Insights on biology and pathology of HIF-1α/-2α TGFβ/BMP, Wnt/β-catenin, and NF-κB pathways in osteoarthritis

Current Pharmaceutical Design

Volumn 18, Issue 22, 2012, Pages 3293-3312

  Wu, Longhuo ^a,b   Huang, Xianhua ^a   Li, Linfu ^a   Huang, Hao ^a,c   Xu, Ruian ^b   Luyten, Walter ^c  

^a GANNAN MEDICAL UNIVERSITY   (China)

^b HUAQIAO UNIVERSITY   (China)

^c UNIVERSITY OF LEUVEN   (Belgium)

Author keywords

HIF; NF B; Osteoarthritis; TGF ; Wnt catenin

Indexed keywords

ACTIVIN RECEPTOR LIKE KINASE 1; ADVANCED GLYCATION END PRODUCT; AGGRECANASE 2; BETA CATENIN; BONE MORPHOGENETIC PROTEIN; CARTILAGE OLIGOMERIC MATRIX PROTEIN; COLLAGEN; COLLAGEN TYPE 1; COLLAGEN TYPE 2; COLLAGENASE 3; CYCLIC AMP DEPENDENT PROTEIN KINASE; ENDOGLIN; HYPOXIA INDUCIBLE FACTOR 1ALPHA; HYPOXIA INDUCIBLE FACTOR 2ALPHA; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INDUCIBLE NITRIC OXIDE SYNTHASE; INTERLEUKIN 6; OSTEOGENIC PROTEIN 1; PHOSPHATIDYLINOSITOL 3 KINASE; PROSTAGLANDIN E2; SMAD3 PROTEIN; STROMELYSIN; THROMBOSPONDIN; TRANSCRIPTION FACTOR RUNX2; TRANSCRIPTION FACTOR SOX9; TRANSFORMING GROWTH FACTOR BETA; TRANSFORMING GROWTH FACTOR BETA RECEPTOR 1; VASCULOTROPIN A; WNT PROTEIN;

APOPTOSIS; AUTOPHAGY; CARTILAGE CELL; CARTILAGE DEGENERATION; CELL DEDIFFERENTIATION; CELL DIFFERENTIATION; CELL HYPOXIA; CELL MATURATION; CELL PROLIFERATION; CELL SURVIVAL; CHONDROGENESIS; CYTOKINE PRODUCTION; DISEASE SEVERITY; FLUID FLOW; GAIN OF FUNCTION MUTATION; HOMEOSTASIS; HUMAN; HYDROSTATIC PRESSURE; HYDROXYLATION; INNATE IMMUNITY; LOSS OF FUNCTION MUTATION; NONHUMAN; OSTEOARTHRITIS; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PROCESSING; REVIEW; SIGNAL TRANSDUCTION; TENSILE STRENGTH; VASCULARIZATION;

EID: 84862545919     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/1381612811209023293     Document Type: Review

References (196)

1. Luyten FP, Tylzanowski P, Lories RJ. Wnt signaling and osteoarthritis. Bone 2009; 44: 522-7.
2. Kawaguchi H. Regulation of osteoarthritis development by wnt-β- catenin signaling through the endochondral ossification process. J Bone Miner Res 2009; 24: 8-10.
3. Dai J, Ikegawa S. Recent advances in association studies of osteoarthritis susceptibility genes. J Hum Genet 2010; 2010; 55: 77-80.
4. Schett G, Zwerina J, David JP. The role of wnt proteins in arthritis. Nat Clin Pract Rheum 2008; 4: 473-80.
5. Bertrand J, Cromme C, Umlauf D, Frank S, Pap T. Molecular mechanisms of cartilage remodeling in osteoarthritis. Int J Biochem Cell B 2010; 2010; 42: 1594-601.
6. Alcaraz MJ, Megias J, Garcia-Arnandis I, Clerigues V, Guillen MI. New molecular targets for the treatment of osteoarthritis. Biochem Pharmacol 2010; 2010; 80: 13-21.
7. Goldring MB, Marcu KB. Cartilage homeostasis in health and rheumatic diseases. Arthritis Res Ther 2009; 11: 224-39.
8. Clevers H. Wnt/β-catenin signaling in development and disease. Cell 2006; 127: 469-80.
9. Luyten FP, Tylzanowski P, Lories RJ. Wnt signaling and osteoarthritis. Bone 2009; 44: 522-7.
10. Blom AB, van Lent PL, van der Kraan PM, van den Berg WB. To seek shelter from the wnt in osteoarthritis? Wnt-signaling as a target for osteoarthritis therapy. Curr Drug Targets 2010; 2010; 11: 620-9.
11. Saito T, Kawaguchi H. HIF-2α as a possible therapeutic target of osteoarthritis. Osteoarthr Cartilage 2010; 2010; 18: 1552-6.
12. Choi H, Chun Y-S, Kim TY, Park J-W. HIF-2α enhances β- catenin/TCF-driven transcription by interacting with β-catenin. Cancer Res 2011, 14: 10101-11.
13. Rankin EB, Giaccia AJ, Schipani E. A central role for hypoxic signaling in cartilage, bone, and hematopoiesis. Curr Osteoporos Rep 2011, 9: 46-52.
14. van der Krann PM, Goumans MJ, Blaney Davidson EN, ten Dijke P. Age-dependent alteration of TGFβ signaling in osteoarthritis. Cell Tissue Res 2011, DOI: 10.1007/s00441-011-1194-6.
15. Plaas A, Velasco J, Gorski DJ, et al. The relationship between fibrogenic TGFβ1 signaling in the joint and cartilage degradation in post-injury osteoarthritis. Osteoarthr Cartilage 2011, 19: 1081-90.
16. van der Krann PM, Blaney Davidson EN, van den Berg WB. A role for age-related changes in TGFβ signaling in aberrant chondrocyte differentiation and osteoarthritis. Arthritis Res Ther 2010; 2010; 12: 201.
