.
27. 28.
29.
30.
31.
32.
33.
osteoarthritis, exhibit elevated levels of both local and systemic inflammatory markers. Comp Med 2011;61(4): 346e55. Velasquez MT, Katz JD. Osteoarthritis: another component of metabolic syndrome? Metab Syndr Relat Disord 2010;8(4): 295e305. Griffin TM, Fermor B, Huebner JL, Kraus VB, Rodriguiz RM, Wetsel WC, et al. Diet-induced obesity differentially regulates behavioral, biomechanical, and molecular risk factors for osteoarthritis in mice. Arthritis Res Ther 2010;12(4):R130. Griffin TM, Huebner JL, Kraus VB, Yan Z, Guilak F. Induction of osteoarthritis and metabolic inflammation by a very high-fat diet in mice: effects of short-term exercise. Arthritis Rheum 2012;64(2):443e53. Gierman LM, van der HF, Koudijs A, Wielinga PY, Kleemann R, Kooistra T, et al. Metabolic stress-induced inflammation plays a major role in the development of osteoarthritis in mice. Arthritis Rheum 2012;64(4):1172e81. Tan ZS, Beiser AS, Vasan RS, Roubenoff R, Dinarello CA, Harris TB, et al. Inflammatory markers and the risk of Alzheimer disease: the Framingham Study. Neurology 2007;68(22):1902e8. Kyrkanides S, Tallents RH, Miller JN, Olschowka ME, Johnson R, Yang M, et al. Osteoarthritis accelerates and exacerbates Alzheimer’s disease pathology in mice. J Neuroinflammation 2011;8:112. Parmelee PA, Harralson TL, McPherron JA, DeCoster J, Schumacher HR. Pain, disability, and depression in osteoarthritis: effects of race and sex. J Aging Health 2012;24(1): 168e87. Krishnadas R, Cavanagh J. Depression: an inflammatory illness? J Neurol Neurosurg Psychiatry 2012. Wu Z, Schimmele CM, Chappell NL. Aging and late-life depression. J Aging Health 2012;24(1):3e28. Silberberg M, Silberberg R. Skeletal growth, aging and osteoarthritis; effects of enriched diets and of ovariectomy. Bull Hosp Joint Dis 1951;12(2):256e72. Loeser RF. Aging and osteoarthritis. Curr Opin Rheumatol 2011;23(5):492e6. Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 2012;13(4): 225e38. Takayama K, Ishida K, Matsushita T, Fujita N, Hayashi S, Sasaki K, et al. SIRT1 regulation of apoptosis of human chondrocytes. Arthritis Rheum 2009;60(9):2731e40. Gabay O, Oppenhiemer H, Meir H, Zaal K, Sanchez C, DvirGinzberg M. Increased apoptotic chondrocytes in articular cartilage from adult heterozygous SirT1 mice. Ann Rheum Dis 2012;71(4):613e6. Merideth MA, Gordon LB, Clauss S, Sachdev V, Smith AC, Perry MB, et al. Phenotype and course of HutchinsoneGilford progeria syndrome. N Engl J Med 2008;358(6):592e604. Attur M, Ben-Artzi A, Yang Q, Al-Mussawir HE, Worman HJ, Palmer G, et al. Perturbation of nuclear lamin A causes cell death in chondrocytes. Arthritis Rheum 2012. Johnson K, Zhu S, Tremblay MS, Payette JN, Wang J, Bouchez LC, et al. A stem cell-based approach to cartilage repair. Science 2012.
