The CRD of Frizzled 7 exhibits chondroprotective effects in osteoarthritis via inhibition of the canonical Wnt3a/β-catenin signaling pathway

被引:11
作者
Ding, Zhenfei [1 ]
Lu, Wei [1 ]
Dai, Ce [1 ]
Huang, Wei [3 ]
Liu, Fuen [1 ]
Shan, Wenshan [1 ]
Cheng, Chao [1 ]
Xu, Jiegou [2 ]
Yin, Zongsheng [1 ]
He, Wei [2 ]
机构
[1] Anhui Med Univ, Dept Orthopaed, Affiliated Hosp 1, 218 Ji Xi Rd, Hefei 230032, Anhui, Peoples R China
[2] Anhui Med Univ, Sch Basic Med Sci, 81 Mei Shan Rd, Hefei 230032, Anhui, Peoples R China
[3] Univ Sci & Technol China, Affiliated Hosp 1, Dept Orthopaed, Div Life Sci & Med, Hefei 230001, Anhui, Peoples R China
基金
中国国家自然科学基金;
关键词
Osteoarthritis; Wnt; beta-catenin; Cysteine-rich domain; Frizzled; Chondrocyte; WNT/BETA-CATENIN; CARTILAGE DEGRADATION; ARTICULAR CHONDROCYTES; WNT; EXPRESSION; RECOGNITION; PROTEIN-1; RECEPTORS; DISEASE; CELLS;
D O I
10.1016/j.intimp.2020.106367
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Osteoarthritis (OA) is a chronic inflammatory joint disease without effective drugs. Frizzled 7 (FzD7) binds its ligand Wnt3a through an extracellular cysteine-rich domain (CRD) to transduce the canonical Wnt/beta-catenin signaling pathway, which has been strongly implicated in OA pathogenesis. Effects of recombinant protein of FzD7 CRD on Wnt/beta-catenin signaling and chondral destruction was evaluated in this study. Firstly, increased protein levels of FzD7, Wnt3a and beta-catenin were detected in human OA cartilage implying that the canonical Wnt/beta-catenin signaling mediated by Wnt3a and FzD7 executes an essential role in OA. Then we showed that FzD7 CRD antagonized the Wnt3a/beta-catenin signaling pathway in a dose-dependent manner by binding Wnt3a. In addition, FzD7 CRD increased the expression of glycosaminoglycans (GAGs), Collagen II, aggrecan and reduced the expression of matrix metalloproteinase (MMP)-1, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) in Wnt3a-stimulated human chondrocytes. Furthermore, a single intraarticular injection of the FzD7 CRD was efficacious in destabilization of the medial meniscus (DMM) mouse OA model, significantly improving Osteoarthritis Research Society International (OARSI) histology scores compared to mice treated with PBS. The results indicate that the FzD7 CRD exhibits chondroprotective effects by binding Wnt3a to suppress the Wnt3a/beta-catenin signaling. Targeting the FzD7 CRD may be a novel therapy for the treatment of OA.
引用
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页数:10
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