Bone cartilage interactions via tgfβ and pathogenesis of osteoarthritis

Bone-Cartilage Interactions via TGFand Pathogenesis of Osteoarthritis
Xu Cao- Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD, USA

Osteoarthritis (OA) is a highly prevalent joint cartilage degeneration disorder. We investigated subchondral bone-articular cartilage as a functional unit in the joints during progression of OA. We found uncoupled osteoclasticbone resorption in the subchondral bone7 days post anterior cruciate ligament transaction (ACLT) of an OA mouse model. The levels of active TGFβ1 were significantly increased in the subchondral bone, which induced increase of mesenchymal stem cells (MSCs) and osterix+osteoprogenitorssignificantly in the subchondral bone marrow one month post ACLT, leading to uncoupled bone formation, angiogenesis and articular cartilage degeneration. As a result, the subchondral plate thickness and calcified cartilage zone increased as progression of OA.We also found that high levels of active TGFβ1 in the subchondral bone of human OA knee joints.To validate the role of high level of active TGF in the subchondral bone, we generated and analyzed osteoblast tissue–specificTGFβ1transgenic mice.All of the transgenic mice develop knee joint OA with increased osteoblast progenitors and angiogenesis in the subchondral bone.

We then examined whether inhibition ofTGF activity in the subchondral bone could reduce development of OA. Injection of TβRI inhibitorimproved subchondral bone structure, decreased angiogenesis and partially attenuated articular cartilage degeneration. Furthermore, local administration of TGFβ antibody in the subchondral bone of ACLT rats prevented articular cartilage degeneration, indicatingthat the pathological changes in subchondral bone contribute to the progression of articular cartilage degeneration.Moreover, we knocked out TGFβ type II receptor (TβRII) specifically in nestin+MSCsby induciblenestin-CreERto further validate the role of nestin+ cells in the onset of OA. The microarchitecture was significantly improved in TβRII knockout mice relative to WT mice sinceMSCsno longer respond to TGFβ.Importantly, proteoglycan loss,advances of calcified cartilage zone,MMP13 and type X collagen expression in chondrocytes wereprevented in ACLT TβRII knockout mice.This study demonstrates that high levels of active TGFβ1 in the subchondral bone contribute to the pathological changes seen at the onset of OA.Inhibition of TGFβ1 prevented OA progression and could an effective therapy of OA.