细胞因子治疗骨关节炎的研究进展

doi:10.3969/j.issn.1674-8115.2022.11.016

摘要/Abstract

摘要：

骨关节炎（osteoarthritis，OA）是一种临床常见的关节病变，多累及下肢负重关节，易导致关节畸形，严重影响生活质量。目前，OA的早期治疗主要集中在对症治疗及减缓关节软骨的磨损。各类细胞因子在OA的发生和发展过程中发挥重要作用。白细胞介素（interleukin，IL）家族中，IL-1β/6/8与OA的发生及进展有关，是主要的致炎因子；IL-4/10作为抗炎成分，对关节起保护作用。肿瘤坏死因子-α也是促进关节炎症发生的主要成分。体内外研究表明，转化生长因子-β、胰岛素样生长因子、成纤维细胞生长因子在延缓OA的进展过程中发挥积极作用。研究相关细胞因子的作用，不仅可以深入了解OA的发病机制，也可为OA的治疗提供新思路，有望解决当下OA传统治疗效果不理想的问题。目前，在细胞因子应用于OA的防治领域，已经获得了很多有益的研究成果，部分已经进入临床试验和应用。该文综述了几类对于OA防治具有潜在效果的细胞因子的研究进展和部分作用机制。

关键词: 骨关节炎, 细胞因子, 软骨缺损修复

Abstract:

Osteoarthritis (OA) is a common joint disease in clinic. OA mostly involves the load-bearing joints of the lower limbs, which is easy to cause joint deformity and affect the quality of life after the disease. At present, early treatment of OA focuses on symptomatic treatment and slowing down the wear of articular cartilage. Various cytokines play an important role in the development of OA. Among the interleukin (IL) family, IL-1β/6/8 are associated with the occurrence and progression of OA and are major inflammatory factors. IL-4/10 play a protective role in the joints as an anti-inflammatory component. Tumor necrosis factor-α is also a major component that promotes joint inflammation. In vitro and in vivo studies show that transforming growth factor-β,insulin-like growth factor, and fibroblast growth factor (FGF) can delay the progression of OA. By investigating the roles of the relevant cytokines, we can not only gain insight into the pathogenesis of OA, but also provide new ideas for the treatment of OA. Cytokines are expected to solve the dilemma of suboptimal efficacy of current traditional treatments for OA. At present, many beneficial research results are achieved in the field of cytokine application to the prevention and treatment of OA, and a part of them begins to enter clinical trials and applications. This review summarizes the research progress and partial mechanisms of several classes of cytokines with potential effects on OA.

Key words: osteoarthritis, cytokine, cartilage defect repair

中图分类号:

R684.3

董玉山, 张文杰. 细胞因子治疗骨关节炎的研究进展[J]. 上海交通大学学报（医学版）, 2022, 42(11): 1627-1632.

DONG Yushan, ZHANG Wenjie. Research progress of cytokines in treatment of osteoarthritis[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(11): 1627-1632.

