基于Wnt/β-catenin信号通路治疗骨关节炎研究热点及应用前景

doi:10.3969/j.issn.2095-4344.2714

中国组织工程研究 ›› 2020, Vol. 24 ›› Issue (29): 4724-4730.doi: 10.3969/j.issn.2095-4344.2714

• 组织构建综述 tissue construction review • 上一篇下一篇

基于Wnt/β-catenin信号通路治疗骨关节炎研究热点及应用前景

贝涛，刘军廷，黄秋霖，苏伟，赵劲民

广西医科大学第一附属医院创伤骨科手外科，广西壮族自治区南宁市 530021

收稿日期:2019-11-08 修回日期:2019-11-14 接受日期:2020-01-02 出版日期:2020-10-18 发布日期:2020-09-15
通讯作者: 赵劲民，主任医师，教授，博士生导师，广西医科大学第一附属医院创伤骨科手外科，广西壮族自治区南宁市 530021
作者简介:贝涛，男，1984年生，河南省平舆县人，汉族，广西医科大学在读博士，主治医师，主要从事组织工程，创伤骨科手外科研究。
基金资助:
广西科技基地和人才专项(桂科AD17129012); 广西大学生创新创业训练计划项目(201910598010)

Wnt/beta-catenin signaling pathway in the treatment of osteoarthritis: new advances and application prospects

Bei Tao, Liu Junting, Huang Qiulin, Su Wei, Zhao Jinmin

Department of Traumatic Orthopaedics and Hand Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China

Received:2019-11-08 Revised:2019-11-14 Accepted:2020-01-02 Online:2020-10-18 Published:2020-09-15
Contact: Zhao Jinmin, Chief physician, Professor, Doctoral supervisor, Department of Traumatic Orthopaedics and Hand Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
About author:Bei Tao, MD candidate, Attending physician, Department of Traumatic Orthopaedics and Hand Surgery , the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Supported by:
Guangxi Key Research and Development plan, No. guikeAD17129012; Guangxi University Student Innovation and Entrepreneurship Training Program, No. 201910598010

摘要/Abstract

摘要：

文题释义：

Wnt信号通路：Wnt是Wingless/Integrated的缩写，由配体蛋白质Wnt和膜蛋白受体结合，激发的一组多下游通道的信号转导的途径，该信号通路在不同的动物物种间极为相似，遗传学上具有高度保守性。通过该途径，细胞表面受体胞内段将活化，将细胞外的信号传递到细胞内。表现为两种信号传导方式，分别是胞间交流(旁分泌)和自体细胞交流(自分泌)，经典代表有：Wnt/β-catenin信号通路、平面细胞极性通路(Wnt/PCP通路)和Wnt/Ca²⁺通路。

骨硬化蛋白：由Sost基因编码，是一种分泌型半胱氨酸结蛋白，是Wnt共受体和低蛋白脂蛋白相关受体蛋白5 /低蛋白脂蛋白相关受体蛋白6相关受体的拮抗剂，作用于通路的上游，抑制Wnt 信号通路，从而起到软骨保护作用。

背景：Wnt/β-catenin信号通路在骨关节炎的发展中起着重要的作用。

目的：基于Wnt/β-catenin信号通路，对骨关节炎的研究进展做一综述。

方法：查阅PubMed、中国知网和万方数据库，以“catenin；wnt；osteoarthritis；arthritis；degenerative；arthritides；deformans；pathway；wnt signaling；signaling pathway；wnt signaling pathways；wnt beta catenin signaling pathway；canonical wnt pathway；canonical wnt；骨关节炎”为检索词，分别组合检索，

查找Wnt/β-catenin信号通路治疗骨关节炎的文献，最终纳入74篇文献进行分析。

结果与结论：基于Wnt/β-catenin信号通路治疗骨关节炎，主要途径有天然的拮抗剂、小分子抑制剂、激动剂、中草药和药物重新定位等方面。药物作用途径通过激活或者抑制Wnt/β-catenin信号通路，对软骨起到保护作用。通过Wnt/β-catenin信号通路治疗骨关节炎，目前处于实验性研究阶段，但具有较好应用前景。如何精准调控通路，更好的转化应用，有望成为未来研究的热点。

ORCID: 0000-0002-9553-7171(贝涛)

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

关键词: 骨关节炎, Wnt/β-catenin, 信号通路, 软骨

Abstract:

BACKGROUND: Wnt/β-catenin signaling pathway plays a vital role in the development of osteoarthritis. OBJECTIVE: To review the recent progress of treating osteoarthritis based on the Wnt/β-catenin signaling pathway.