Review
Osteoarthritis year 2012 in review: biology P.M. van der Kraan* Department of Rheumatology, Radboud University, Medical Centre, Geert Grooteplein 28, 6525 Nijmegen, The Netherlands
a r t i c l e i n f o
s u m m a r y
Article history: Received 3 May 2012 Accepted 17 July 2012
This review focuses on recent findings in pathobiology of osteoarthritis (OA). The progress in this field will be illustrated based on three questions; 1. What factors maintain or alter the articular chondrocyte phenotype? 2. What is the role of inflammation in OA? 3. Is there a role for aging-related genes in OA? Recent findings make it more and more obvious that OA is not a single tissue disease, but that development and progression of OA is the resulted of an integrated complex of local and systemic factors that contribute to the pathobiology of this widespread disease. Ó 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Keywords: Inflammation Complement SirT1 Lamin A Obesity miRNA FRZB BMP
Introduction Osteoarthritis (OA) is a common and until now untreatable disease, except by total joint replacement, that leads to loss of joint function. The main characteristic of OA is loss of articular cartilage, but also other joint tissues appear to play an important role in the disease process. The biology of OA is very broad and covers several different tissues and a vast number of molecular players. In this review, addressing findings reported in 7 months before the OARSI meeting in Barcelona, it is impossible to deal with all potential processes and an in depth review of all biological actors is therefore unattainable. The focus of this paper will be on a small number of central questions in the biology of OA that are currently attentiongrabbing, but remain a personal selection. Elucidation of these questions is important for our view on the biology of OA and the development of adequate treatments of this widespread disease. This review will focus on the following questions; 1. What factors maintain or alter the articular chondrocyte phenotype? 2. What is the role of inflammation in OA? 3. Is there a role for aging-related genes in OA? A selection of findings concerning these questions will be discussed.
* Address correspondence and reprint requests to: P.M. van der Kraan, Department of Rheumatology, Radboud University, Medical Centre, Geert Grooteplein 28, 6525 Nijmegen, The Netherlands. Tel: 31-24-3616568; Fax: 31-24-3540403. E-mail address: [email protected].
What factors maintain or alter the articular chondrocyte phenotype? OA is characterized by degradation of articular cartilage. The chondrocytes itself contribute to the degradation of articular chondrocytes, by enzymatic degradation of the extracellular matrix (chondrocytic chondrolysis). These cells, that in healthy cartilage maintain the homeostasis of this tissue, are not able to preserve articular cartilage in OA. Since chondrocytes play a crucial role in articular cartilage homeostasis, the regulation of chondrocyte behavior is a central theme in OA research. Healthy articular cartilage is a stable tissue that functions for decades to keep normal joint movement possible. In contrast, growth plate and osteophytic cartilage are temporary and subject to endochondral ossification. Features of this process are thought to occur in OA cartilage at least in a part of the patients. Gelse et al. compared gene expression in intact human articular cartilage with gene expression in the cartilaginous layer of osteophytes1. As expected, osteophytic chondrocytes showed expression of genes involved in endochondral ossification, such as BMP-8B, sclerostin and Runx2. Also enzymes mediating tissue remodeling, like MMP9 and MMP13, were significantly higher expressed in osteophytic chondrocytes. In contrast, articular chondrocytes showed elevated expression of inhibitors for the BMP- and wnt-signaling pathways. The BMP inhibitor gremlin was the gene with the highest expression in articular chondrocytes compared to osteophytic chondrocytes. The high gremlin expression suggests that blocking BMP
1063-4584/$ e see front matter Ó 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.joca.2012.07.010
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signaling in articular cartilage inhibits chondrocyte terminal differentiation and that loss of this blockage and elevated BMP signaling might release the brake on chondrocyte endochondral ossification and matrix breakdown. Chondrocyte differentiation is regulated by protein encoding genes, but more and more it becomes clear that additional mechanisms and actors are in play. Small non-coding RNAs (microRNAs, miRs) are important regulators of gene expression and cellular differentiation2. In an experiment with ATDC5 cells stimulated to undergo chondrogenic differentiation, miR-455 and miR-140, increased alongside the chondrogenic differentiation. Expression of miRNA-455 was induced by TGF-b1, TGF-b3 and activin and blocked Smad-dependent signaling3. Three direct targets of miR455 appeared to be Smad2, chordin-like 1 and activin receptor 2B. In an earlier study, the same authors showed that miR-140 targets Smad34. Both miR-140 and miR-455 showed increased expression in OA cartilage compared to controls. The authors suggest that terminal differentiation of chondrocytes is regulated by miRNAs and that elevated expression of miR-140 and miR-455 decreases Smad2/3 signaling and that