参考文献 60

1	MIYAZAKI T, WADA M, KAWAHARA H, et al. Dynamic load at baseline can predict radiographic disease progression in medial compartment knee osteoarthritis[J]. Ann Rheum Dis, 2002, 61(7): 617-622.
2	谷艳超, 刘世清, 夏韶强, 等. 骨关节炎发病机制和治疗的研究进展[J]. 中国骨与关节杂志, 2016, 5(10): 770-774.
	GU Y C, LIU S Q, XIA S Q, et al. Advances on the pathogenesis and treatment of osteoarthritis[J]. Chin J Bone Joint, 2016, 5(10):770-774.
3	秦迪, 李石伦, 郑占乐, 等. 膝关节骨关节炎病因与关节软骨磨损的相关性研究[J]. 河北医科大学学报, 2016, 37(2): 227-229.
	QIN D, LI S L, ZHENG Z L, et al. Study on the correlation between the etiology of knee osteoarthritis and articular cartilage wear[J]. J Hebei Med Univ, 2016, 37(2): 227-229.
4	薛庆云, 王坤正, 裴福兴, 等. 中国40岁以上人群原发性骨关节炎患病状况调查[J]. 中华骨科杂志, 2015, 35(12): 1206-1212.
	XUE Q Y, WANG K Z, PEI F X, et al. The survey of the prevalence of primary osteoarthritis in the population aged 40 years and over in China[J]. Chin J Orthop, 2015, 35(12): 1206-1212.
5	ARMIENTO A R, STODDART M J, ALINI M, et al. Biomaterials for articular cartilage tissue engineering: learning from biology[J]. Acta Biomater, 2018, 65: 1-20.
6	CHEN S, FU P, WU H, et al. Meniscus, articular cartilage and nucleus pulposus: a comparative review of cartilage-like tissues in anatomy, development and function[J]. Cell Tissue Res, 2017, 370(1): 53-70.
7	VAN DEN BOSCH M H, BLOM A B, VAN LENT P L, et al. Canonical Wnt signaling skews TGF-β signaling in chondrocytes towards signaling via ALK1 and smad 1/5/8[J]. Cell Signal, 2014, 26(5): 951-958.
8	RICHMOND R S, CARLSON C S, REGISTER T C, et al. Functional estrogen receptors in adult articular cartilage: estrogen replacement therapy increases chondrocyte synthesis of proteoglycans and insulin-like growth factor binding protein 2[J]. Arthritis Rheum, 2000, 43(9): 2081-2090.
9	张洪亮, 王文波, 李明宇, 等. 致炎细胞因子在骨性关节炎病理生理中的作用[J]. 现代生物医学进展, 2014, 14(5): 989-992.
	ZHANG H L, WANG W B, LI M Y, et al. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis[J]. Prog Mod Biomed, 2014, 14(5): 989-992.
10	SHIOZAWA S, TSUMIYAMA K. Pathogenesis of rheumatoid arthritis and c-fos/AP-1[J]. Cell Cycle, 2009, 8(10): 1539-1543.
11	HARDY M M, SEIBERT K, MANNING P T, et al. Cyclooxygenase 2-dependent prostaglandin E2 modulates cartilage proteoglycan degradation in human osteoarthritis explants[J]. Arthritis Rheum, 2002, 46(7): 1789-1803.
12	SCARPELLINI M, LURATI A, VIGNATI G, et al. Biomarkers, type II collagen, glucosamine and chondroitin sulfate in osteoarthritis follow-up: the “Magenta osteoarthritis study”[J]. J Orthop Traumatol, 2008, 9(2): 81-87.
13	SHIOMI T, LEMAÎTRE V, D′ARMIENTO J, et al. Matrix metalloproteinases, a disintegrin and metalloproteinases, and a disintegrin and metalloproteinases with thrombospondin motifs in non-neoplastic diseases[J]. Pathol Int, 2010, 60(7): 477-496.
14	许蓓, 林进. 骨关节炎发病机制及治疗进展[J]. 浙江医学, 2017, 39(21): 1833-1835, 1851.
	XU B,LIN J. Progress in pathogenesis and treatment of osteoarthritis [J]. Zhejiang Med J, 2017, 39(21): 1833-1835, 1851.
15	LAI Y, BAI X, ZHAO Y, et al. ADAMTS-7 forms a positive feedback loop with TNF-α in the pathogenesis of osteoarthritis[J]. Ann Rheum Dis, 2014, 73(8): 1575-1584.