METHODS: An electronical literature retrieval of PubMed, CNKI and WanFang databases was performed to search the literatures concerning the Wnt/β-catenin pathway in the treatment of osteoarthritis. The keywords

were “catenin; wnt; osteoarthritis;arthritis; degenerative; arthritides; deformans; pathway; wnt signaling; signaling pathway; wnt signaling pathways; wnt beta catenin signaling pathway; canonical wnt pathway; canonical wnt” in English and Chinese, respectively. Finally, 74 articles were included in result analysis.

RESULTS AND CONCLUSION: The potential treatments of osteoarthritis based on the Wnt/β-Catenin signal pathway include natural antagonists, small molecule inhibitors, agonists, traditional Chinese medicine and drug reposition. These drug pathways provide chondroprotective effect via activating or inhibiting the Wnt/β-catenin signaling pathway. The treatment of osteoarthritis based on the Wnt/β-catenin signaling pathway is currently in the laboratory stage, but it has a great application prospect. How to accurately regulate the pathway and better transfer the research results into the application will become a hotspot in the future.

Key words: osteoarthritis, Wnt/β-catenin, signaling pathway, cartilage

中图分类号:

贝涛, 刘军廷, 黄秋霖, 苏伟, 赵劲民. 基于Wnt/β-catenin信号通路治疗骨关节炎研究热点及应用前景[J]. 中国组织工程研究, 2020, 24(29): 4724-4730.

Bei Tao, Liu Junting, Huang Qiulin, Su Wei, Zhao Jinmin. Wnt/beta-catenin signaling pathway in the treatment of osteoarthritis: new advances and application prospects[J]. Chinese Journal of Tissue Engineering Research, 2020, 24(29): 4724-4730.

图/表（结果） 3

参考文献

[1] LOESER RF, GOLDRING SR, SCANZELLO CR, et al. Osteoarthritis: A disease of the joint as an organ. Arthritis & Rheumatism. 2012;64(6):1697-1707.

[2] ZHOU Y, WANG T, HAMILTON JL, et al. Wnt/β-catenin Signaling in Osteoarthritis and in Other Forms of Arthritis. Current Rheumatology Reports. 2017;19(9).

[3] 王超华,朱梅. Wnt/β-catenin信号通路与骨关节炎[J].中华骨质疏松和骨矿盐疾病杂志,2011,4(2):122-126.

[4] WU Q, ZHU M, ROSIER RN, et al. β-catenin, cartilage, and osteoarthritis. Annals of the New York Academy of Sciences. 2010;1192(1):344-350.

[5] 中华医学会骨科学分会关节外科学组.骨关节炎诊疗指南(2018年版)[J].中华骨科杂志,2018,38(12):705-715.

[6] 王华敏,宓轶群,刚嘉鸿.信号通路在膝骨关节炎实验研究中的进展[J].中国组织工程研究,2016,20(2):267-272.

[7] YUASA T, OTANI T, KOIKE T, et al. Wnt/beta-catenin signaling stimulates matrix catabolic genes and activity in articular chondrocytes: its possible role in joint degeneration. Lab Invest.2008;88(3):264-274.

[8] VAN DEN BOSCH MH, BLOM AB, SLOETJES AW, et al. Induction of Canonical Wnt Signaling by Synovial Overexpression of Selected Wnts Leads to Protease Activity and Early Osteoarthritis-Like Cartilage Damage. Am J Pathol. 2015;185(7):1970-1980.

[9] GUO X, DAY TF, JIANG X, et al. Wnt/beta-catenin signaling is sufficient and necessary for synovial joint formation. Genes Dev. 2004;18(19):2404-2417.

[10] SPATER D, HILL TP, GRUBER M, et al. Role of canonical Wnt-signalling in joint formation. Eur Cell Mater. 2006;12: 71-80.

[11] MONTEAGUDO S, LORIES RJ. Cushioning the cartilage: a canonical Wnt restricting matter. Nature Reviews Rheumatology. 2017;13(11):670-681.

[12] JI Q, XU X, KANG L, et al. Hematopoietic PBX-interacting protein mediates cartilage degeneration during the pathogenesis of osteoarthritis. Nat Commun. 2019;10(1):313.

[13] USAMI Y, GUNAWARDENA AT, IWAMOTO M, et al. Wnt signaling in cartilage development and diseases: lessons from animal studies. Lab Invest. 2016;96(2):186-196.

