骨关节炎病理进程相关机制的研究进展_West China Medical Journal

Authors：

牛振东 ¹ , 刘恒 ² ,  曹瑞治 ²

Corresponding author：

曹瑞治, Email: nzd1113@163.com

Keywords：

骨关节炎; 破坏机制; 软骨细胞; 细胞因子; 信号通路

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骨关节炎（OA）的发病机制比较复杂，其发生与年龄、性别、遗传、肥胖、创伤有关。目前对于OA的治疗还没有很好的措施，其发生后病情发展的机制研究成为本领域的研究重点。目前已发现与OA病情发展相关的细胞因子、信号通路、蛋白酶类的作用机制的研究均处于初级阶段，且以各种作用机制指导的临床治疗措施效果欠佳。为进一步明确OA发展的相关病理机制，现对近几年来国内外本领域的相关研究作一综述，为探索更加有效的治疗方法提供新的理论依据。

Citation： 牛振东,刘恒,曹瑞治. 骨关节炎病理进程相关机制的研究进展. West China Medical Journal, 2012, 27(11): 1741-1744. doi: Copy

1.	李宁华, 薛庆云, 张毅, 等. 中国六城市中老年人群X线膝骨关节炎流行病学分析[J]. 实用医学杂志, 2008, 24(16): 2887-2888.
2.	Marks PH, Donaldson ML. Inflammatory cytokine profiles associated with chondral damage in the anterior cruciate ligament-deficient knee[J]. Arthroscopy, 2005, 21(11): 1342-1347.
3.	林木南, 刘献祥. 骨性关节炎中细胞因子的协同效应[J]. 福建中医学院学报, 2006, 16(2): 69-70.
4.	Arend WP. Interleukin-1 receptor antaganist[J]. Adv Immunol, 2007, 54(16): 721-723.
5.	Abramson SB. Nitric oxide in inflammation and pain associated with osteoarthritis[J]. Arthritis Res Ther, 2008, l0(Suppl 2): 2.
6.	Mix KS, Mengshol JA, Benbow U, et al. A synthetic triterpenoid selectively inhibits the induction of matrix metalloproteinases 1 and 13 by inflammatory cytokines[J]. Arthritis Rheum, 2001, 44(5): 1096-1104.
7.	Daheshia M, Yao JQ. The interleukin 1beta pathway in the pathogenesis of osteoarthritis[J]. Rheum, 2008, 35(12): 2306-2312.
8.	Wang X, Li F, Fan C, et al. Effects and relationship of ERK1 and ERK2 in interleukin-1β-induced alteration in MMP3, MMP13, type Ⅱcollagen and aggrecan expression in human chondrocytes[J]. Int J Mol Med, 2011, 27(4): 583-589.
9.	Im HJ, Pacione C, Chubinskaya S, et al. Inhibitory effects of fibronectin fragment and interleukin-1β-stimulated matrix metal oproteinase-13 expression in human chondrocytes[J]. J Biol Chem, 2003, 278(28): 25386-25394.
10.	Ghivizzani SC, Kang R, Georgescu HI, et al. Constitutive intra-articular expression of human IL-1 beta following gene transfer to rabbit synovium produces all major pathologies of human rheumatoid arthritis[J]. J Immunol, 1997, 159(7): 3604-3612.
11.	Tak PP, Gerlag DM, Aupperle KR, et al. Inhibitor of nuclear factor kappa B kinase beta is a key regulator of synovial inflammation[J]. Arthritis Rheum, 2001, 44(8): 1897-1907.
12.	亓建洪, 赵庆华, 刘延菊. 白细胞介素-l对人软骨细胞基质金属蛋白酶-13 mRNA表达的作用[J]. 中华风湿病学杂志, 2005, 9(3): 138-141.
13.	巫桁锞, 李荣亨. 白介素-l在骨关节炎发病制中的作用[J]. 中国老年医学杂志, 2008, 8(15): 1550-1553.
14.	刘健, 赵文海. 对骨性关节炎发病机制的研究概况[J]. 辽宁中医药大学学报, 2008, 46(2): 80-82.
15.	Davies CM, Guilak F, Weinberg JB, et al. Reactive Nitrogen and Oxygen species interleukin-1β-mediated DNA damage associated with osteoarthritis[J]. Osteoarthritis Cartilage, 2008, 16(5): 624-630.