16	许曼珊, 姜婷, 秦盈盈. 骨关节炎发病机制研究进展[J]. 国际骨科学杂志, 2020, 41(4): 229-233.
	XU M S, JIANG T, QIN Y Y. Research progress in pathogenesis of osteoarthritis[J]. Int J Orthop, 2020, 41(4): 229-233.
17	STEEN-LOUWS C, POPOV-CELEKETIC J, MASTBERGEN S C, et al. IL4-10 fusion protein has chondroprotective, anti-inflammatory and potentially analgesic effects in the treatment of osteoarthritis[J]. Osteoarthritis Cartilage, 2018, 26(8): 1127-1135.
18	冯明利. 骨关节炎发病机制研究进展[J]. 北京医学, 2015, 12(4): 372-374.
	FENG M L. Research progress in pathogenesis of osteoarthritis[J]. Beijing Med J, 2015, 12(4): 372-374.
19	SARTORI-CINTRA A R, MARA C S, ARGOLO D L, et al. Regulation of hypoxia-inducible factor-1α (HIF-1α) expression by interleukin-1β (IL-1 β), insulin-like growth factors I (IGF-I) and II (IGF-II) in human osteoarthritic chondrocytes[J]. Clinics (Sao Paulo), 2012, 67(1): 35-40.
20	李明征, 刘兴龙, 王国栋, 等. 胰岛素样生长因子Ⅰ与转化生长因子β2对兔软骨细胞立体三维培养的作用[J]. 中华临床医师杂志(电子版), 2013, 7(6): 2541-2545.
	LI M Z, LIU X L, WANG G D, et al. Effects of IGF-Ⅰ and TGF-β2 on rabbit chondrocytes in three-dimensional culture[J]. Chin J Clinicians(Electronic Edition), 2013, 7(6): 2541-2545.
21	DICKSON M C, MARTIN J S, COUSINS F M, et al. Defective haemato-poiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice[J]. Development, 1995, 121(6): 1845-1854.
22	ALBRO M B, NIMS R J, CIGAN A D, et al. Dynamic mechanical compression of devitalized articular cartilage does not activate latent TGF-β[J]. J Biomech, 2013, 46(8): 1433-1439.
23	WANG Q, TAN Q Y, XU W, et al. Cartilage-specific deletion of Alk5 gene results in a progressive osteoarthritis-like phenotype in mice[J]. Osteoarthritis Cartilage, 2017, 25(11): 1868-1879.
24	张立智, 卫禛, 张世民. 转化生长因子β信号在骨关节炎中的作用[J]. 中华骨与关节外科杂志, 2019, 12(9): 727-732.
	ZHANG L Z, WEI Z, ZHANG S M. Roles of TGF-β signaling in the development of osteoarthritis[J]. Chin J Bone Joint Surg, 2019,12(9): 727-732.
25	BLANEY DAVIDSON E N, VAN CAAM A P, VITTERS E L, et al. TGF-β is a potent inducer of nerve growth factor in articular cartilage via the ALK5-Smad2/3 pathway. Potential role in OA related pain?[J]. Osteoarthritis Cartilage, 2015, 23(3): 478-486.
26	ZHEN G, WEN C, JIA X, et al. Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis[J]. Nat Med, 2013, 19(6): 704-712.
27	VAN DER KRAAN P M. Differential role of transforming growth factor-beta in an osteoarthritic or a healthy joint[J]. J Bone Metab, 2018, 25(2): 65-72.
28	RUIZ M, TOUPET K, MAUMUS M, et al. TGFBI secreted by mesenchymal stromal cells ameliorates osteoarthritis and is detected in extracellular vesicles[J]. Biomaterials, 2020, 226: 119544.
29	ITOH N, ORNITZ D M. Functional evolutionary history of the mouse Fgf gene family[J]. Dev Dyn, 2008, 237(1): 18-27.
30	ORNITZ D M, XU J, COLVIN J S, et al. Receptor specificity of the fibroblast growth factor family[J]. J Biol Chem, 1996, 271(25): 15292-15297.
31	MOORE E E, BENDELE A M, THOMPSON D L, et al. Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis[J]. Osteoarthritis Cartilage, 2005, 13(7): 623-631.
32	李嘉怡. 成纤维细胞生长因子18(FGF₁₈)腺病毒包装及其在小鼠骨关节炎治疗中的作用[D]. 衡阳: 南华大学, 2019.