17. Marcu KB, Otero M, Olivotto E, Borzi RM, Goldring MB. NF-κB signaling: multiple angles to target OA. Curr Drug Targets 2010; 11: 599-613.
18. Blom AB, van der Kraan PM, van den Berg WB. Cytokine targeting in osteoarthritis. Curr Drug Target 2007; 8: 283-92.
19. Golding MB, Otero M, Plumb DA, et al. Roles of inflammatory and anabolic cytokines in cartilage metabolism: signals and multiple effectors converge upon MMP-13 regulation in osteoarthritis. Eur Cell Mater 2011, 21: 202-20.
20. Beier F, Loeser RF. Biology and pathology of Rho GTPase, PI-3 Kinase-Akt, and MAP Kinase signaling pathways in chondrocytes. J Cell Biochem 2010; 110: 573-80.
21. Semenza GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 2000; 88: 1474-80.
22. Saito T, Fukai A, Mabuchi A, et al. Transcriptional regulation of endochondral ossification by HIF-2α during skeletal growth and osteoarthritis development. Nature Medicine 2010; 16: 678-89.
23. Gales K, Dfander D, Obier S, et al. Role of hypoxia-inducible factor 1 alpha in the integrity of articular cartilage in murine knee joints. Arthritis Res Ther 2008; 10: R111.
24. Bohensky J, Terkhorn SP, Freeman T, et al. Regualtion of autophagy in cartilage: HIF-2 suppresses chondrocyte autophagy. Arthritis Rheum 2009; 60: 1406-15.
25. Schipani E, Ryan HE, Didrickson S, Kobayashi T, Knight M, Johnson RS. Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival. Gene Dev 2001; 15: 2865-76.
26. Schipani E. Posttranslational modifications of collagens as targets of hypoxa and Hif-1α in endochondral bone development. Ann N Y Acad Sci 2010; 1192: 317-21.
27. Duval E, Leclercq S, Elissalde J-M, Demoor M, Galera P, Boumediene K. Hypoxia- inducible factor 1α inhibits the fibroblast-like markers type I and type III collagen during hypoxia-induced chondrocyte redifferentiation. Arthritis Rheum 2009; 60: 3038-48.
28. Zhang C, Yang F, Cornelia R, Tang W, Swisher S, Kim H. Hypoxia- inducible factor-1 is a positive regulator of Sox9 activity in femoral head osteonecrosis. Bone 2011, 48: 507-13.
29. Lafont JE, Talma S, Hopfgarten C, Murphy CL. Hypoxia promotes the differentiated human articular chondrocyte phenotype through SOX9-dependent and -independent pathways. J Biol Chem 2008; 283: 4778-86.
30. Zelzer E, Mamluk R, Ferrara N, Johnson RS, Schipani E, Olsen BR. VEGFA is necessary for chondrocyte survival during bone development. Development 2004; 131: 2161-71.
31. Araldi E, Schipani E, Hypoxia, HIFs and bone development. Bone 2010; 47: 190-6.
32. Genetos DC, Wong A, Watari S, Yellowley CE. Hypoxia increases Annexin A2 expression in osteoblastic cells via VEGF and ERK. Bone 2010; 47, 1013-9.
33. Schipani E, Ryan HE, Didrickson S, Kobayashi T, Knight M, Johnson RS. Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival. Genes Dev 2001; 15: 2865-76.
34. Nishida T, Kondo S, Maeda A, Kubota S, Lyons KM, Takigawa M. CCN family 2/connective tissue growth factor (CCN2/CTGF) regulates the expression of Vegf through Hif-1α expression in a condrocytic cell line, HCS-2/8, under hypoxic condition. Bone 2009; 44: 24-31.
35. Takeda N, O'Dea EL, Doedens A, et al. Differential activation and antagonistic function of HIF-α isoforms in macrophages are essential for NO homeostasis. Genes Dev 2010; 24: 491-501.
36. Imtiyaz HZ, Williams EP, Hickey MM, et al. Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation. J Chin Invest 2010; 120: 2699-714.
37. van Uden P, Kenneth, NS, Webster R, Muller HA, Mudie S, Rocha S. Evolutionary conserved regulation of HIF-1b by NF-kB. PLoS Genet 2011, 7: e1001285.
38. Kaidi A, Williams AC, Parsakeva C. Interaction between betacatenin and HIF-1 promotes cellular adaptation to hypoxia. Nat Cell Biol 2007; 9: 210-7.
39. Choi H, Chun Y-S, Kim T-Y, Park J-W. HIF-2α enhances β- catenin/TCF-driven transcription by interacting with β-catenin. Cancer Res 2010; 70: 10101-11.
40. Srinivas V, Bohensky J, Shapiro IM. Autophagy: a new phase in the maturation of growth plate chondrocytes is regulated by HIF, mTOR and AMP kinase. Cells Tissue Organs 2009; 189: 88-92.
41. Bohensky J, Leshinsky S, Srinivas V, Shapiro IM. Chondrocyte autophagy is stimulated by HIF-1 dependent AMPK activation and mTOR suppression. Pediatr Nephrol 2010; 25: 633-42.
42. Watanabe H, Bohensky J, Freeman T, Srinivas V, Shapiro IM. Hypoxic induction of UCP3 in the growth plate: UCP3 suppresses chondrocyte autophagy. J Cell Physiol 2008; 216: 419-25.
43. Ryu J-H, Shin Y, Huh YH, Yang S, Chun C-H, Chun JS. Hypoxiainducible factor-2α regulates Fas-mediated chondrocyte apoptosis during osteoarthritic cartilage destruction. Cell Death Differ 2011, doi: 10. 1038.
44. Peansukmanee S, Vaughan-Thomas A, Carter SD, et al. Effects of hypoxia on glucose transport in primary equine chondrocytes in vitro and evidence of reduced GLUT1 gene expression in pathologic cartilage in vivo. J Orthop Res 2009; 27: 529-35.