[14] JOHNSON ML, KAMEL MA. The Wnt signaling pathway and bone metabolism. Curr Opin Rheumatol. 2007;19(4):376-382.

[15] WANG Y, FAN X, XING L, et al. Wnt signaling: a promising target for osteoarthritis therapy. Cell Commun Signal. 2019; 17(1):97.

[16] LORIES RJ, CORR M, LANE NE. To Wnt or not to Wnt: the bone and joint health dilemma. Nat Rev Rheumatol. 2013; 9(6):328-39.

[17] BOUAZIZ W, FUNCK-BRENTANO T, LIN H, et al. Loss of sclerostin promotes osteoarthritis in mice via beta-catenin- dependent and -independent Wnt pathways. Arthritis Res Ther. 2015;17:24.

[18] THYSEN S, LUYTEN FP, LORIES RJ. Loss of Frzb and Sfrp1 differentially affects joint homeostasis in instability-induced osteoarthritis. Osteoarthritis Cartilage. 2015;23(2):275-279.

[19] DAY TF, GUO X, GARRETT-BEAL L, et al. Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell. 2005;8(5):739-750.

[20] CORR M. Wnt-β-catenin signaling in the pathogenesis of osteoarthritis. Nature Clinical Practice Rheumatology. 2008; 4(10):550-556.

[21] CLEVERS H, NUSSE R. Wnt/beta-catenin signaling and disease. Cell.2012;149(6):1192-1205.

[22] YANO F, KUGIMIYA F, OHBA S, et al. The canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner. Biochem Biophys Res Commun. 2005;333(4):1300-1308.

[23] NG LF, KAUR P, BUNNAG N, et al. WNT Signaling in Disease. Cells. 2019;8(8). pii: E826.

[24] CADIGAN KM, NUSSE R. Wnt signaling: a common theme in animal development. Genes Dev.1997;11(24): 3286-3305.

[25] BLOM AB, BROCKBANK SM, VAN LENT PL, et al. Involvement of the Wnt signaling pathway in experimental and human osteoarthritis: prominent role of Wnt-induced signaling protein 1. Arthritis Rheum. 2009;60(2):501-512.

[26] RYU JH. Regulation of the chondrocyte phenotype by beta-catenin. Development. 2002;129(23):5541-5550.

[27] WANG MN, SAMPSON ER, JIN HT, et al. MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Research & Therapy. 2013;15(1).

[28] ZHU M, TANG D, WU Q, et al. Activation of β-Catenin Signaling in Articular Chondrocytes Leads to Osteoarthritis- Like Phenotype in Adult β-Catenin Conditional Activation Mice. Journal of Bone and Mineral Research. 2009;24(1):12-21.

[29] ZHU M, CHEN M, ZUSCIK M, et al. Inhibition of beta-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum. 2008;58(7):2053-264.

[30] 于彩云,刘重慧,魏涛.靶向Wnt/β-catenin信号通路抑制剂研究进展[J]. 河南师范大学学报(自然科学版), 2016;44(2):125-130.

[31] ONUORA S. Wnt inhibitor shows potential as a DMOAD. Nature Reviews Rheumatology. 2017;13(11):634.

[32] HUANG Y, JIANG L, YANG H, et al. Variations of Wnt/beta-catenin pathway-related genes in susceptibility to knee osteoarthritis: A three-centre case-control study. J Cell Mol Med. 2019;23(12):8246-8257.

[33] TONG W, ZENG Y, CHOW DHK, et al. Wnt16 attenuates osteoarthritis progression through a PCP/JNK-mTORC1- PTHrP cascade. Ann Rheum Dis. 2019;78(4):551-561.

[34] CHAN BY, FULLER ES, RUSSELL AK, et al. Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis. Osteoarthritis Cartilage. 2011;19(7):874-885.

[35] WU J, MA L, WU L, et al. Wnt-β-catenin signaling pathway inhibition by sclerostin may protect against degradation in healthy but not osteoarthritic cartilage. Molecular Medicine Reports. 2017;15(5):2423-2432.

[36] BOUAZIZ W, FUNCK-BRENTANO T, LIN H, et al. Loss of sclerostin promotes osteoarthritis in mice via β-catenin- dependent and -independent Wnt pathways. Arthritis Res Ther. 2015;17(1):24.

[37] CHANG JC, CHRISTIANSEN BA, MURUGESH DK, et al. SOST/Sclerostin Improves Posttraumatic Osteoarthritis and Inhibits MMP2/3 Expression After Injury. J Bone Miner Res. 2018;33(6):1105-1113.