	LI J Y. Packaging of fibroblast growth factor 18 (FGF₁₈) adenovirus and its effect in on osteoarthritis in mice[D]. Hengyang: University of South China, 2019.
33	CINQUE L, FORRESTER A, BARTOLOMEO R, et al. FGF signalling regulates bone growth through autophagy[J]. Nature, 2015, 528(7581): 272-275.
34	MORI Y, SAITO T, CHANG S H, et al. Identification of fibroblast growth factor-18 as a molecule to protect adult articular cartilage by gene expression profiling[J]. J Biol Chem, 2014, 289(14): 10192-10200.
35	DAHLBERG L E, AYDEMIR A, MUURAHAINEN N, et al. A first-in-human, double-blind, randomised, placebo-controlled, dose ascending study of intra-articular rhFGF18 (sprifermin) in patients with advanced knee osteoarthritis[J]. Clin Exp Rheumatol, 2016, 34(3): 445-450.
36	LOHMANDER L S, HELLOT S, DREHER D, et al. Intraarticular sprifermin (recombinant human fibroblast growth factor 18) in knee osteoarthritis: a randomized, double-blind, placebo-controlled trial[J]. Arthritis Rheumatol, 2014, 66(7): 1820-1831.
37	XIAO L P, WILLIAMS D, HURLEY M M. Inhibition of FGFR signaling partially rescues osteoarthritis in mice overexpressing high molecular weight FGF₂ isoforms[J]. Endocrinology, 2020, 161(1): bqz016.
38	NUMMENMAA E, HÄMÄLÄINEN M, MOILANEN T, et al. Effects of FGF-2 and FGF receptor antagonists on MMP enzymes, aggrecan, and type II collagen in primary human OA chondrocytes[J]. Scand J Rheumatol, 2015, 44(4): 321-330.
39	CHIA S L, SAWAJI Y, BURLEIGH A, et al. Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS-5 and delays cartilage degradation in murine osteoarthritis[J]. Arthritis Rheum, 2009, 60(7): 2019-2027.
40	ISHII I, MIZUTA H, SEI A, et al. Healing of full-thickness defects of the articular cartilage in rabbits using fibroblast growth factor-2 and a fibrin sealant[J]. J Bone Joint Surg Br, 2007, 89(5): 693-700.
41	牟方政, 李荣亨. 胰岛素样生长因子-1与骨关节炎研究进展[J]. 中国老年学杂志, 2012, 32(22): 5089-5092.
	MOU F Z, LI R H. Research progress of insulin-like growth factor-1 and osteoarthritis[J]. Chin J Gerontol, 2012, 32(22): 5089-5092.
42	宋红星, 李佛保, 刘淼, 等. 胰岛素样生长因子-Ⅰ对软骨细胞移植修复关节软骨缺损的作用[J]. 中华创伤杂志, 2001(11): 679-680.
	SONG H X, LI F B, LIU M, et al. Effect of insulin-like growth factor-Ⅰ on the repair of articular cartilage defects[J]. Chin J Trauma, 2001, 17(11): 679-680.
43	蓝旭, 刘雪梅, 葛宝丰, 等. IGF-Ⅰ对培养兔关节软骨细胞作用的实验研究[J]. 中国骨伤, 2001, 14(6): 341-342.
	LAN X, LIU X M, GE B F, et al. Effects of IGF-Ⅰ on proliferation and metabolism of cultured rabbit artiular chondrocytes[J]. Chin J Orthop Trauma, 2001, 14(6): 341-342.
44	魏优秀, 韦卓, 刘平, 等. 注射胰岛素样生长因子-1、转化生长因子-β1治疗关节软骨缺损及预防骨关节炎的实验研究[J]. 中国临床保健杂志, 2010, 13(3): 274-277.
	WEI Y X, WEI Z, LIU P, et al. Experimental study on the repair of articular cartilage defect and prevention on osteoarthritis by intra- articular injection of IGF-1, TGF-β1[J]. Chin J Clin Healthcare, 2010, 13(3): 274-277.
45	HOSSAIN M A, ADITHAN A, ALAM M J, et al. IGF-1 facilitates cartilage reconstruction by regulating PI3K/AKT, MAPK, and NF-kB signaling in rabbit osteoarthritis[J]. J Inflamm Res, 2021, 14: 3555-3568.
46	黄建荣, 李卫平, 沈慧勇, 等. 胰岛素样生长因子Ⅰ与透明质酸对人关节软骨细胞的作用[J]. 中华生物医学工程杂志, 2008, 14(3): 180-184.