45. Idelevich A, Rais Y, Monsonego-Ornan E. Bone Gla Protein increases HIF-1α-dependent glucose metabolism and induces cartilage and vascular calcification. Arterioscler Thromb Vasc Biol 2011, 31: e55-e71.
46. Gogate SS, Nasser R, Shapiro IM, Risbud MV. Hypoxic regulation of β-1,3-Glucuronyltranserase 1 expression in nucleus pulposus cells of the rat intervertebral disc. Role of hypoxia-inducible factor proteins. Arthritis Rheum 2011, 63: 1950-60.
47. Zhu G, Tang Y, Liang X, et al. Role of hypoxia- inducible factor-1 alpha in the regulation of plasminogen activator activity in rat knee joint chondrocytes. Osteoarthr Cartilage 2009; 17: 1494-502.
48. Tchetina EV. Developmental mechanisms in articular cartilage degradation in osteoarthritis. Arthritis 2011, 2011: 683970.
49. Drissi H, Zuscik M, Rosier R, O'Keefe R. Transcriptional regulation of chondrocyte maturation: potential involvement of transcription factors in OA pathogenesis. Mol Aspects Med 2005; 26(3): 169-79.
50. Gerald N. Smith, Jr. The role of collagenolytic matrix metalloproteinases in the loss of articular cartilage in osteoarthritis. Front Biosci 2006; 11: 3081-95.
51. Ortega N, Behonick DJ, Werb Z. Matrix remodeling during endochondral ossification. Trends Cell Biol 2004; 14: 86-93.
52. Yang S, Kim J, Ryu JH, et al. Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction. Nat Med 2010; 16: 687-93.
53. Ryu JH, Yang S, Shin Y, Rhee J, Chun CH, Chun JS. Interleukin 6 plays an essential role in hypoxia-inducible factor-2α-induced experimental osteoarthritic cartilage destruction in mice. Arthritis Rheum 2011, doi: 10. 1002.
54. Blaney Davidson EN, Remst DF, Vitters EL, 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: 7937-45.
55. Hellingman CA, Davidson EN, Koevoet W, et al. Smad signaling determines chondrogenic differentiation of bone-marrow-derived mesenchymal stem cells: inhibition of Smad1/5/8P prevents terminal differentiation and calcification. Tissue Eng Part A 2011, 17: 1157-67.
56. Pogue R, Lyons K. BMP signaling in the cartilage growth plate. Curr Top Dev Biol 2006; 76: 1-48.
57. Horiki M, Imamura T, Okamoto M, et al. Smad6/Smurf1 overexpression in cartilage delays chondrocyte hypertrophy and causes dwarfism with osteopenia. J Cell Biol, 2004; 165: 433-45.
58. Wu Q, Wang M, Zuscik MJ, Chen D, O'Keefe RJ, Rosier RN. Regulation of embryonic endochondral ossification by Smurf2. J Orthop Res 2008; 26: 704-12.
59. Ding M, Abbassi S, Li F, et al. Targeting Runx2 expression in hypertrophhic chondrocytes impairs endochondral ossification during early skeletal development. J Cell Physiol 2011, doi: 10.1002/jcp.24045.
60. Javed A, Bae J, Afzal F, et al. Structural coupling of Smad and Runx2 for execution of the BMP2 osteogenic signal. J Biol Chem 2008; 283: 8412-22.
61. Javed A, Afzal F, Bae JS, et al. Specific residues of RUNX2 are obligatory for formation of BMP2-induced RUNX2-SMAD complex to promote osteoblast differentiation. Cells Tissues Organs 2009; 189: 133-7.
62. Goumans MJ, Valdimarsdottir G, Itoh S, et al. Activin receptorlike kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling. Mol Cell 2003; 12(4): 817-28.
63. Frazier K, Thomas R, Scicchitano M, et al. Inhibition of ALK5 signaling induces physeal dysplasia in rats. Toxicol Pathol 2007; 35: 284-495.
64. Miyaki S, Nakasa T, Otsuki S, et al. MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin- 1 responses. Arthritis Rheum 2009; 60: 2723-30.
65. Miyaki S, Sato T, Inoue A, et al. MicroRNA-140 plays dual roles in both cartilage development and homeostasis. Genes Dev 2010; 24: 1173-85.
66. Pais H, Nicolas FE, Soond SM, Swingler TE, et al. Analyzing mRNA expression identifies Smad3 as a microRNA-140 target regulated only at protein level. RNA 2010; 16: 489-94.
67. Li J, Anemaet W, Diaz MA, et al. Knockout of ADAMTS5 does not eliminate cartilage aggrecanase activity but abrogates joint fibrosis and promotes cartilage aggrecan deposition in murine osteoarthritis models. J Orthop Res 2011, 29, 516-22.
68. Velasco J, Li J, Dipietro L, Stepp MA, Sandy JD, Plaas A. Admats5 deletion blocks murine dermal repair through CD44- mediated aggrecan accumulation and modulation of transforming growth factorβ1 (TGFβ1) signaling. J Biol Chem 2011, 286: 26016-27.
69. Surridge AK, Rodgers UR, Swingler TE, et al. Characterization and regulation of ADAMTS-16. Matrix Biol 2009; 28: 416-24.
70. Ionescu AM, Schwarz EM, Zuscik MJ, et al. ATF-2 cooperates with Smad3 to mediate TGFβ effects on chondrocyte maturation. Exp Cell Res 2003; 288: 198-207.
71. Li T-F, Gao L, Sheu T-J, et al. Aberrant hypertrophy in Smad3- deficient murine chondrocytes is rescued by restoring transforming growth factor β-activated kinase1/activating transcription factor 2 signaling. Arthritis Rheum 2010; 62: 2359-69.
72. Finnson KW, Parker WL, ten Dijke P, Thorikay M, Philip A. ALK1 opposes ALK5/Smad3 signaling and expression of extracellular matrix components in human chondrocytes. J Bone Miner Res 2008; 23: 896-906.
