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

A mechanistic framework for age-induced osteoarthritis (OA) has remained largely elusive, leading to challenges in designing effective therapies for this debilitating disorder. Meanwhile, the models that induce OA in young animals through surgical, pharmacological, or genetic alterations fail to mimic OA that stems with age. In this study, we examined the molecular, cellular, and radiological changes in the articular cartilage (AC) of the C57BL/6J wild-type mice from postnatal day 15 to 3 years of age. In juvenile mice, AC, while all the layers express the BMPR1A receptor, only a thin layer of cells in the deep zone of AC express BMP ligands, and chondrocyte hypertrophy ensues first in this layer. With age, the BMP ligands’ expression domain expands throughout the AC, leading to BMP signaling activation and resultant chondrocyte hypertrophy. Further, exposure to healthy AC with BMP ligands was sufficient to induce premature OA-like changes in the young adult mice, suggesting BMP signaling is the limiting factor behind age-induced OA. We found that activation of BMP signaling upregulates ICAT expression, a known inhibitor of the canonical Wnt pathway in the AC. Our results suggest that with aging, the spread of BMP signaling throughout the cartilage is a certainty and the underlying cause for age-induced OA. Further, in situ inhibition of BMP signaling appears to be a potent therapeutic strategy for age-induced OA.