[38] DESHMUKH V, O'GREEN AL, BOSSARD C, et al. Modulation of the Wnt pathway through inhibition of CLK2 and DYRK1A by lorecivivint as a novel, potentially disease-modifying approach for knee osteoarthritis treatment. Osteoarthritis and Cartilage. 2019;27(9):1347-1360.

[39] DESHMUKH V, HU H, BARROGA C, et al. A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee. Osteoarthritis and Cartilage. 2018;26(1):18-27.

[40] YAZICI Y, MCALINDON TE, FLEISCHMANN R, et al. A novel Wnt pathway inhibitor, SM04690, for the treatment of moderate to severe osteoarthritis of the knee: results of a 24-week, randomized, controlled, phase 1 study. Osteoarthritis Cartilage. 2017;25(10):1598-1606.

[41] JONES SE, JOMARY C. Secreted Frizzled-related proteins: searching for relationships and patterns. Bioessays. 2002; 24(9):811-820.

[42] LORIES RJU, PEETERS J, BAKKER A, et al. Articular cartilage and biomechanical properties of the long bones inFrzb-knockout mice. Arthritis Rheum. 2007;56(12): 4095-4103.

[43] LIETMAN C, WU B, LECHNER S, et al. Inhibition of Wnt/β-catenin signaling ameliorates osteoarthritis in a murine model of experimental osteoarthritis. JCI Insight. 2018;3(3). pii: 96308.

[44] MIN S, WANG C, LU W, et al. Serum levels of the bone turnover markers dickkopf-1, osteoprotegerin, and TNF-alpha in knee osteoarthritis patients. Clin Rheumatol. 2017;36(10): 2351-2358.

[45] HONSAWEK S, TANAVALEE A, YUKTANANDANA P, et al. Dickkopf-1 (Dkk-1) in plasma and synovial fluid is inversely correlated with radiographic severity of knee osteoarthritis patients. BMC Musculoskelet Disord. 2010;11:257.

[46] OH H, CHUN CH, CHUN JS. Dkk-1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice. Arthritis Rheum. 2012;64(8):2568-2578.

[47] FUNCK-BRENTANO T, BOUAZIZ W, MARTY C, et al. Dkk-1-mediated inhibition of Wnt signaling in bone ameliorates osteoarthritis in mice. Arthritis Rheumatol. 2014; 66(11):3028-3039.

[48] 王晓凯,张志成,孙天胜. SIRT1的生理作用及调控机制的研究进展[J].中华临床医师杂志(电子版),2011,5(24):7315-7318.

[49] LI Y, XIAO W, WU P, et al. The expression of SIRT1 in articular cartilage of patients with knee osteoarthritis and its correlation with disease severity. J Orthop Surg Res. 2016; 11(1):144.

[50] HE DS, HU XJ, YAN YQ, et al. Underlying mechanism of Sirt1 on apoptosis and extracellular matrix degradation of osteoarthritis chondrocytes. Mol Med Rep. 2017;16(1): 845-850.

[51] 钟翔,彭婷,涂月菊,等. WISP-1在IgA肾病患者中的表达与肾间质纤维化的关系[J]. 中华肾脏病杂志,2017,33(9):649-655.

[52] VAN DEN BOSCH MHJ, RAMOS YFM, den Hollander W,et al. Increased WISP1 expression in human osteoarthritic articular cartilage is epigenetically regulated and decreases cartilage matrix production. Rheumatology (Oxford). 2019;58(6): 1065-1074.

[53] LANDMAN EB, MICLEA RL, VAN BLITTERSWIJK CA, et al. Small molecule inhibitors of WNT/beta-catenin signaling block IL-1beta- and TNFalpha-induced cartilage degradation. Arthritis Res Ther.2013;15(4):R93.

[54] 鄢德洪,徐美晨,王婧惠,等.青蒿素类药物靶标及其免疫调节抗肿瘤机制研究进展[J].免疫学杂志,2018,34(8):713-21.

[55] ZHONG G, LIANG R, YAO J, et al. Artemisinin Ameliorates Osteoarthritis by Inhibiting the Wnt/β-Catenin Signaling Pathway. Cellular Physiology and Biochemistry. 2018;51(6): 2575-2590.

[56] WENG X, LIN P, LIU F, et al.Achyranthes bidentata polysaccharides activate the Wnt/β-catenin signaling pathway to promote chondrocyte proliferation.Int J Mol Med. 2014; 34(4):1045- 1050.

