CTHRC1 inhibits the proliferation and promotes apoptosis of osteoarthritis chondrocytes by activating Wnt / ß-Catenin pathway

Abstract

This study aimed to elucidate the function of CTHRC1 and its linkage to the Wnt/β-catenin signaling pathway in the pathogenesis of osteoarthritis (OA), and to preliminarily explore whether a similar molecular interplay exists in rheumatoid arthritis (RA). We employed an integrated strategy combining bioinformatics, in vitro, and in vivo approaches. Bioinformatic screening of GEO-derived RNA-seq data identified CTHRC1 as a key differentially expressed gene in osteoarthritis. Its functional role was subsequently investigated in OA chondrocyte models, where we measured proliferation (via CCK-8 and EdU assays) and apoptosis (by Western blot analysis of Bax, Bcl-2, and Cleaved Caspase-3), along with key proteins in the Wnt/β-catenin pathway. Furthermore, to assess its relevance to inflammatory arthritis in vivo, we utilized a collagen-induced arthritis (CIA) rat model, evaluating clinical arthritis indices, inflammatory cytokine levels, and joint histopathology by HE staining. We found that CTHRC1 expression was significantly upregulated in OA tissues. Functional enrichment analysis indicated its close association with the Wnt/β-catenin signaling pathway. In vitro experiments confirmed increased CTHRC1 expression in IL-1β–induced OA chondrocytes, while knockdown of CTHRC1 effectively promoted cell proliferation and inhibited apoptosis. Mechanistic studies revealed that the protective effects of CTHRC1 knockdown were reversed by the Wnt/β-catenin pathway agonist BML-284, confirming that CTHRC1 mediates chondrocyte degeneration through activation of this pathway. Furthermore, intra- articular knockdown of CTHRC1 in a CIA rat model significantly alleviated joint swelling, reduced levels of inflammatory factors (IL-1β, IL-6, and TNF-α), and effectively mitigated synovial inflammation and collagen deposition. This study identifies CTHRC1 as an upregulated gene in OA and validates its role in promoting chondrocyte dysfunction. CTHRC1 knockdown reverses these effects by attenuating Wnt/β-catenin signaling, a mechanism confirmed by pharmacological rescue. Preliminary in vivo evidence further suggests a similar pathogenic role in RA. Collectively, CTHRC1 emerges as a potential therapeutic target in arthritis through modulation of the Wnt/β-catenin axis.