Impact of broad regulatory regions on Gdf5 expression and function in knee development and susceptibility to osteoarthritis

Citation:

Pregizer SK, Kiapour AM, Young M, Chen H, Schoor M, Liu Z, Cao J, Rosen V, Capellini TD. Impact of broad regulatory regions on Gdf5 expression and function in knee development and susceptibility to osteoarthritis. Ann Rheum Dis [Internet]. 2018;77 (3) :450.

Date Published:

2018 03

Abstract:

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

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Last updated on 07/09/2019