[57] 马勇,王礼宁,郭杨,等.姜黄素通过调节Wnt/β-catenin信号通路促进软骨细胞增殖的研究[J].广州中医药大学学报,2017,34(1): 90-95.

[58] 陈琼,赵明才,陈悦,等. 姜黄素对骨关节炎软骨细胞增殖及分泌MMP-13,IL-6的影响[J]. 现代中西医结合杂志,2013,22(5): 459-61.

[59] 李洪涛,刘昊,杨方军,等. 针对膝关节骨性关节炎大鼠关节软骨中Wnt3a､β-catenin蛋白表达的影响[J].针灸临床杂志.2017, 33(3):65-68.

[60] 张媛媛,李西海,吴明霞.电针调节Wnt/β-catenin信号通路抑制大鼠膝骨关节炎软骨退变的研究[J].中国针灸,2019,39(10): 1081-1086.

[61] 谢晚晴,郑洪新.基于Wnt/β-catenin信号通路的中医药干预骨关节炎的研究进展[J].中国骨质疏松杂志,2018;24(5):664-670.

[62] 崔建梅,尹大力.药物重新定位策略在新药发现中的应用与进展[J].中国药学杂志,2005,40(20):8-10.

[63] TAKAMATSU A, OHKAWARA B, ITO M, et al. Verapamil protects against cartilage degradation in osteoarthritis by inhibiting Wnt/beta-catenin signaling. PLoS One. 2014;9(3): e92699.

[64] MA L, LIU Y, ZHAO X, et al. Rapamycin attenuates articular cartilage degeneration by inhibiting β-catenin in a murine model of osteoarthritis. Connect Tissue Res.2019;60(5): 452-462.

[65] MIYAMOTO K, OHKAWARA B, ITO M, et al. Fluoxetine ameliorates cartilage degradation in osteoarthritis by inhibiting Wnt/beta-catenin signaling. PLoS One. 2017; 12(9):e0184388.

[66] NAITO M, OHASHI A, TAKAHASHI T. Dexamethasone inhibits chondrocyte differentiation by suppression of Wnt/beta-catenin signaling in the chondrogenic cell line ATDC5. Histochem Cell Biol. 2015;144(3):261-272.

[67] HUANG K, WU LD. Dehydroepiandrosterone: Molecular mechanisms and therapeutic implications in osteoarthritis. J Steroid Biochem Mol Biol. 2018;183:27-38.

[68] BAI M, GE L, CHEN H, et al. Calcitonin protects rat chondrocytes from IL‑1β injury via the Wnt/β‑catenin pathway. Exp Ther Med. 2019;18(3):2079-2085.

[69] MA L, WU J, JIN QH. The association between parathyroid hormone 134 and the Wnt/betacatenin signaling pathway in a rat model of osteoarthritis. Mol Med Rep. 2017;16(6): 8799-8807.

[70] ZHANG Y, HUANG X, YUAN Y. MicroRNA-410 promotes chondrogenic differentiation of human bone marrow mesenchymal stem cells through down-regulating Wnt3a. Am J Transl Res. 2017;9(1):136-145.

[71] BOUAZIZ W, SIGAUX J, MODROWSKI D, et al. Interaction of HIF1alpha and beta-catenin inhibits matrix metalloproteinase 13 expression and prevents cartilage damage in mice. Proc Natl Acad Sci U S A. 2016;113(19):5453-5458.

[72] SUN Y, WANG F, SUN X, et al. CX3CR1 regulates osteoarthrosis chondrocyte proliferation and apoptosis via Wnt/beta-catenin signaling. Biomed Pharmacother. 2017;96: 1317-1323.

[73] ZHONG L, SCHIVO S, HUANG X, et al. Nitric Oxide Mediates Crosstalk between Interleukin 1beta and WNT Signaling in Primary Human Chondrocytes by Reducing DKK1 and FRZB Expression. Int J Mol Sci. 2017;18(11). pii: E2491.

[74] CHEN YY, CHEN Y, WANG WC, et al. Cyclin D1 regulates osteoarthritis chondrocyte apoptosis via WNT3/beta-catenin signalling. Artif Cells Nanomed Biotechnol. 2019;47(1): 1971-1977.