reduced Smad2/3 signaling leads to OA development, as reported earlier5. Not only BMP and TGF-b signaling appears to play a role in regulation of chondrocyte behavior, also the wnt-signaling pathway is considered to be, as also suggested in the study mentioned above, vital in this process. Glycogen synthase kinase3b (GSK3b) blocks the canonical wnt pathway by promoting degradation of b-catenin. When blocking GSK3b activity by intraarticular injection of the potent and specific inhibitor GIN, b-catenin accumulation was observed in the chondrocytes of rat knee joints6,7. Three intra-articular injections with GIN in rat knee joints led to OA-like features in the articular cartilage after 6 weeks. A limitation of this study is the fact that GSK3b is not only involved in canonical wnt signaling but also in other signaling routes, such as the TGF-b signaling route via modulation of Smad degradation8. Autophagy is an important cell survival mechanism that has drawn great attention lately, also for its role chondrocyte in homeostasis. Autophagy is an evolutionary conserved process that leads to the degradation of “unnecessary” cellular components and has been suggested to play a role in OA9. In a study of Sasaki et al., it was shown that autophagy was up regulated in human OA chondrocytes compared to normal chondrocytes10. Moreover, they showed that cellular stress increased expression of autophagy markers in chondrocytes. Induction of autophagy, using rapamycin, inhibited IL-1-induced gene expression changes while inhibition of autophagy, blocking the autophage essential gene ATG5, exacerbated these effects. This shows that autophagy is a protective mechanism for chondrocytes under stress. The above described observations exemplify that regulation of chondrocyte behavior is a complex process. Apparently, cartilage homeostasis is controlled by a myriad of interacting factors. In addition, aging, genetic make-up, local environmental factors, like inflammation and joint loading, affect the chondrocyte. To develop an adequate treatment for OA, the elucidation of a dominant aberrant process that is abnormal in OA should be very helpful, but until now a single biological pathway that leads to OA appears hard to identify. Moreover, most likely different players and pathways will be prevalent in different OA patient groups. What keeps an articular chondrocyte functioning as an articular chondrocytes is a central question in the structural cartilage changes seen in OA. The chondrocytes have to be in good shape to maintain functioning cartilage. However, since cartilage damage on its own does not immediately lead to clinical symptoms and pain, changes in other joint tissues, such as synovial inflammation, are highly relevant for the treatment of OA symptoms. Moreover, pathological alterations in other joint tissues than cartilage will
have their effects on articular cartilage. The synovial joint has to be considered as an organ with communicating tissues that influence each others behavior. What is more, increasingly it becomes clear that also systemic factors influence OA development11. What is the role of inflammation in OA? Although a large part of OA patients show inflammation in their affected joints, the pathological role of inflammation in OA development and progression is not clarified12. In a study in Nature Medicine by Wang et al., it was reported that proteins of the complement system were differently expressed in OA synovial fluid in comparison with healthy synovial fluid13. Complement activation was apparent both during early and late stages of OA and it was found that the synovium contributed to the elevated complement activation in OA. The authors furthermore investigated the role of complement in an OA mouse model that was induced by medial meniscectomy, comparing C5-deficient and wild type mice. The effector C5 is central in the complement cascade14. The C5-deficient mice were protected against OA and showed 16 weeks after surgery less cartilage damage, synovitis and osteophyte formation than controls. In contrast, mice deficient for CD59a, an inhibitor of the complement cascade effector machinery (Membrane Attack Complex, MAC), developed more severe OA and synovitis. Moreover, CD59b deficiency worsened the spontaneous OA both in old mice and in mice with surgically (DMM)-induced OA. Extensive deposition of MAC can lead to cell death while moderate MAC deposition can activate pro-inflammatory signaling pathways. The authors demonstrated that in human OA cartilage MAC co-localized with MMP13. In C5-deficient mice, that were also deficient in MAC, lower expression of inflammatory and degradative mediators was observed. These data point toward a significant role for complement activation in the pathogenesis of OA. Inflammation can be a local process but it has its systemic counterpart. Obesity is considered to be a form of systemic lowgrade inflammation and highly-associated with OA15. A mouse strain that is both obese and shows spontaneous OA development at a young age is the STR/ort strain. Kyostio-Moore et al. found that this mouse strain showed both a local and systemic proinflammatory state compared to the control CBA strain16. Serum analysis showed elevated levels of several inflammatory cytokines, such as IL-1b, and serum cytokine concentrations correlated with joint pathology. Tissue markers of inflammation, AGE and HMBG1, were strongly