16.	Hashimoto S, Setareh M, Ochs RL, et al. Fas/Fas ligand expression and induction of apoptosis in chondrocytes[J]. Arthritis Rheum, 1997, 40(10): 1749-1755.
17.	Zheng X, Xia C, Chen Z, et al. Requirement of the phosphatidylinositol 3-kinase/Akt signaling pathway for the effect of nicotine on interleukin-1beta-induced chondrocyte apoptosis in a rat model of osteoarthritis[J]. Biochem Biophys Res Commun, 2012, 423(3): 606-612.
18.	张志奇, 廖威明, 傅明. 骨关节炎信号通路及其治疗靶点[J]. 国际骨科学杂志, 2008, 29(5): 324-326.
19.	Fukuhara A, Matsuda M, Nishizawa M, et al. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin[J]. Science, 2005, 307(5708): 426-430.
20.	Sethi JK, Vidal-Puig A. Visfatin: the missing Link between intra-abdominal obesity and diabetes?[J]. Trends Mol Med, 2005, 11(8): 344-347.
21.	de Boer TN, van Spil WE, Huisman AM, et al. Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage[J]. Osteoarthritis Cartilage, 2012, 20(8): 846-853.
22.	Busso N, Karababa M, Nobile M, et al. Pharmacological inhibition of nicotinamide phosphoribosyltransferase/visfatin enzymatic activity identifies a new inflammatory pathway linked to NAD[J]. PLoS One, 2008, 3(5): e2267.
23.	Toda Y, Toda T, Takemura S, et al. Change in body fat,but not body weight or metabolic correlates of obesity,is related to symptomatic relief of obese patients with knee osteoarthritis after a weight control program[J]. Rheum, 1998, 25(11): 2181-2186.
24.	Hedbom E, Häuselmann HJ. Motecular aspects of pathogenesis in osteoarthrithe role of inflammation[J]. Cell Mot Life Sci, 2002, 59(1): 45-53.
25.	Tsou HK, Chen HT, Chang CH, et al. Apoptosis signal-regulating kinase 1 is mediated in TNF-α-induced CCL2 expression in human synovial fibroblasts[J]. J Cell Biochem, 2012, 113(11): 3509-3519.
26.	Kostopoulou F, Gkretsi V, Malizos KN, et al. Central role of SREBP-2 in the pathogenesis of osteoarthritis[J]. PLoS One, 2012, 7(5): e35753.
27.	郑卫军, 孙红桥. 血清IL-1β和IL-6表达水平与膝骨关节炎病程关系的研究[J]. 临床外科学杂志, 2011, 7(19): 490-495.
28.	Chen DY, Lan JL, Lin FJ. Predominance of Th1 cytokine in peripheral blood and pathological tissues of patients with active untreated adult onset Still’s disease[J]. Ann Rheum Dis, 2004, 63(10): 1300-1306.
29.	Meini S, Cucchi P, Tinti L, et al. Fasitibant prevents the bradykinin and interleukin 1β synergism on prostaglandin E2 release and cyclooxygenase 2 expression in human fibroblast-like synoviocytes[J]. Naunyn Schmiedebergs Arch Pharmacol, 2012, 385(8): 777-786.
30.	Lee YA, Choi HM, Lee SH, et al. Synergy between adiponectin and interleukin-1β on the expression of interleukin-6, interleukin-8, and cyclooxygenase-2 in fibroblast-like synoviocytes[J]. Exp Mol Med, 2012, 44(7): 440-447.
