PT  - JOURNAL ARTICLE
AU  - Steven K Pregizer
AU  - Ata M Kiapour
AU  - Mariel Young
AU  - Hao Chen
AU  - Michael Schoor
AU  - Zun Liu
AU  - Jiaxue Cao
AU  - Vicki Rosen
AU  - Terence D Capellini
TI  - Impact of broad regulatory regions on Gdf5 expression and function in knee development and susceptibility to osteoarthritis
AID  - 10.1136/annrheumdis-2017-212475
DP  - 2018 Mar 01
TA  - Annals of the Rheumatic Diseases
PG  - 450--450
VI  - 77
IP  - 3
4099  - http://ard.bmj.com/content/77/3/450.short
4100  - http://ard.bmj.com/content/77/3/450.full
SO  - Ann Rheum Dis2018 Mar 01; 77
AB  - Objectives Given the role of growth and differentiation factor 5 (GDF5) in knee development and osteoarthritis risk, we sought to characterise knee defects resulting from Gdf5 loss of function and how its regulatory regions control knee formation and morphology.Methods The brachypodism (bp) mouse line, which harbours an inactivating mutation in Gdf5, was used to survey how Gdf5 loss of function impacts knee morphology, while two transgenic Gdf5 reporter bacterial artificial chromosome mouse lines were used to assess the spatiotemporal activity and function of Gdf5 regulatory sequences in the context of clinically relevant knee anatomical features.Results Knees from homozygous bp mice (bp/bp) 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. bp/bp 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 Gdf5 were weakly active in the prenatal knee, while downstream regulatory sequences were active throughout life. Importantly, downstream but not upstream Gdf5 regulatory sequences fully restored all the key morphological features disrupted in the bp/bp mice.Conclusions Knee morphology is profoundly affected by Gdf5 absence, and downstream regulatory sequences mediate its effects by controlling Gdf5 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.