elevated in cartilage, meniscus, ligaments and hyperplastic synovium. In this obese mouse strain both local and systemic and inflammatory mediators go hand in hand with increased susceptibility for OA and the authors consider this model therefore a clinically relevant OA model. In humans the metabolic syndrome is associated with OA17. Recently Griffin et al. showed that also in mice diet-induced obesity was related to OA development and that OA development went hand in hand with expression of behavioral, biomechanical, and molecular risk factors17,18. In a follow-up study, these authors showed that short-term wheel running protected against obesityinduced OA in fat mice by modulating systemic inflammation19. Obesity induced by a very high-fat diet caused OA and systemic inflammation was proportional to body fat. Short-term running did not result in reduced body weight or body fat but partially elevated glucose clearance. Remarkably, wheel running partly prevented the fat-induced OA in the medial femur. A high-fat diet led to significant increased leptin and adiponectin levels as expected, but also in an increase in KC and MIG and a decrease in the anti-inflammatory cytokine IL-4. Exercise increased IL-10 fifteenfold in the high-fat diet mice. The concentration of KC, leptin and IL-1Ra were positively associated with the
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knee OA score. The independent contribution of systemic inflammation to knee OA was not obvious; inflammation was related to increased adiposity and not to knee OA. However, exercise improved glucose clearance and interrupted the co-expression of pro-inflammatory cytokines. Moreover, since the running mice did not loose weight but were partly protected against OA this study indicates that increased joint loading is not the major factor in obesity-induced OA in mice. Another study examined the effect of a high-fat diet on OA development in human CRP-transgenic mice20. Part of the animals on a high-fat diet was treated with a statin (rosuvastatin) or a PPARg inhibitor (rosiglitazone). The switch to a high-fat diet resulted in increased expression of human CRP that was prevented by both drugs. After 42 weeks male mice showed significantly more severe OA than mice on chow but there was no association between body weight and OA. Remarkably, both drug treatments resulted in OA grades comparable to those in control animals. Apparently, high-fat diet-induced OA can be modulated with drugs with antiinflammatory properties in mice. Systemic inflammation appears to be associated with OA development. This appears to be not only the case for OA but also for other age-related diseases such as Alzheimer’s Disease (AD)21. An association between OA and AD in a mouse model has been recently suggested22. Local over expression of human IL-1b in murine knee joints resulted in fibrillation and erosions after 8 weeks. Surprisingly, 2 months after the induction of OA, in the brain of these mice astrocyte and microglia activation was observed. Moreover, a significant up regulation of IL-1b and TNF-a was demonstrated. Both cell activation and cytokine up regulation returned to base line after 6 months. No evidence for IL-1b in the serum of OA mice was found. In a mouse model of AD, APP/PS1 mice, IL-1b-induced OA-like pathology was associated with accelerated and enhanced AD pathology. These and above data indicate that systemic inflammation is a risk factor for both OA and AD, and that peripheral inflammation is associated with AD. Circulating cytokines, triggered by the OA process in the joint, might influence the central nervous system. Since OA is a very prevalent disease in the elderly such a relationship could have a large impact on the overall mental health. In this respect it is interesting to point to the relationship between OA and depression, and the association between depression and circulating cytokines23,24. Fascinatingly, although it is obvious that mouse OA is not a precise copy of human OA, it appears that these complex associations between inflammation, pathology and behavior can be reproduced in a small animal model. Is there a role for aging-related genes in OA? Like depression and AD, development of OA is highly agerelated, and age is the risk factor most strongly correlated to OA25. This strong association has triggered the research in the role of aging in OA for several decades26,27. The protein deacetylase SirT1 has an important role in life span determination and regulates fat and glucose metabolism28. It has been reported that chondrocyte survival is increased by full-length SirT129. A decrease of full-length SirT1 levels in aging mice was recently described by Gabay et al.30. Comparing wild type mice with SirT1 heterozygous mice showed no significant differences in cartilage morphology at an age of 1 month, but loss of aggrecan and increased OA severity were seen in 9 month old heterozygous mice. Moreover, 9 month old heterozygous mice showed a marked increase in chondrocyte apoptosis compared to wild type mice. The authors suggest that a cathepsin B cleavage product of SirT1, 75SirT1, that was only found in 9 month old wild type mice protects chondrocytes against apoptosis. The investigators conclude that loss of full-length SirT1
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Fig. 1. Local and systemic interactions that are involved in OA pathophysiology and symptoms.
