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

Osteoarthritis (OA) is among the leading causes of disability across the world. Presently no effective therapy of OA is available as neither the molecular mechanism of disease pathology nor the development and maintenance of articular cartilage is well understood. During OA, articular cartilage undergoes cellular and molecular changes reminiscent of transient cartilage, which is the embryonic precursor of endochondral bone. During endochondral ossification, a precise spatio-temporally regulated WNT-BMP signaling interplay dictates differentiation of a common progenitor pool to either articular or transient cartilage fate in adjacent domains. In the embryonic context, Wnt signaling promotes articular cartilage fate while transient cartilage differentiation is critically BMP signaling dependent. Moreover, any ectopic activation of BMP signaling leads to ectopic transient cartilage differentiation at the expense of articular cartilage. In this study, we show that BMP signaling is sufficient and necessary for the pathogenesis of OA by ectopically activating BMP signaling and depleting BMP ligands in adult mice articular cartilage, respectively. Analysis of human osteoarthritic specimens demonstrated association between OA and ectopic BMP signaling in the articular cartilage. Local inhibition of BMP signaling using a potent pharmacological inhibitor LDN-193189, when administered prophylactically, resulted in delayed onset and reduced severity of OA in mice. Additionally, the same treatment afforded protection against cartilage degeneration post onset of OA in a surgical model of OA in mice. Therefore, inhibiting BMP signaling and consequent block of transient cartilage differentiation within the cells of the joint cartilage can be a possible avenue for developing a disease modifying therapy for OA.