The Wnt inhibitor Tiki2 maintains articular cartilage homeostasis and protects against osteoarthritis

Osteoarthritis (OA) is a common chronic joint disease with limited treatment options. Cartilage degeneration in OA is driven by increased matrix catabolism and decreased matrix production and is characterized by chondrocyte hypertrophy. Aberrant activation of both β-catenin–dependent and β-catenin–independent Wnt signaling is implicated in OA progression and represents a potential therapeutic target. Here, we investigated the role of Tiki2, a membrane-tethered proteolytic inhibitor of Wnt ligands, in OA. Expression of Tiki2 was reduced in a mouse model of OA induced by joint destabilization, and expression of TIKI2 was reduced across multiple independent human OA transcriptomic datasets. Tiki2 haploinsufficiency in mice led to spontaneous cartilage degeneration, and loss of Tiki2 accelerated the progression of instability-induced OA. Tiki2 suppressed Wnt3a-induced β-catenin signaling and Wnt5a-induced β-catenin–independent signaling in chondrocytes and promoted anabolic gene expression to preserve cartilage integrity. Intra-articular overexpression of human TIKI2 attenuated OA-associated cartilage degeneration in mice. In vitro, Tiki2 inhibited hypertrophic differentiation in primary mouse chondrocytes and ATDC5 cells, and overexpression of TIKI2 promoted chondrogenic differentiation in primary mouse and human chondrocytes. Together, these results identify Tiki2 as a regulator of articular cartilage homeostasis and OA susceptibility and suggest that enhancing Tiki2-mediated Wnt inhibition may be a potential disease-modifying strategy for OA.