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

Abstract

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/β-catenin signaling pathway, which has been strongly implicated in OA pathogenesis. Effects of recombinant protein of FzD7 CRD on Wnt/β-catenin signaling and chondral destruction was evaluated in this study. Firstly, increased protein levels of FzD7, Wnt3a and β-catenin were detected in human OA cartilage implying that the canonical Wnt/β-catenin signaling mediated by Wnt3a and FzD7 executes an essential role in OA. Then we showed that FzD7 CRD antagonized the Wnt3a/β-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 intra-articular 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/β-catenin signaling. Targeting the FzD7 CRD may be a novel therapy for the treatment of OA.