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SP0212 TGFBeta: An Ambivalent Role in Bone and Cartilage
  1. X. Cao
  1. Orthopedics, Johns Hopkins University, Baltimore, United States

Abstract

Osteoarthritis (OA) is a highly prevalent joint cartilage degeneration disorder. Articular cartilage and subchondral bone act as a functional unit. TGFb in maintenance of articular cartilage metabolic homeostasis and structural integrity has been well established. However, understanding of subchondral bone in OA is still limited. In our recent study, we investigated subchondral bone-articular cartilage as a functional unit in the joints during progression of OA. We found uncoupled osteoclastic bone resorption in the subchondral bone 7 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+ osteoprogenitors significantly 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 TGFβ in the subchondral bone of human OA knee joints. To validate the role of high level of active TGFb in the subchondral bone, we generated and analyzed osteoblast tissue–specific TGFβ transgenic 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 of TGFb activity in the subchondral bone could reduce development of OA. Injection of TβRI inhibitor (1mg/kg for 1 month) improved 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, indicating that 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+ MSCs by inducible nestin-CreER to 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 since MSCs no longer respond to TGFβ. Importantly, proteoglycan loss, advances of calcified cartilage zone, MMP13 and type X collagen expression in chondrocytes were prevented in ACLT TβRII knockout mice. This study demonstrates that high levels of active TGFβ in the subchondral bone contribute to the pathological changes seen at the onset of OA. Alteration of subchondral bone structure likely changes the stress distribution on the articular cartilage and leads to its degeneration. Thus, inhibition of TGFb activity in the subchondral bone may provide a new avenue of treatment for OA.

Disclosure of Interest None declared

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