73. Finnson KW, Parker WL, Chi Y, et al. Endoglin differentially regulates TGFβ-induced Smad2/3 and Smad1/5 signaling and its expression correlates with extracellular matrix production and cellular differentiation state in human chondrocytes. Osteoarthr Cartilage 2010; 18: 1518-27.
74. Kou I, Nakajima M, Ikegawa S. Binding characteristics of the osteoarthritis-associated protein asporin. J Bone Miner Metab 2010; 28: 395-402.
75. Sakao K, Takahashi KA, Arai Y, et al. Asporin and transforming growth factor β gene expression in osteoblast from subchondral bone and osteophytes in osteoarthritis. J Orthop Sci 2009; 14: 738-47.
76. Polein P-E, Etienne S, Velot E, Netter P, Bianchi A. Activation of PPARs α, β/β, and γ impairs TGF-β1-induced collagens' production and modulates the TIMP-1/MMPs balance in three dimensional cultured chondroctes. PPAR Res 2010; 2010: 635912.
77. Li H, Haudenschild DR, Posey KL, Hecht JT, Di Cesare PE, Yik JHN. Comparative analysis with collagen type II distinguishes cartilage oligomeric matrix protein as a primay TGFβ responsive gene. Osteoarthr Cartilage 2011, 19(10): 1246-53.
78. Haudenschild DR, Hong E, Yik JHN, et al. Enhanced activity of transformaing growth factor β1 (TGF-β1) bound to cartilage oligomeric matrix protein. J Biol Chem 2011, 286(50): 43250-8.
79. Motaung SCKM, Di Cesare PE, Reddi AH. Differential response of cartilage oligomeri matrix protein (COMP) to morphaogens of bone morphogenetic protein/transforming growth factor β family in the surface, middle and deep zones of articular cartilage. J Tissue Eng Med 2011, 5: e87-96.
80. Liu C, Zhang Y, Xu K, Parsons D, Alfonso D, Di Cesare PE. Transcriptional activation of cartilage oligomeric matrix protein by Sox9, Sox5, and Sox6 transcription factors and CBP/p300 coactivators. Front Biosci 2007; 12: 3899-910.
81. Zhou S, Eid K, Glowacki J. Cooperation between TGF-b and Wnt pathways during chondrocyte and adipocyte differentiation of human marrow stromal cells. J Bone Min Res 2004; 19: 463-70.
82. Zhou, S. TGF-β regulates β-catenin signaling and osteoblast differentiation in human mesenchymal stem cells. J Cell Biochem 2011, 112: 1651-60.
83. Jian H, Shen X, Liu I, Semenov M, He X, Wang XF. Smad3- dependent nuclear translocation of β-catenin is required for TGF-β β1-induced proliferation of bone marrow-derived adult human mesenchymal stem cells. Genes Dev 2006; 20: 666-74.
84. [Zhang M, Wang M, Tan X, Li TF, Zhang YE, Chen D. Smad3 prevents β-catenin degradation and facilitates b-catenin nuclear translocation in chondrocytes. J Biol Chem 2010; 285: 8703-10.
85. Jinnin M, Ihn H, Tamaki K. Characterization of SIS3, a novel specific inhibitor of Smad3, and its effect on transforming growth factor-b1-induced extracellular matrix expression. Mol Pharmacol 2006; 69: 597-607.
86. Liu Z, Tang Y, Qiu T, Cao X, Clemens TL. A disheveled-1/Smad1 interaction couples Wnt and bone morphogenetic protein signaling pathways in uncommitted bone marrow stromal cells. J Biol Chem 2006; 281: 17156-63.
87. Pujol J-P, Chadjichritstos C, Legendre F, et al. Interleukin-1 and transforming growth factor-β1 as crucial factors in osteoarthritic cartilage metabolism. Connet Tissue Res 2008; 49: 293-7.
88. Ghayor C, Chadjichristos C, Herrouin J-F, et al. Sp3 represses the Sp1-mediated transcription of the human COL2A1 gene in primary and dedifferentiated chondrocytes. J Biol Chem 2001; 276: 36881-95.
89. Bauge C, Attia J, Leclercq S, Pujo J-P, Galera P, Boumediene K. Interleukin-1β up-reuglation of Smad7 via NF-κB activation in human chondrocytes. Arthritis Rheum 2008; 58: 221-6.
90. Bauge C, Beauchef G, Leclercq S, et al. NF-κB mediates IL-1β- induced down-regulation of TβRII through the modulation of Sp3 expression. J Cell Mol Med 2008; 12: 1754-66.
91. Bauge C, Cauvard O, Leclercq S, Galera P, Boumediene K. Modulation of transforming growth factor beta signaling pathway genes by transforming growth factor beta in human osteoarthritic chondrocytes: involvement of Sp1 in both early and late response cells to transforming growth factor beta. Arthritis Res Ther 2011, 13: R23.
92. Morimoto-Tomita M, Uchimura K, Werb Z, Hemmerich S, Rosen SD. Cloning and characterization of two extracellular heparindegrading endosulfatases in mice and humans. J Biol Chem 2002; 277: 49175-85.
93. Otsuki S, Hanson SR, Miyaki S, et al. Extracellular sulfatases support cartilage homeostasis by regulating BMP and FGF signaling pathways. Pro Natl Acad Sci USA 2010; 107: 10202-7.
94. Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptor. Cytokine Growth Factor Rev 2005; 16: 139-49.
95. Retting KN, Song B, Yoon BS, Lyons KM. BMP canonical Samd signaling through Smad1 and Smad5 is required for endochondral bone formation. Development 2009; 136: 1093-104.
96. Minina E, Wenzel HM, Kreschel C, et al. BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation. Development 2001; 128: 4523-34.
97. Wrighton KH, Lin X, Yu PB, Feng XH. Transforming growth factor β can stimulate smad1 phosphorylation independently of bone morphogenic protein receptors. J Biol Chem 2009; 284: 9755-63.
