Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Gdf5 Deficient Mice Have Increased Susceptibility to Osteoarthritis
Daans, Melina, Luyten, Frank P., Lories, Rik J.
A functional polymorphism leading to reduced levels of growth and differentiation factor-5 (GDF5) was recently identified as a susceptibility factor for osteoarthritis (OA). GDF5, also known as cartilage derived morphogenetic protein (CDMP1) is a member of the bone morphogenetic protein family originally identified from a chondrogenic extract of articular cartilage. During development the gene is expressed in early stages of chondrogenesis and in the prospective joint interzone. Postnatally, GDF5 biology has not only been associated with cartilage but also with ligaments and tendons. Mice with a spontaneous mutation in the Gdf5 gene (brachypodism mouse, Gdf5Bp-J/Bp-J) develop a severe phenotype with joint fusions and shortening of the skeletal elements. Here, we studied the role and mechanism of Gdf5 involvement in OA using haploinsufficient Gdf5Bp-J/+ mice.
Gdf5Bp-J/+ mice were kept on a CD1/Swiss genetic background. OA development was studied in the collagenase-induced arthritis model, the medial meniscus destabilization model, the papain-induced arthritis model and a treadmill running model. Bone density and subchondral bone parameters were determined using DEXA and peripheral quantitative computed tomography (pQCT). Additional in vitro and ex vivo analyses studied cartilage metabolism, gait and collagen characteristics.
Gdf5Bp-J/+ mice appear phenotypically normal but show discrete signs of haploinsufficiency during limb development and in trabecular bone area. Gdf5Bp-J/+ mice developed more severe OA in the meniscal destabilization model, in the treadmill model and on the contralateral side in the collagenase-induced model but not in the papain-induced model. These data suggest that stability of the joint is impaired in Gdf5Bp-J/+ mice. This was confirmed by gait analysis demonstrating that distances between 2 steps are smaller in Gdf5Bp-J/+ mice as compared to wild-type mice. Cartilage breakdown analysis did not show differences between the mice but analysis of the subchondral bone demonstrated that Gdf5Bp-J/+ mice have a decreased subchondral bone density and a distorted arrangement of collagen fibers.
These data support a role for GDF5 in OA development. Of interest, the observed phenotypes pointed to an effect of decreased GDF5 levels on joint stability and subchondral bone rather than on the articular cartilage. This highlights the importance of the joint as an organ in concepts of joint disease.
To cite this abstract, please use the following information:
Daans, Melina, Luyten, Frank P., Lories, Rik J.; Gdf5 Deficient Mice Have Increased Susceptibility to Osteoarthritis [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1913