引言

骨关节炎又称退行性骨关节病，临床症状主要表现为疼痛、关节僵硬和功能障碍，由于发病率较高，目前已经成为一个全世界公共健康问题^[1^-^2]。骨关节炎病理学改变主要为软骨退变、软骨下骨增生、骨赘形成及滑膜增生^[1]。研究发现骨关节炎患者的关节软骨中，白细胞介素8、白细胞介素1和肿瘤坏死因子α等细胞因子合成增多，金属蛋白酶类和蛋白聚糖酶类(Aggrecanases，ADAMTS)等基质降解酶合成增加，导致软骨细胞外基质分解，尤其是Ⅱ型胶原、蛋白聚糖和糖胺多糖类的分解，从而导致软骨退变，出现剥脱、皲裂和软骨下骨外露，进而出现关节间隙的变窄和导致骨关节炎的发生^[3-4]。

骨关节炎的诱因有很多因素，包括年龄、种族、基因、创伤、畸形、炎症、关节不稳定、关节的慢性损伤和先天性疾病等^[5]。骨关节炎的软骨内合成和分解代谢失衡，可导致软骨进行性退变，但发病机制尚未清楚，信号通路在骨关节炎的发生进展中起重要的作用^[6]。软骨表型从静息状态向肥大状态转化，是骨关节炎一个主要的病理学特点，而这个转换通常伴随着经典的Wnt/β-catenin信号通路的激活^[7^-^8]。Wnt/β-catenin信号通路不仅仅在机体胚胎时期的骨骼关节发生发育中起作用^[9^-^10]，而且对成熟机体的关节软骨、滑膜和成骨细胞起着调节作^[11-15]。Wnt信号通路的关键分子(如Wnt16、Wnt2、Wnt3a和Wnt5b)在骨关节炎软骨或者骨膜中发现高表达，而Wnt信号通路的拮抗剂(如骨硬化蛋白、SM04690、sFRP、XAV939、C113、DKK1、Sirt1、WISP-1、PKF115-584、PKF118-310 和 CGP049090等)在骨关节炎软骨表达下调^[16]。骨硬化蛋白为Wnt信号通路的一个较强的拮抗剂，该基因敲除小鼠较野生型更容易发生骨关节炎，而使用骨硬化蛋白治疗后，则可逆转关节软骨的损伤^[17]。分泌型卷曲体相关蛋白3(secreted frizzled-related protein 3，sFRP3)的单核苷酸多态性(Single nucleotide polymorphism，SNP)证明 Arg324Gly羟基端替换，可增加负重关节患骨关节炎的风险，sFRP基因敲除可增加小鼠对骨关节炎的易感性^[18]。文章就基于Wnt/β-catenin通路方面治疗骨关节炎进展作一综述。

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

材料方法

讨论

早期骨关节炎，没有非常特效的治疗方法。在病变的早期，软骨出现代谢平衡紊乱，此时，关节软骨无破坏，膝关节无形变。早期如能进行有效的干预，有望取得较满意的效果。骨关节炎的发病机制相当复杂，Wnt/β-catenin信号通路是发病机制中较为重要的机制之一。其他骨关节炎有关的信号通路如转化生长因子β、Notch、Hippo-YAP、MAPKs、p38、ERK1/2等，也有学者在研究。

Wnt信号通路的小分子抑制剂在实验研究方面，取得了较好的效果，但目前的研究大多还在实验室阶段，到临床应用还有一定的距离。目前，只有SM04690进入了Ⅱ期临床试验阶段。此类药物需要关腔内注射，给患者的应用带来不便，研究一种应用方便的可口服制剂也是一个重要的方向。开发通过Wnt信号通路作用骨关节炎的药物，实现膝关节炎早期治疗，将从科研到临床的转化的重大突破，也是未来的研究方向。

中草药治疗骨关节炎的机制比较复杂，有可能出现双向调节或不同作用位点起作用，即在同一个通路，抑制其活性起作用，也可通过抑制激活该通路的某个作用位点起作用。此外，是否同时对其他信号通路如转化生长因子β、Notch等通路也起到类似作用，是否存在不同信号通路的相互作用还需要进一步研究和探讨。目前研究显示，中草药对Wnt/β-catenin信号通路有抑制作用，具体的抑制位点还需要深入研究。Wnt信号通路的小分子抑制剂和中草药等，有望成为治疗早期骨关节炎的有效手段，将来在临床应用方面，需要更多样本和开展多中心随机对照临床试验，进一步的在实践中验证。

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

基于Wnt/β-catenin信号通路治疗骨关节炎研究热点及应用前景

Wnt/beta-catenin signaling pathway in the treatment of osteoarthritis: new advances and application prospects

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