98. Wang S, Hirschberg R. BMP7 antagonizes TGF-beta -dependent fibrogenesis in mesangial cells. Am J Physiol Renal Physiol 2003; 284: F1006-13.
99. Izumi N, Mizuguchi S, Inagaki Y, et al. BMP-7 opposes TGFbeta1- mediated collagen induction in mouse pulmonary myofibroblasts through Id2. Am J Physiol Lung Cell Mol Physiol 2006; 290: L120-6.
100. Keller B, Yang T, Chen Y, et al. Interaction of TGFβ and BMP signaling pathways during chondrogenesis. PLoS ONE 2011, 6: e16421.
101. Pan Q, Wu Y, Lin T, et al. Bone morphogenetic protein-2 induces chromatin remodeling and modification at the proximal promoter of Sox9 gene. Biochem Biophys Res Commun 2009; 379: 356-61.
102. Lories RJU, Luyten FP. Bone morphogenetic protein signaling in joint homeostasis and disease. Cytokine Growth Factor Rev 2005; 16: 287-98.
103. Smith RL, Lindsey DP, Dhulipala L, Harris AHS, Goodman SB, Maloney WJ. Effects of intermittent hydrostatic pressure and BMP- 2 on osteoarthritic human chondrocyte metabolism in vitro. J Orthop Res 2011, 29: 361-8.
104. Kamiya, N.; Mishina, Y. New insights on the roles of BMP signaling in bone-A review of recent mouse genetic studies. Biofactors 2011, 37: 75-82.
105. van der Kraan PM, Blaney Davidson EN, van den Berg WB. Bone morphogenetic proteins and articular cartilage to serve and protect or a wolf in sheep clothing's? Osteoarthr Cartilage 2010; 18: 735-41.
106. Uusitalo H, Hiltunen A, Ahonen M, et al. Accelerated upregulation of L-Sox5, Sox6, and Sox9 by BMP-2 gene transfer during murine fracture healing. J Bone Miner Res 2001; 16: 1837-45.
107. Majumdar MK, Chockalingam PS, Bhat RA, et al. Immortalized mouse articular cartilage cell lines retain chondrocyte phenotype and respond to both anabolic factor BMP-2 and pro-in fl ammatory factor IL-1. J Cell Physiol 2008; 215: 68-76.
108. Chubinskaya S, Hakimiyan AA, Rappoport L, Yanke A, Rueger DC, Cole BJ. Response of human chondrocytes prepared for autologous implantation to growth factors, J Knee Surg 2008; 21: 192-9.
109. Hayashi M, Muneta T, Takahashi T, Ju Y-J, Tsuji K, Swkiya I. Intra-articular injections of bone morphogenetic protein-7 retard progression of existing cartilage degeneration. J Orthop Res 2010; 28: 1502-6.
110. Honsawek S, Chayanupatkul M, Tanavalee A, et al. Relationship of plasma and synovial fluid BMP-7 with disease severity in knee osteoarthritis patients: a pilot study. Int Orthop 2009; 33: 1171-5.
111. Gavenis K, Pufe T, Brandeburg LO, Schiffl K, Schmidt-Rohlfing B. Effects of controlled released BMP-7 on markers of inflammation and degradation during the cultivation of human osteoarthritis chondrocytes. J Biomater Appl 2010; July, 12.
112. Gavenis K, Schneider U, Wallich R, Mueller-Rath R, Schmidt-Rohlfing B, Andereya S. Effects of low concentrated BMP-7 administered by co-cultivation or plasmid transfection on human osteoarthritic chondrocytes. Int J Artif Organs 2010; 33: 339-47.
113. Kawaguchi H. Regulation of osteoarthritis development by Wnt-α- catenin signaling through the endochondral ossification process. J Bone Miner Res 2009; 24: 8-11.
114. Rokutanda S, Fujita T, Kanatani N, et al. Akt regulates skeletal development through GSK3, mTOR, and FoxOs. Dev Biol 2009; 328: 78-93.
115. Hiyama A, Sakai D, Risbud MV, Tanaka M, Arai F, Abe K, Mochida J. Enhancement of initervertebral disc cell senescence by Wnt/α-catenin signaling-induced matrix metalloproteinase expression. Arthritis Rheum 2010; 62: 3036-47.
116. Ning B, Wang P, Pei X, et al. Dual function of α-catenin in articular cartilage growth and degeneration at different stages of postnatal cartilage development. Int Orthop 2011, DOI: 10.1007/s00264- 011-1315-6.
117. Kawasaki Y, Kugimiya F, Chikuda H, et al. Phosphorylation of GSK-3α by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murin chondrocytes. J Clin Inves 2008; 118: 2506-15.
118. ZilBergerg A, Yaniv A, Gazit A. The low density lipoprotein receptor- 1, LRP1, interacts with the human frizzled-1(HFzl) and down-regulates the canonical Wnt signaling pathway. J Biol Chem 2004; 279: 17535-42.
119. Kawata K, Kubota S, Eguchi T, et al. Role of the low-density lipoprotein receptor-related protein-1 in regulation of chondrocyte differentiation. J Cell Physiol 2010; 222: 138-48.
120. van Noort M, Meeldijk J, van der Zee R, Destree O, Clevers H. Wnt signaling controls the phosphorylation status of beta-catenin. J Biol Chem 2002; 277: 17901-5.
121. Leung JY, Kolligs FT, Wu R, et al. Activation of AXIN2 expression by beta-catenin-T cell factor. A feedback repressor pathway regulating Wnt signaling. J Biol Chem 2002; 277: 21657-65.
122. Liu W, Rui H, Wang J. Axin is a scaffold protein in TGF-beta signaling that promotes degradation of Smad7 by Arkadia. EMBO J 2006; 25: 1646-58.
