BMP signaling is necessary and sufficient for osteoarthritis and a target for disease modifying therapy

Abstract

ObjectiveTo investigate the role of BMP signaling in osteoarthritis' pathogenesis and propose a disease-modifying therapy for OA. MethodsC57BL6/J mouse line was used to perform ACLT surgery at P120 to study the expression pattern of the BMP signaling readout pSMAD1/5/9. To investigate whether activation of BMP signaling is sufficient and necessary to induce osteoarthritis, we have used conditional GOF and LOF mouse lines in which BMP signaling can be activated or depleted, respectively, upon intra-peritoneal injection of tamoxifen. Finally, we locally inhibited BMP signaling through intra-articular injection of LDN-193189 pre- and post-onset surgically induced OA. Most of the analysis has been done through immunohistochemistry, histopathological staining, and micro-CT to evaluate the status of the pathogenesis of the disease. ResultsWe observed concomitant activation of BMP signaling, as judged by pSMAD1/5/9 immunoreactivity in the articular cartilage, upon induction of osteoarthritis with simultaneous depletion of SMURF1, an intra-cellular BMP signaling inhibitor in articular cartilage. Even without surgical induction of osteoarthritis, only BMP gain-of-function mutation induces OA in mouse articular cartilage. Also, genetic, or pharmacological inhibition of BMP signaling offered significant protection against OA pathogenesis. Interestingly, post-onset of the disease, inhibition of BMP signaling by intra-articular injection of LDN-193189 retarded OA progression with a significant reduction in inflammatory markers. ConclusionOur study demonstrated that BMP signaling plays an essential role in the pathogenesis of OA and that local BMP inhibition can be an effective therapeutic strategy to mitigate osteoarthritis.