inhibits the expression of type II collagen and aggrecan but that the 75SirT1 variant protects chondrocytes against apoptosis. A disease showing accelerated aging is the HutchinsoneGilford progeria syndrome. This syndrome is associated with a mutation that leads to accumulation of a truncated, farnesylated lamin A form. Patients with this mutation show bone and joint abnormalities at a young age31. In OA cartilage, lamin A appears to be up regulated both on mRNA and protein level32. In addition, over expression of lamin A in chondrocytes resulted in a decreased cell proliferation and viability. This was accompanied by increased expression of cellular senescence markers, caspase-3 activation and apoptosis. These findings indicate that alterations in lamin A function are related to chondrocyte senescence and apoptosis. However, although both aging-related molecules show a relationship between alterations in these molecules and chondrocyte apoptosis, the specific contribution of apoptosis to OA development and progression is not settled yet. Concluding remarks This review focuses on a number of biological findings in the field of OA research reported in the last year. These findings illustrate that although articular cartilage is the tissue considered to be mainly affected by OA, and that chondrocytes are the major players in cartilage degradation, other joint tissue as well as systemic metabolic processes determine the development and progression of OA (Fig. 1). This in combination with the genetic background, the structure of the extracellular matrix, effect of joint loading, joint shape and the unpreventable aging process determine the initiation and progression of OA. This view of OA, that has changed form a single tissue disease to a “complex, multisystem disease”, has the major advantage that it has provided several new levels that can be targeted for the treatment of OA patients. That OA can be successfully targeted, at least in animal models, was shown in a study by Johnson et al.33. The small molecule kartogenin that was identified in a high trough-put screen from 22.000 candidates showed significant OA protective effects in two OA animal models. Author contribution PM van der Kraan analyzed and interpreted the reported data and drafted the article.
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Conflict of interest The author has no competing interests. References 1. Gelse K, Ekici AB, Cipa F, Swoboda B, Carl HD, Olk A, et al. Molecular differentiation between osteophytic and articular cartilage e clues for a transient and permanent chondrocyte phenotype. Osteoarthritis Cartilage 2012;20(2):162e71. 2. Huang Y, Shen XJ, Zou Q, Wang SP, Tang SM, Zhang GZ. Biological functions of microRNAs: a review. J Physiol Biochem 2011;67(1):129e39. 3. Swingler TE, Wheeler G, Carmont V, Elliott HR, Barter MJ, buElmagd M, et al. The expression and function of microRNAs in chondrogenesis and osteoarthritis. Arthritis Rheum 2011. 4. Pais H, Nicolas FE, Soond SM, Swingler TE, Clark IM, Chantry A, et al. Analyzing mRNA expression identifies Smad3 as a microRNA-140 target regulated only at protein level. RNA 2010;16(3):489e94. 5. Blaney Davidson EN, Remst DF, Vitters EL, van Beuningen HM, Blom AB, Goumans MJ, et al. Increase in ALK1/ALK5 ratio as a cause for elevated MMP-13 expression in osteoarthritis in humans and mice. J Immunol 2009;182(12):7937e45. 6. Engler TA, Henry JR, Malhotra S, Cunningham B, Furness K, Brozinick J, et al. Substituted 3-imidazo[1,2-a]pyridin-3-yl- 4(1,2,3,4-tetrahydro-[1,4]diazepino-[6,7,1-hi]indol-7-yl) pyrrole-2,5-diones as highly selective and potent inhibitors of glycogen synthase kinase-3. J Med Chem 2004;47(16):3934e7. 7. Miclea RL, Siebelt M, Finos L, Goeman JJ, Lowik CW, Oostdijk W, et al. Inhibition of Gsk3beta in cartilage induces osteoarthritic features through activation of the canonical Wnt signaling pathway. Osteoarthritis Cartilage 2011;19(11):1363e72. 8. Aragon E, Goerner N, Zaromytidou AI, Xi Q, Escobedo A, Massague J, et al. A Smad action turnover switch operated by WW domain readers of a phosphoserine code. Genes Dev 2011;25(12):1275e88. 9. Lotz MK, Carames B. Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA. Nat Rev Rheumatol 2011;7(10):579e87. 10. Sasaki H, Takayama K, Matsushita T, Ishida K, Kubo S, Matsumoto T, et al. Autophagy modulates osteoarthritis-related gene expressions in human chondrocytes. Arthritis Rheum 2011. 11. Bijsterbosch J, van Bemmel JM, Watt I, Meulenbelt I, Rosendaal FR, Huizinga TW, et al. Systemic and local factors are involved in the evolution of erosions in hand osteoarthritis. Ann Rheum Dis 2011;70(2):326e30. 12. Goldring MB, Otero M. Inflammation in osteoarthritis. Curr Opin Rheumatol 2011;23(5):471e8. 13. Wang Q, Rozelle AL, Lepus CM, Scanzello CR, Song JJ, Larsen DM, et al. Identification of a central role for complement in osteoarthritis. Nat Med 2011;17(12):1674e9. 14. Kirschfink M. Controlling the complement system in inflammation. Immunopharmacology 1997;38(1e2):51e62. 15. Rai MF, Sandell LJ. Inflammatory mediators: tracing links between obesity and osteoarthritis. Crit Rev Eukaryot Gene Expr 2011;21(2):131e42. 16. Kyostio-Moore S, Nambiar B, Hutto E, Ewing PJ, Piraino S, Berthelette P, et al. STR/ort mice, a model for spontaneous
17.