123. Dao DY, Yang X, Chen D, Zuscik M, O'Keefe RJ. Axin1 and Axin2 are regulated by TGF-β and mediate cross-talk between TGFand Wnt signaling pathways. Ann N Y Acad Sci 2007; 1116: 82-99.
124. Dao DY, Yang X, Flick LM, Chen D, Hilton MJ, O'Keefe RJ. Axin2 regulates chondrocyte maturation and axial skeletal development. J Orthop Res 2010; 28: 89-95.
125. Zhu M, Tang D, Wu Q, et al. Activation of α-catenin signaling in articular chondrocytes leads to osteoarthritis-like pyenotype in adult α-catenin conditional activation mice. J Bone Miner Res 2009; 23: 12-21.
126. Lories RJ, Peeters J, Bakker A, et al. Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice. Arthritis Rheum 2007; 56: 4095-103.
127. Chan BY, Fuller ES, Russell AK, et al. Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis. Osteoarthr Cartilage 2011, 19: 874-85.
128. Diarra D, Stolina M, Polzer K, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med 2007; 13: 156-63.
129. Chen Y, Alman BA. Wnt pathway, an essential role in bone regeneration. J Cell Biochem 2009; 106: 353-62.
130. Zhu M, Chen M, Zuscik M, et al. Inhibition of α-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum 2008; 58: 2053-64.
131. Huang Y, Zhang X, Du K, et al. Inhibition of α-catenin signaling in chondrocytes induces delayed fracture healing in mice. J Orthop Res 2011, DOI: 10.1002/jor.21505.
132. Taniguchi N, Carames B, Kawakami Y, Amendt BA, Komiya S, Lotz M. Chromatin protein HMGB2 regulates articular cartilage surface maintenance via α-catenin pathway. PNAS 2009; 106, 16817-22.
133. Weng LH, Wang CJ, Ko JY, Sun YC, Su YS, Wang FS. Inflammation induction of Dickkopf-1 mediates chondrocyte apoptosis in osteoarthritic joint. Osteoarthr Cartilage 2009; 17: 933-43.
134. Weng LH, Wang CJ, Ko JY, Sun YC, Wang FS. Control of DKK-1 ameliorates chondrocyte apoptosis, cartilage destruction, and subchondral bone deterioration in osteoarthritic knees. Arthritis Rheum 2010; 62: 1393-402.
135. Wu Q, Kim KO, Sampson E, et al. Induction of an osteoarthritislike phenotype and degrades phosphorylated Smad3 by Smurf2 in transgenic mice. Arthritis Rheum 2008; 58: 3132-44.
136. Wu Q, Huang JH, Sampson ER, et al. Smurf2 induces degradation of GSK-3beta and upregulates beta-catenin in chondrocytes: A potential mechanism for Smurf2-induced degeneration of articular cartilage. Exp. Cell. Res 2009; 315: 2386-98.
137. Wu Q, Wang M, Zuscik MJ, Chen D, O'Keefe RJ, Rosier RN. Regulation of embryonic endochondral ossification by Smurf2. J Orthop Res 2008; 26: 704-12.
138. Wu Q, Chen D, Zuscik MJ, O'Keefe RJ, Rosier RN. Overexpression of Smurf2 stimulates endochondral ossification through upregulation of beta-catenin. J Bone Miner Res 2008; 23: 552-63.
139. van der Kraan PM, Blaney Davidson EN, Blom A, van den Berg WB. TGF-beta signaling in chondrocyte terminal differentiation and osteoarthritis. Osteoarthr Cartilage 2009; 17: 1539-45.
140. Hwang S-G, Ryu J-H, Kim I-C, et al. Wnt-7a causes loss of differentiated phenotype and inhibits apoptosis of articular chondrocytes via different mechanisms. J Biol Chem 2004; 279, 26597-604.
141. Ryu JH, Chun JS. Opposing roles of Wnt-5a and Wnt-11 in interleukin -1α regulation of type II collagen expression in articular chondrocytes. J Biol Chem 2006; 281: 22039-47.
142. Ge X-P, Gan Y-H, Zhang C-G, et al. Requirement of the NF-βB pathway for induction of Wnt-5a by interleukin-1α in condylar chondrocytes of the tempromandibular joint: functional crosstalk between the Wnt-5a and NF-βB signaling pathways. Osteoarthr Cartilage 2011, 19: 111-7.
143. Du Q, Geller DA. Cross-regulation between Wnt and NF-βB signaling pathways. For Immunopathol Dis Therap 2010; 1: 155-81.
144. Du Q, Zhang X, Cardinal J, et al. Wnt/α-catenin signaling regulates cytokine-induced human inducible nitric oxide synthase expression by inhibiting nuclear factor-βB activation in cancer cells. Cancer Res 2009; 69: 3764-71.
145. Scanzello CR, Plaas A, Crow MK. Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound? Curr Opin Rheumatol 2008; 20: 565-72.
146. Roman-Blas JA, Jimenez SA. NF-βB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis. Osteoarthr Cartilage 2006; 14: 839-48.
147. Golding MB, Otero M. Inflammation in osteoarthritis. Curr Opin Rheumatol 2011, 23: 471-8.
148. Kim HA, Cho ML, Choi HY, et al. The catabolic pathway mediated by Toll-like receptors in human osteoarthritis chondrocytes. Arthritis Rheum 2006; 54: 2152-63.
149. Punzi L, Oliviero F, Ramonda R. New horizons in osteoarthritis. Swiss Med Wkly 2010; 140: w13098.
150. Liu F-C, Hung L-F, Wu W-L, et al. Chondroprotective effects and mechanisms of resveratrol in advanced glycation end roductsstimulated chondrocytes. Arthritis Res Ther 2010; 12: R167.
151. Nishitani K, Ito H, Hiramitsu T, et al. PGE2 inhibits MMP expression by suppressing MKK4-JNK MAP kinase-c-JUN pathway via EP4 in human articular chondrocytes. J Cell Biochem 2010; 109: 425-33.