31.	Kawaguchi H. Regulation of osteoarthritis development by Wnt-beta-catenin signaling through the endochondral ossification process[J]. J Bone Miner Res, 2009, 24(1): 8-11.
32.	Dell’accio F, De Bari C, Eltawil NM, et al. Identification of the molecular response of articular cartilage to injury, by microarray screening: Wnt-16 expression and signaling after injury and in osteoarthritis[J]. Arthritis Rheum, 2008, 58(5): 1410-1421.
33.	Zhu M, Tang D, Wu Q, et al. Activation of beta-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice[J]. J Bone Miner Res, 2009, 24(1): 12-21.
34.	Day TF, Guo X, Garrett-Beal L, et al. Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis[J]. Dev Cell, 2005, 8(5): 739-750.
35.	Tamamura Y, Otani T, Kanatani N, et al. Developmental regulation of Wnt/beta-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification[J]. J Biol Chem, 2005, 280(19): 19185-19195.
36.	Wu Q, Zhu M. Beta-catenin, cartilage and osteoarthritis[J]. Ann N Y Acad Sci, 2010, 3(1192): 344-350.
37.	Zhu M, Chen M, Zuscik M, et al. Inhibition of beta-catenin signaling in articular chondrocytes results in articular cartilage destruction[J]. Arthritis Rheum, 2008, 58(7): 2053-2064.
38.	周庆军, 胡若真, 邵健忠, 等. Notch信号转导与调控[J]. 生物化学与生物物理进展, 2004, 31(3): 198-203.
39.	Hardinqham TE, Oldershaw RA, Cartilage TS. SOX9 and notch signals in chondroqenesis[J]. J Anat, 2006, 209(4): 4460-4480.
40.	Brew CJ, Clegg PD, Boot-Handford RP, et al. Gene expression in human chondrocytes in late osteoarthritis is changed in both fibrillated and intact cartilage without evidence of generalised chondrocyte hypertrophy[J]. Ann Rheum Dis, 2010, 69(1): 234-240.
41.	Karlsson C, Brantsing C, Egell S, et al. Notch1, and HES5 are abundantly expressed in osteoarthritis[J]. Cells Tissues Organs, 2008, 188(3): 287-298.
42.	Konttinen YT, Mandelin J, Li TF, et al. Acidic cysteine endoproteinase cathepsin K in the degeneration of the superficial articular hyaline cartilage in osteoarthritis[J]. Arthritis Rheum, 2002, 46(4): 953-960.
43.	Berardi S, Lang A, Kostoulas G, et al. Alternative messenger RNA splicing and enzyme forms of cathepsin B in human osteoarthritic cartilage and cultured chondrocytes[J]. Arthritis Rheum, 2001, 44(8): 1819-1831.
44.	孙西涛, 孙水. Cathepsin K及其抑制剂cystatin C在骨关节炎滑膜组织中的表达[D]. 山东: 山东大学临床医学系, 2010.
45.	青玉凤, 杨其彬. 类风湿关节炎成纤维滑膜细胞端粒保护蛋白TPPl及POTl mRNA表达的研究[J]. 中华风湿病学杂志, 2009, 10(13): 693-697.
46.	李良军, 曾凯斌. 骨关节炎软骨中衰老相关β-半乳糖苷酶和c-Fos蛋白的表达[J]. 中国组织工程研究与临床康复, 2011, 2(15): 196-200.
47.	张丽君. 骨关节炎的治疗研究进展[J]. 中华风湿病学杂志, 2008, 12(8): 572-576.

