Age-induced BMP signaling inhibits the ICAT-mediated Wnt pathway to promote osteoarthritis.

Abstract

Osteoarthritis (OA) is a highly prevalent and debilitating musculoskeletal disorder that affects billions of aging individuals worldwide, causing chronic pain, impaired mobility, and a substantial decline in quality of life, yet effective disease-modifying therapies remain unavailable. Moreover, existing experimental models, however, inadequately capture the complex, age-related factors that contribute to OA pathogenesis, limiting our understanding of underlying molecular mechanisms and hindering therapeutic development. To address this gap, we examined mouse articular cartilage (AC) during natural aging, without surgical or chemical intervention. In young AC, BMP ligand expression is restricted to the bone-cartilage junction, limiting BMP signaling despite widespread BMPR1A receptor expression, while Wnt/{beta}-catenin signaling predominates in the outer layers. With aging, BMP ligand expression expands throughout the cartilage, leading to widespread activation of BMP signaling, which induces ICAT expression, a known inhibitor of Wnt/{beta}-catenin signaling. This elevated BMP signaling triggers chondrocyte hypertrophy while concurrently suppressing Wnt/{beta}-catenin activity. Moreover, genetic or pharmacological activation of BMP signaling in young AC recapitulates the cellular and molecular features of aged cartilage, independent of chronological age. Collectively, our findings demonstrate that an age-dependent shift in BMP-Wnt signaling disrupts AC homeostasis and drives OA progression in mice. Author SummaryDespite the prevalence of osteoarthritis in aging individuals, there are no effective treatments that can stop or reverse disease progression. In this study, we investigated how joint cartilage changes during natural aging in mice. We observed that healthy, young articular cartilage exhibits robust Wnt/{beta}-catenin with minimal BMP siganling. With age, this balance shifts, with BMP signaling becoming dominant, coupled with reduced Wnt/{beta}-catenin activity. This disruption of Wnt-BMP homeostasis induces the pathogenesis of OA. Importantly, local inhibition of BMP signaling significantly alleviates the severity of the disease. Overall, these results show that age-associated changes in key signaling pathways drive OA progression and suggest potential targets for therapeutic intervention. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/616036v2_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@b2be12org.highwire.dtl.DTLVardef@dcb1f3org.highwire.dtl.DTLVardef@126fc40org.highwire.dtl.DTLVardef@7af96c_HPS_FORMAT_FIGEXP M_FIG C_FIG