152. Lim H, Park H, Kim HP. Effects of flavonoids on matrix metalloproteinase- 13 expression of interleukin-1β-treated articular chondrocytes and their cellular mechanisms: inhibition of c-Fos/AP-1 and JAK/STAT signaling pathways. J Pharmacol Sci 2011, 116: 221-31.
153. Raymond L, Eck S, Mollmark J, et al. Interleukin-1 beta induction of matrix metalloproteinase-1 transcription in chondrocytes requires ERK-dependent activation of CCAAT enhancer-binding protein-beat. J Cell Physiol 2006; 207: 683-8.
154. Goldring MB, Otero M, Tsuchimochi K, Ijiri K, Li Y. Defining the roles of inflammatory and anabolic cytokines in cartilage metabolism. Ann Rheum Dis 2008; 67 Suppl 3: 375-82.
155. Grall FT, Prall WC, Wei W, et al. The Ets transcription factor ESE- 1 mediates induction of the COX-2 gene by LPS in monocytes. FEBS J 2005; 272: 1676-87.
156. Little CB, Fosang AJ. Is cartilage matrix breakdown an appropriate therapeutic target in osteoarthritis: insights from studies of aggrecan and collagen proteolysis? Curr Drug Targets 2010; 11: 561-75.
157. Muddasani P, Norman JC, Elman M, van Wijnen AJ, Im HJ. Basic fibroblast growth factor activates the MAPK and NFkappaB pathways that converge on Elk-1 to control production of matrix metalloproteinase- 13 by human adult articular chondrocytes. J Biol Chem 2007; 282: 31409-21.
158. Osiri M, McNicholl J, Moreland LW, Bridges SL Jr. A novel single nucleotide polymorphism and five probable haplotypes in the 5' flanking region of the IL-6 gene in African-Americans. Gene Immun. 1999, 1(2): 166-7.
159. Valdes AM Arden NK, Tamm A, et al. A meta-analysis of interleukin- 6 promoter polymorphisms on risk of hip and knee osteoarthritis. Osteoarthr Cartilage 2010; 18: 699-704.
160. Kämäräinen OP, Solovieva S, Vehmas T, et al. Common interleukin- 6 promoter variants associate with the more severe forms of distal interphalangeal osteoarthritis. Arthritis Res Ther 2008; 10(1): R21.
161. Pola E, Papaleo P, Pola R, et al. Interleukin-6 gene polymorphism and risk of osteoarthritis of the hip: a caseecontrol study. Osteoarthr Cartilage 2005; 13(11): 1025-8.
162. Limer KL, Tosh K, Bujac SR, et al. Attempt to replicate published genetic associations in a large, well-defined osteoarthritis caseecontrol population (the GOAL study). Osteoarthr Cartilage 2009; 17(6): 782-9.
163. Kiszel P, Mako V, Prohaszka Z, Cervenak L. Interleukin-6-174 promoter polymorphism does not influence IL-6 production after LPS and IL-1 beta stimulation in human umbilical cord vein endothelial cells. Cytokine 2007; 40: 17-22
164. Huth C, Illig T, Herder C, et al. Joint analysis of individual participants' data from 17 studies on the association of the IL6 variant α174G>C with circulating glucose levels, interleukin-6 levels, and body mass index. Ann Med 2008; 41(2): 128-38.
165. Samuel JM, Kelberman D, Smith AJ, Humphries SE, Woo P. Identification of a novel regulatory region in the interleukin-6 gene promoter. Cytokine 2008; 42: 256-64.
166. Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem 2000; 275(24): 18138-44.
167. Kaneko S, Satoch T, Chiba J, Ju C Inoue K, Kagawa J. Interleukin- 6 and interleukin-8 levels in serum and synovial fluid of patients with osteoarthritis. Cytokines Cell Mol Ther 2000; 6: 71-9.
168. de Hooge AS, van de Loo FA, Bennink MB, Arntz OJ, de Hooge P, van den Berg WB. Male IL-6 gene knock out mice developed more advanced osteoarthritis upon aging. Osteoarthr Cartilage 2005; 13: 66-73.
169. Cho TJ, Lehmann W, Edgar C, et al. Tumor necrosis factor alpha activation of the apoptotic cascade in murine articular chondrocytes is associated with the induction of metalloproteinases and specific pro-resorptive factors. Arthritis Rheum 2003; 48: 2845-54.
170. Lee SW, Song YS, Lee SY, et al. Downregulation of protein kinase CK2 activity facilitates tumor necrosis factor-β-mediated chondrocyte death through apoptosis and autophagy. PLoS ONE 2011, 6: e19163.
171. Li D, Wu Z, Duan Y, et al. TNFβ-mediated apoptosis in human osteoarthritic chondrocytes sensitized by PI3K-NF-κB inhibitor, not mTOR inhibitor. Rheumatol Int 2011, DOI: 10.1007/s00296- 011-1929-4.
172. Dvir-Ginzberg M, Gagarina V, Lee EJ, Booth R, Gabay O, Hall DJ. Tumor necrosis factor β-mediated cleavage and inactivation of SirT1 in human osteoarthritic chondrocytes. Arthritis Rheum 2011, 63: 2363-73.
173. Terkeltaub R, Yang B, Lotz M, Liu-Bryan R. Chondrocyte AMPactivated protein kinase acitivity suppresses matrix degradation responses to proinflammatory cytokines interleukin-1β and tumor necrosis factor β. Arthritis Rheum 2011, 63: 1928-37.
174. Shimpo H, Sakai T, Kondo S, et al. Regulation of prostaglandin E2 synthesis in cells derived from chondrocytes of patients with osteoarthritis. J Orthop Sci 2009; 15: 611-7.
175. Miwa M, Saura R, Hirata S, Hayashi Y, Mizuno K, Itoh H. Induction of apoptosis in bovine articular chondrocyte by prostaglandin E (2) through cAMP-dependent pathway. Osteoarthr Cartilage 2000; 8: 17-24.
