Targeting TGFβ signaling in subchondral bone and articular cartilage homeostasis

Abstract

Osteoarthritis (OA) is the most common degenerative joint disease and no disease-modifying therapy for OA is currently available. Targeting articular cartilage alone may not be sufficient to halt this disease progression. Articular cartilage and subchondral bone act as a functional unit. Increasing evidence indicates that transforming growth factor β (TGFβ) plays a crucial role in maintaining homeostasis of both articular cartilage and subchondral bone. Activation of extracellular matrix (ECM) latent TGFβ at the appropriate time and location is a prerequisite for its function. Aberrant activation of TGFβ in the subchondral bone in response to an abnormal mechanical loading environment induces formation of osteroid islets at the onset of OA. As a result, alteration of subchondral bone structure changes the stress distribution on the articular cartilage and leads to its degeneration. Thus, inhibition of TGFβ activity in the subchondral bone may provide a new avenue of treatment for OA. In this review we will discuss the role of TGFβ in the homeostasis of articular cartilage and subchondral bone as a novel target for OA therapy.

Keywords: TGFβ; articular cartilage; osteoarthritis; subchondral bone.

Figure 1. Active TGF-β released during bone resorption coordinates bone formation by inducing migration of bone marrow MSCs (mesenchymal stem cells)

Under normal circumstances, TGFβ is stored in the bone matrix in a latent form. During osteoclast bone resorption, active TGFβ is freed from latent protein and diffuses to the marrow cavity. Following the gradient of active TGFβ, bone marrow MSCs are recruited to the bone resportion site. The MSCs then differentiate to osteoblasts and form new bone to fill the resorbed bone cavities.

Figure 2. Association of articular cartilage degeneration and pathological changes in subchondral bone at onset of OA

Left panel: Maintenance of homeostasis in articular cartilage and subchondral bone at normal conditions. Right panel: Increased bone turn-over at onset of OA results in elevated active TGFβ levels in subchondral bone. Increased active TGFβ stimulates angiogenesis, marrow fibrosis, clustering of MSC and osteoprogenitors. These cellular pathologies further lead to uncoupled bone remodeling and potentially bone marrow lesion formation. Disrupted architecture of subchondral bone changes its mechanical property and the reduced ability of subchondral bone to dissipate the load contribute to the articular cartilage degeneration.