Regulation of Gdf5 expression in joint remodelling, repair and osteoarthritis

Abstract

AbstractGrowth and Differentiation Factor 5 (GDF5) is a key risk locus for osteoarthritis (OA). However, little is known regarding regulation ofGdf5expression following joint tissue damage. Here, we employedGdf5-LacZreporter mouse lines to assess the spatiotemporal activity ofGdf5regulatory sequences in experimental OA following destabilisation of the medial meniscus (DMM) and after acute cartilage injury and repair.Gdf5expression was upregulated in articular cartilage post-DMM, and was increased in human OA cartilage as determined by immunohistochemistry and microarray analysis.Gdf5expression was also upregulated during cartilage repair in mice and was switched on in injured synovium in prospective areas of cartilage formation, where it inversely correlated with expression of the transcriptional co-factor Yes-associated protein (Yap). Indeed, overexpression of Yap suppressedGdf5expression in chondroprogenitorsin vitro.Gdf5expression in both mouse injury models required regulatory sequence downstream ofGdf5coding exons. Our findings suggest thatGdf5upregulation in articular cartilage and synovium is a generic response to knee injury that is dependent on downstream regulatory sequence and in progenitors is associated with chondrogenic specification. We propose a role for Gdf5 in tissue remodelling and repair after injury, which may partly underpin its association with OA risk.