At the Crux of Joint Crosstalk: TGFβ Signaling in the Synovial Joint

Abstract

Purpose of review: The effect of the transforming growth factor beta (TGFβ) signaling pathway on joint homeostasis is tissue-specific, non-linear, and context-dependent, representing a unique complexity in targeting TGFβ signaling in joint disease. Here we discuss the variety of mechanisms that TGFβ signaling employs in the synovial joint to maintain healthy joint crosstalk and the ways in which aberrant TGFβ signaling can result in joint degeneration.

Recent findings: Osteoarthritis (OA) epitomizes a condition of disordered joint crosstalk in which multiple joint tissues degenerate leading to overall joint deterioration. Synovial joint tissues, such as subchondral bone, articular cartilage, and synovium, as well as mesenchymal stem cells, each demonstrate aberrant TGFβ signaling during joint disease, whether by excessive or suppressed signaling, imbalance of canonical and non-canonical signaling, a perturbed mechanical microenvironment, or a distorted response to TGFβ signaling during aging. The synovial joint relies upon a sophisticated alliance among each joint tissue to maintain joint homeostasis. The TGFβ signaling pathway is a key regulator of the health of individual joint tissues, and the subsequent interaction among these different joint tissues, also known as joint crosstalk. Dissecting the sophisticated function of TGFβ signaling in the synovial joint is key to therapeutically interrogating the pathway to optimize overall joint health.

Keywords: Articular cartilage; Joint crosstalk; Osteoarthritis; Subchondral bone; TGF beta.

Fig. 1

Synovial joint homeostasis relies upon intricate control of TGFβ signaling across multiple joint tissues. Disruption of the complex hierarchical regulation of TGFβ signaling, whether through physical cues, receptor recruitment, or effector selection, impairs synovial joint health and results in joint degeneration in a tissue-specific manner. Proteases, such as MMP13, have differential TGFβ-dependent regulation within each tissue in joint disease, such that elevated proteases in subchondral bone improve bone quality and joint health, yet elevated proteases in cartilage leads to cartilage degeneration