MSAB limits osteoarthritis development and progression through inhibition of β-catenin-DDR2 signaling

Abstract

The aberrant activation of the canonical Wnt/β-catenin signaling has been identified as a significant contributor to the pathogenesis of osteoarthritis (OA), exacerbating OA symptoms and driving OA progression. Despite its potential as a therapeutic target, clinical translation is impeded by the lack of a targeting delivery system and effective drug candidate that can modulate steady-state protein levels of β-catenin at post-translational level. Our study addresses these challenges by offering a new approach for OA treatment. To overcome these challenges, we introduced a novel delivery system using human serum albumin (HSA) to deliver a small molecule β-catenin inhibitor, Methyl-Sulfonyl AB (MSAB). This system is designed to enhance the bioavailability of MSAB, ensuring its accumulation inside the joint space, and facilitating the degradation of β-catenin protein. We have demonstrated that MSAB, when delivered via HSA, not only effectively inhibits cartilage damage but also ameliorates OA-related pain in an OA mouse model. We then performed proteomic analysis and biochemical studies to determine the molecular mechanisms underlying the therapeutic effects of MSAB. We identified that discoidin domain receptor 2 (DDR2), a critical mediator in OA pathology, is a downstream molecule of β-catenin signaling and β-catenin/TCF7 directly controls DDR2 gene transcription. MSAB suppressed the DDR2 expression in chondrocytes. MSAB ameliorated OA progression and OA-associated pain through inhibition of β-catenin-DDR2 signaling. This study underscores the efficacy of MSAB/HSA in OA treatment, providing new insights into its molecular mechanism of OA. It suggests that targeted therapies with MSAB/HSA could be a new OA management strategy.