Selenoprotein S deficiency activates Wnt/β-catenin signaling causing impaired terminal chondrocyte differentiation in Kashin-Beck disease.

Selenoproteins serve as the primary carriers for the biological functions of selenium (Se) within the body, which can harm health if deficient. Se deficiency is related to cartilage damage and osteoarticular diseases, wherein compromised chondrocyte function leads to disturbed cartilage homeostasis. Preliminary in vitro research showed that low selenium levels reduced chondrocyte selenoprotein S (SelS) expression, but the precise function of SelS in the terminal differentiation of chondrocytes, along with the signaling pathways by which SelS deficiency influences this process, has remained to be thoroughly clarified. This study, focusing on SelS deficiency, was the inaugural investigation into the mechanism by which SelS deficiency activates the Wnt/β-catenin pathway, resulting in impaired terminal differentiation of chondrocytes, and aims to provide an early intervention target for the prevention and treatment of bone and joint diseases associated to low selenium levels. SelS expression was initially evaluated in cartilage samples from rats fed a low-selenium diet and from patients with Kashin-Beck disease (KBD), and reduced SelS expression was found to be associated with cartilage degradation under selenium-deficient conditions. Using in vivo SelS knockout mice and in vitro chondrocyte models, it was found SelS deficiency reduced cartilage thickness and increased terminal differentiation markers OCN and Col1α1. RNA sequencing implicated the Wnt/β-catenin pathway, confirmed by functional rescue and inhibition experiments. SelS deficiency activates Wnt/β-catenin, impairing terminal differentiation and contributing to selenium-deficiency cartilage injury. This study offers critical insights into the pathogenesis of selenoprotein-related diseases and presents new experimental evidence regarding the aetiology of cartilage terminal differentiation-associated osteoarthritis, while also establishing a significant strategy for targeted interventions against selenium related diseases.