176. Healy ZR, Zhu F, Stull JD, Konstantopoulos K. Elucidation of the signaling network of COX-2 induction in sheared chondrocytes: COX-2 is induced via a Rac/MEKK1/MKK7/JNK2/ c-Jun-C/EBP beta dependent pathways. Am J Physiol Cell Physiol 2008; 294: C1146-57.
177. Karsdal MA, Sumer EU, Wulf H, Madsen SH, Christiansen C, Fosan AJ. Induction of increased cAMP levels in articular chondrocytes blocks matrix metalloproteinase-mediated cartilage degradation, but not aggrecanase-mediated cartilage degradation. Arthritis Rheum 2007; 56: 1549-58.
178. Fushimi K, Nakashima S, You F, Takigawa M, Shimizu K. Prostaglandin E2 downregulates TNF-alpha-induced production of matrix metalloproteinase-1 in HCS-2/8 chondrocytes by inhibiting Raf- 1/MEK/ERK cascade through EP4 prostanoid receptor activation. J Cell Biochem 2007; 100: 783-93.
179. Tchetina EV, Di Battista JA, Zukor DJ, Antoniou J, Poole AR. Prostaglandin PGE2 at very low concentrations suppresses collagen cleavage in cultured human osteoarthritic articular cartilage: This involves a decrease in expression of proinflammatory genes, collagenases and COL10A1, a gene linked to chondrocyte hypertrophy. Arthritis Res Ther 2007; 9: R75.
180. Nah, S-S.; Choi, I-Y.; Lee, C.K, et al. Effects of advanced glycation end products on the expression of COX-2, PGE2 and NO in human osteoarthritic chondrocytes. Rheumatology 2008; 47: 425-31.
181. Huang CY, Hung LF, Liang CCT, Ho LJ. COX-2 and iNOS are critical in advanced glycation end product-activated chondrocytes in vitro. Eur J Clin Invest 2009; 39: 417-28.
182. Rasheed Z, Akhtar N, Haqqi TM. Advanced glycation end products induce the expression of interleukin-6 and interleukin-8 by receptor for advanced glycation end product-mediated activation of mitogen- activated protein kinases and nuclear factor--κB in human osteoarthritis chondrocytes. Rheumatology 2011, 50: 838-51.
183. Schmidt N, Pautz A, Art J, et al. Transcriptional and posttranscritptional regulation of iNOS expression in human chondrocytes. Biochem Pharmacol 2010; 79: 722-32.
184. Connelly L, Palacios-Callender M, Ameixa C, Moncada S, Hobbs AJ. Biphasic regulation of NF-κB activity underlies the pro- and anti-inflammatory actions of nitric oxide. J Immunol 2001; 166: 3873-81.
185. Rosa SC, Judas F, Lopes MC, Mendes AF. Nitric oxide synthase isoforms and NF-κB activity in normal and osteoarthritic human chondrocytes: regulation by inducible nitric oxide. Nitric Oxide 2008; 19: 276-83.
186. Yokota H, Goldring MB, Sun HB. CITED2-mediated regulation of MMP-1 and MMP-13 in human chondrocytes under flow shear. J Biol Chem 2003; 278: 47275-80.
187. Zayed N, Li X, Chabane N, et al. Increased expression of lipocalintype prostaglandin D2 synthesis in osteoarthritis cartilage. Arthritis Res Ther 2008; 10: R146.
188. Wang P, Zhu F, Lee NH, Onstantopoulos K. Shear-induced interleukin- 6 synthesis in chondrocytes: the roles of E prostanoid (EP)2 and EP3 in cAMP/protein kinase A- and PI3-K/Akt dependent NF- βB activation 2010; J Biol Chem 2010; 285: 24793-804.
189. Zhu F, Wang P, Kontrogianni-Konstantopoulos A, Konstantopoulos K. Prostaglandin (PG) and 15-deoxy-delta12,14-PGJ2, but not PGE2, mediate shear-induced chondrocyte apoptosis via protein kinase A-dependent regulation of polo-like kinases. Cell Death and Differentiation 2010; 17: 1325-34.
190. Fioravanti A, Collodel G, Petraglia A, Nerucci F, Moretti E, Galeazzi M. Effect of hydrostatic pressure of various magnitudes on osteoarthritic chondrocytes exposed to IL-1α. Indian J Med Res 2010; 132: 209-17.
191. Fioravanti A, Benetti D, Coppola G, Collodel G. Effect of continuous high hydrostatic pressure on the morphology and cytoskeleton of normal and osteoarthritic human chondrocytes cultivated in alginate gels. Clin Exp Rheumatol 2005; 23: 847-53.
192. Smith RL, Lindsey DP, Dhulipala L, Harris AHS, Goodman SB, Maloney WJ. Effects of intermittent hydrostatic pressure and BMP- 2 on osteoarthritic human chondrocyte metabolism in vitro. J Orthop Res 2011, 29: 361-8.
193. Wenger R, Hans MG, Welter JF, Solchaga LA, Sheu YR, Malemud CJ. Hydrostatic pressure increases apoptosis in cartilage-constructs produced from human osteoarthritis chondrocytes. Frontiers in Bioscience 2006; 11: 1690-5.
194. Nakamura S, Arai Y, Takahashi KA, et al. Hydrostatic pressure induces apoptosis of chondrocytes cultured in alginate beads. J Orthop Res 2006; 24: 733-9.
195. Kunitomo T, Takahashi KA, Arai Y, et al. Influence of extracellular matrix on the expression of inflammatory cytokines, proteases, and apoptosis-related genes induced by hydrostatic pressure in three-dimensionally cultured chondrocytes. J Orthop Sci 2009; 14: 776-83.
196. Wu L, Li P, Wang X, Zhang Z, Farzaneh F, Xu R. Evaluation of anti-inflammatory and antinociceptive activities of Murraya exotica. Pharmaceut Biol 2010; 2010; 48: 1344-53.