1. 　李宁华, 薛庆云, 张毅, 等. 中国六城市中老年人群X线膝骨关节炎流行病学分析[J]. 实用医学杂志, 2008, 24(16): 2887-2888.
2. 　Marks PH, Donaldson ML. Inflammatory cytokine profiles associated with chondral damage in the anterior cruciate ligament-deficient knee[J]. Arthroscopy, 2005, 21(11): 1342-1347.
3. 　林木南, 刘献祥. 骨性关节炎中细胞因子的协同效应[J]. 福建中医学院学报, 2006, 16(2): 69-70.
4. 　Arend WP. Interleukin-1 receptor antaganist[J]. Adv Immunol, 2007, 54(16): 721-723.
5. 　Abramson SB. Nitric oxide in inflammation and pain associated with osteoarthritis[J]. Arthritis Res Ther, 2008, l0(Suppl 2): 2.
6. 　Mix KS, Mengshol JA, Benbow U, et al. A synthetic triterpenoid selectively inhibits the induction of matrix metalloproteinases 1 and 13 by inflammatory cytokines[J]. Arthritis Rheum, 2001, 44(5): 1096-1104.
7. 　Daheshia M, Yao JQ. The interleukin 1beta pathway in the pathogenesis of osteoarthritis[J]. Rheum, 2008, 35(12): 2306-2312.
8. 　Wang X, Li F, Fan C, et al. Effects and relationship of ERK1 and ERK2 in interleukin-1β-induced alteration in MMP3, MMP13, type Ⅱcollagen and aggrecan expression in human chondrocytes[J]. Int J Mol Med, 2011, 27(4): 583-589.
9. 　Im HJ, Pacione C, Chubinskaya S, et al. Inhibitory effects of fibronectin fragment and interleukin-1β-stimulated matrix metal oproteinase-13 expression in human chondrocytes[J]. J Biol Chem, 2003, 278(28): 25386-25394.
10. 　Ghivizzani SC, Kang R, Georgescu HI, et al. Constitutive intra-articular expression of human IL-1 beta following gene transfer to rabbit synovium produces all major pathologies of human rheumatoid arthritis[J]. J Immunol, 1997, 159(7): 3604-3612.
11. 　Tak PP, Gerlag DM, Aupperle KR, et al. Inhibitor of nuclear factor kappa B kinase beta is a key regulator of synovial inflammation[J]. Arthritis Rheum, 2001, 44(8): 1897-1907.
12. 　亓建洪, 赵庆华, 刘延菊. 白细胞介素-l对人软骨细胞基质金属蛋白酶-13 mRNA表达的作用[J]. 中华风湿病学杂志, 2005, 9(3): 138-141.
13. 　巫桁锞, 李荣亨. 白介素-l在骨关节炎发病制中的作用[J]. 中国老年医学杂志, 2008, 8(15): 1550-1553.
14. 　刘健, 赵文海. 对骨性关节炎发病机制的研究概况[J]. 辽宁中医药大学学报, 2008, 46(2): 80-82.
15. 　Davies CM, Guilak F, Weinberg JB, et al. Reactive Nitrogen and Oxygen species interleukin-1β-mediated DNA damage associated with osteoarthritis[J]. Osteoarthritis Cartilage, 2008, 16(5): 624-630.
16. 　Hashimoto S, Setareh M, Ochs RL, et al. Fas/Fas ligand expression and induction of apoptosis in chondrocytes[J]. Arthritis Rheum, 1997, 40(10): 1749-1755.
17. 　Zheng X, Xia C, Chen Z, et al. Requirement of the phosphatidylinositol 3-kinase/Akt signaling pathway for the effect of nicotine on interleukin-1beta-induced chondrocyte apoptosis in a rat model of osteoarthritis[J]. Biochem Biophys Res Commun, 2012, 423(3): 606-612.
18. 　张志奇, 廖威明, 傅明. 骨关节炎信号通路及其治疗靶点[J]. 国际骨科学杂志, 2008, 29(5): 324-326.
19. 　Fukuhara A, Matsuda M, Nishizawa M, et al. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin[J]. Science, 2005, 307(5708): 426-430.
20. 　Sethi JK, Vidal-Puig A. Visfatin: the missing Link between intra-abdominal obesity and diabetes?[J]. Trends Mol Med, 2005, 11(8): 344-347.
21. 　de Boer TN, van Spil WE, Huisman AM, et al. Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage[J]. Osteoarthritis Cartilage, 2012, 20(8): 846-853.
22. 　Busso N, Karababa M, Nobile M, et al. Pharmacological inhibition of nicotinamide phosphoribosyltransferase/visfatin enzymatic activity identifies a new inflammatory pathway linked to NAD[J]. PLoS One, 2008, 3(5): e2267.
23. 　Toda Y, Toda T, Takemura S, et al. Change in body fat,but not body weight or metabolic correlates of obesity,is related to symptomatic relief of obese patients with knee osteoarthritis after a weight control program[J]. Rheum, 1998, 25(11): 2181-2186.
24. 　Hedbom E, Häuselmann HJ. Motecular aspects of pathogenesis in osteoarthrithe role of inflammation[J]. Cell Mot Life Sci, 2002, 59(1): 45-53.