18.
19.
20.
21.
22.
23.
24. 25. 26.
27. 28.
29.
30.
31.
32.
33.
osteoarthritis, exhibit elevated levels of both local and systemic inflammatory markers. Comp Med 2011;61(4): 346e55. Velasquez MT, Katz JD. Osteoarthritis: another component of metabolic syndrome? Metab Syndr Relat Disord 2010;8(4): 295e305. Griffin TM, Fermor B, Huebner JL, Kraus VB, Rodriguiz RM, Wetsel WC, et al. Diet-induced obesity differentially regulates behavioral, biomechanical, and molecular risk factors for osteoarthritis in mice. Arthritis Res Ther 2010;12(4):R130. Griffin TM, Huebner JL, Kraus VB, Yan Z, Guilak F. Induction of osteoarthritis and metabolic inflammation by a very high-fat diet in mice: effects of short-term exercise. Arthritis Rheum 2012;64(2):443e53. Gierman LM, van der HF, Koudijs A, Wielinga PY, Kleemann R, Kooistra T, et al. Metabolic stress-induced inflammation plays a major role in the development of osteoarthritis in mice. Arthritis Rheum 2012;64(4):1172e81. Tan ZS, Beiser AS, Vasan RS, Roubenoff R, Dinarello CA, Harris TB, et al. Inflammatory markers and the risk of Alzheimer disease: the Framingham Study. Neurology 2007;68(22):1902e8. Kyrkanides S, Tallents RH, Miller JN, Olschowka ME, Johnson R, Yang M, et al. Osteoarthritis accelerates and exacerbates Alzheimer’s disease pathology in mice. J Neuroinflammation 2011;8:112. Parmelee PA, Harralson TL, McPherron JA, DeCoster J, Schumacher HR. Pain, disability, and depression in osteoarthritis: effects of race and sex. J Aging Health 2012;24(1): 168e87. Krishnadas R, Cavanagh J. Depression: an inflammatory illness? J Neurol Neurosurg Psychiatry 2012. Wu Z, Schimmele CM, Chappell NL. Aging and late-life depression. J Aging Health 2012;24(1):3e28. Silberberg M, Silberberg R. Skeletal growth, aging and osteoarthritis; effects of enriched diets and of ovariectomy. Bull Hosp Joint Dis 1951;12(2):256e72. Loeser RF. Aging and osteoarthritis. Curr Opin Rheumatol 2011;23(5):492e6. Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 2012;13(4): 225e38. Takayama K, Ishida K, Matsushita T, Fujita N, Hayashi S, Sasaki K, et al. SIRT1 regulation of apoptosis of human chondrocytes. Arthritis Rheum 2009;60(9):2731e40. Gabay O, Oppenhiemer H, Meir H, Zaal K, Sanchez C, DvirGinzberg M. Increased apoptotic chondrocytes in articular cartilage from adult heterozygous SirT1 mice. Ann Rheum Dis 2012;71(4):613e6. Merideth MA, Gordon LB, Clauss S, Sachdev V, Smith AC, Perry MB, et al. Phenotype and course of HutchinsoneGilford progeria syndrome. N Engl J Med 2008;358(6):592e604. Attur M, Ben-Artzi A, Yang Q, Al-Mussawir HE, Worman HJ, Palmer G, et al. Perturbation of nuclear lamin A causes cell death in chondrocytes. Arthritis Rheum 2012. Johnson K, Zhu S, Tremblay MS, Payette JN, Wang J, Bouchez LC, et al. A stem cell-based approach to cartilage repair. Science 2012.