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Given  GDF5  involvement in hip development, and osteoarthritis (OA) and developmental hip dysplasia (DDH) risk, here we sought to assess the role(s) of  GDF5  and its regulatory sequence on the development of hip morphology linked to injury risk. The  brachypodism (bp)  mouse, which harbors a  Gdf5  inactivating mutation, was used to survey how  Gdf5  loss of function impacts the development of hip morphology. Two transgenic  Gdf5  reporter BAC lines were used to assess the spatiotemporal expression of  Gdf5  regulatory sequences. Each BAC line was also used to assess the functional roles of upstream and downstream sequence on hip morphology.  bp/bp  mice had shorter femora with smaller femoral heads and necks as well as larger alpha angles, smaller anterior offsets, and smaller acetabula, compared to  bp/+  mice (p<0.04). Regulatory sequences downstream of  Gdf5  drove strong prenatal (E17) expression and low postnatal (6 months) expression across regions of femoral head and acetabulum. Conversely, upstream regulatory sequences drove very low expression at E17 and no detectable expression at 6 months. Importantly, downstream, but not upstream  Gdf5  regulatory sequences fully restored all the key morphologic features disrupted in  bp/bp  mice. Hip morphology is profoundly affected by  Gdf5  absence, and downstream regulatory sequences mediate its effects by controlling  Gdf5  expression during development. This downstream region contains numerous enhancers harboring risk variants related to hip OA, DDH, and dislocation. We posit that subtle alterations to morphology driven by changes in downstream regulatory sequence underlie this locus’ role in hip injury risk.

The role of Gdf5 regulatory regions in development of hip morphology