25. 　Tsou HK, Chen HT, Chang CH, et al. Apoptosis signal-regulating kinase 1 is mediated in TNF-α-induced CCL2 expression in human synovial fibroblasts[J]. J Cell Biochem, 2012, 113(11): 3509-3519.
26. 　Kostopoulou F, Gkretsi V, Malizos KN, et al. Central role of SREBP-2 in the pathogenesis of osteoarthritis[J]. PLoS One, 2012, 7(5): e35753.
27. 　郑卫军, 孙红桥. 血清IL-1β和IL-6表达水平与膝骨关节炎病程关系的研究[J]. 临床外科学杂志, 2011, 7(19): 490-495.
28. 　Chen DY, Lan JL, Lin FJ. Predominance of Th1 cytokine in peripheral blood and pathological tissues of patients with active untreated adult onset Still’s disease[J]. Ann Rheum Dis, 2004, 63(10): 1300-1306.
29. 　Meini S, Cucchi P, Tinti L, et al. Fasitibant prevents the bradykinin and interleukin 1β synergism on prostaglandin E2 release and cyclooxygenase 2 expression in human fibroblast-like synoviocytes[J]. Naunyn Schmiedebergs Arch Pharmacol, 2012, 385(8): 777-786.
30. 　Lee YA, Choi HM, Lee SH, et al. Synergy between adiponectin and interleukin-1β on the expression of interleukin-6, interleukin-8, and cyclooxygenase-2 in fibroblast-like synoviocytes[J]. Exp Mol Med, 2012, 44(7): 440-447.
31. 　Kawaguchi H. Regulation of osteoarthritis development by Wnt-beta-catenin signaling through the endochondral ossification process[J]. J Bone Miner Res, 2009, 24(1): 8-11.
32. 　Dell’accio F, De Bari C, Eltawil NM, et al. Identification of the molecular response of articular cartilage to injury, by microarray screening: Wnt-16 expression and signaling after injury and in osteoarthritis[J]. Arthritis Rheum, 2008, 58(5): 1410-1421.
33. 　Zhu M, Tang D, Wu Q, et al. Activation of beta-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice[J]. J Bone Miner Res, 2009, 24(1): 12-21.
34. 　Day TF, Guo X, Garrett-Beal L, et al. Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis[J]. Dev Cell, 2005, 8(5): 739-750.
35. 　Tamamura Y, Otani T, Kanatani N, et al. Developmental regulation of Wnt/beta-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification[J]. J Biol Chem, 2005, 280(19): 19185-19195.
36. 　Wu Q, Zhu M. Beta-catenin, cartilage and osteoarthritis[J]. Ann N Y Acad Sci, 2010, 3(1192): 344-350.
37. 　Zhu M, Chen M, Zuscik M, et al. Inhibition of beta-catenin signaling in articular chondrocytes results in articular cartilage destruction[J]. Arthritis Rheum, 2008, 58(7): 2053-2064.
38. 　周庆军, 胡若真, 邵健忠, 等. Notch信号转导与调控[J]. 生物化学与生物物理进展, 2004, 31(3): 198-203.
39. 　Hardinqham TE, Oldershaw RA, Cartilage TS. SOX9 and notch signals in chondroqenesis[J]. J Anat, 2006, 209(4): 4460-4480.
40. 　Brew CJ, Clegg PD, Boot-Handford RP, et al. Gene expression in human chondrocytes in late osteoarthritis is changed in both fibrillated and intact cartilage without evidence of generalised chondrocyte hypertrophy[J]. Ann Rheum Dis, 2010, 69(1): 234-240.
41. 　Karlsson C, Brantsing C, Egell S, et al. Notch1, and HES5 are abundantly expressed in osteoarthritis[J]. Cells Tissues Organs, 2008, 188(3): 287-298.
42. 　Konttinen YT, Mandelin J, Li TF, et al. Acidic cysteine endoproteinase cathepsin K in the degeneration of the superficial articular hyaline cartilage in osteoarthritis[J]. Arthritis Rheum, 2002, 46(4): 953-960.
43. 　Berardi S, Lang A, Kostoulas G, et al. Alternative messenger RNA splicing and enzyme forms of cathepsin B in human osteoarthritic cartilage and cultured chondrocytes[J]. Arthritis Rheum, 2001, 44(8): 1819-1831.
44. 　孙西涛, 孙水. Cathepsin K及其抑制剂cystatin C在骨关节炎滑膜组织中的表达[D]. 山东: 山东大学临床医学系, 2010.
45. 　青玉凤, 杨其彬. 类风湿关节炎成纤维滑膜细胞端粒保护蛋白TPPl及POTl mRNA表达的研究[J]. 中华风湿病学杂志, 2009, 10(13): 693-697.
46. 　李良军, 曾凯斌. 骨关节炎软骨中衰老相关β-半乳糖苷酶和c-Fos蛋白的表达[J]. 中国组织工程研究与临床康复, 2011, 2(15): 196-200.
47. 　张丽君. 骨关节炎的治疗研究进展[J]. 中华风湿病学杂志, 2008, 12(8): 572-576.

West China Medical Journal

骨关节炎病理进程相关机制的研究进展

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