Impact of Broad Regulatory Regions on Gdf5 Expression and Function in Knee Development and Susceptibility to Osteoarthritis

摘要: Objectives Given the role of growth and differentiation factor 5 ( GDF5 ) in knee development osteoarthritis risk, we sought to characterise defects resulting from Gdf5 loss function how its regulatory regions control formation morphology. Methods The brachypodism bp mouse line, which harbours an inactivating mutation , was used survey impacts morphology, while two transgenic reporter bacterial artificial chromosome lines were assess spatiotemporal activity sequences context clinically relevant anatomical features. Results Knees homozygous mice bp/bp exhibit underdeveloped femoral condyles tibial plateaus, no cruciate ligaments, poorly developed menisci. Secondary ossification is also delayed distal femur proximal tibia. have significantly narrower condyles, notches curvier medial shallower trochlea, steeper lateral slopes smaller spines. Regulatory upstream weakly active prenatal knee, downstream throughout life. Importantly, but not fully restored all key morphological features disrupted mice. Conclusions Knee morphology profoundly affected by absence, mediate effects controlling expression tissues. This region contains numerous enhancers harbouring human variants that span association interval. We posit subtle alterations driven changes sequence underlie this locus’ risk.