	HUANG J R, LI W P, SHEN H Y. Role of insulin-like growth factor Ⅰ and hyaluronic acid on the articular chondrocytes[J]. Chin J Biomed Engineer, 2008, 14(3): 180-184.
47	MUSHTAQ T, BIJMAN P, AHMED S F, et al. Insulin-like growth factor-I augments chondrocyte hypertrophy and reverses glucocorticoid-mediated growth retardation in fetal mice metatarsal cultures[J]. Endocrinology, 2004, 145(5): 2478-2486.
48	MORISSET S, FRISBIE D D, ROBBINS P D, et al. IL-1ra/IGF-1 gene therapy modulates repair of microfractured chondral defects[J]. Clin Orthop Relat Res, 2007, 462: 221-228.
49	DEMAZIÈRE A, LEEK R, ATHANASOU N A. Histological distribution of the interleukin-4 receptor (IL4R) within the normal and pathological synovium[J]. Revue Du Rhumatisme Des Maladies Osteo Articul, 1992, 59(3): 219-224.
50	MILLWARD-SADLER S J, KHAN N S, BRACHER M G, et al. Roles for the interleukin-4 receptor and associated JAK/STAT proteins in human articular chondrocyte mechanotransduction[J]. Osteoarthritis Cartilage, 2006, 14(10): 991-1001.
51	FORSTER T, CHAPMAN K, LOUGHLIN J. Common variants within the interleukin 4 receptor alpha gene (IL4R) are associated with susceptibility to osteoarthritis[J]. Hum Genet, 2004, 114(4): 391-395.
52	JOHN T, MÜLLER R D, OBERHOLZER A, et al. Interleukin-10 modulates pro-apoptotic effects of TNF-alpha in human articular chondrocytes in vitro[J]. Cytokine, 2007, 40(3): 226-234.
53	SALTER D M, NUKI G, WRIGHT M O. IL-4 inhibition of cartilage breakdown in bovine articular explants[J]. J Rheumatol, 1996, 23(7): 1314-1315.
54	ALAAEDDINE N, DI BATTISTA J A, PELLETIER J P, et al. Inhibition of tumor necrosis factor alpha-induced prostaglandin E2 production by the antiinflammatory cytokines interleukin-4, interleukin-10, and interleukin-13 in osteoarthritic synovial fibroblasts: distinct targeting in the signaling pathways[J]. Arthritis Rheum, 1999, 42(4): 710-718.
55	JOOSTEN L A, LUBBERTS E, DUREZ P, et al. Role of interleukin-4 and interleukin-10 in murine collagen-induced arthritis. Protective effect of interleukin-4 and interleukin-10 treatment on cartilage destruction[J]. Arthritis Rheum, 1997, 40(2): 249-260.
56	VAN ROON J A, VAN ROY J L, GMELIG-MEYLING F H, et al. Prevention and reversal of cartilage degradation in rheumatoid arthritis by interleukin-10 and interleukin-4[J]. Arthritis Rheum, 1996, 39(5): 829-835.
57	VAN HELVOORT E M, POPOV-CELEKETIC J, EIJKELKAMP N, et al. Canine IL4-10 fusion protein provides disease modifying activity in a canine model of OA; an exploratory study[J]. PLoS One, 2019, 14(7): e0219587.
58	POPOV-CELEKETIC J, VISSER H M, COELEVELD K,et al. IL4-10 fusion protein as a disease modifying therapy for osteoarthritis evaluated in a rat groove model in vivo[J]. Osteoarthr Cartil, 2018, 26(1): S292.
59	PUSTJENS M F, MASTBERGEN S C, STEEN-LOUWS C, et al. IL4-10 synerkine induces direct and indirect structural cartilage repair in osteoarthritis[J]. Osteoarthr Cartil, 2016, 24: S532.
60	OO W M, YU S P, DANIEL M S, et al. Disease-modifying drugs in osteoarthritis: current understanding and future therapeutics[J]. Expert Opin Emerg Drugs, 2018, 23(4): 331-347.

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