ABSTRACT
TGF-ß is a prominent anabolic signaling molecule associated with synovial joint health. Recent work has uncovered mechanochemical mechanisms that activate the latent form of TGF-ß (LTGF-ß) in the synovial joint-synovial fluid (SF) shearing or cartilage compression-pointing to mechanobiological phenomena, whereby enhanced TGF-ß activity occurs during joint stimulation. Here, we implement computational and experimental models to better understand the role of mechanochemical-activated TGF-ß (aTGF-ß) in regulating the functional biosynthetic activities of synovial joint tissues. Reaction-diffusion models describe the pronounced role of extracellular chemical reactions-load-induced activation, reversible ECM-binding, and cell-mediated internalization-in modulating the spatiotemporal distribution of aTGF-ß in joint tissues. Of note, aTGF-ß from SF shearing predominantly acts on cells in peripheral tissue regions (superficial zone [SZ] chondrocytes and synoviocytes) and aTGF-ß from cartilage compression acts on chondrocytes through all cartilage layers. Further, ECM reversible binding sites in cartilage act to modulate the temporal delivery of aTGF-ß to cells, creating a dynamic where short durations of joint activity give rise to extended periods of aTGF-ß exposure at moderated doses. Ex vivo tissue models were subsequently utilized to characterize the influence of physiologic aTGF-ß activity regimens in regulating functional biosynthetic activities. Physiologic exposure regimens of aTGF-ß in SF induce strong 4-fold to 9-fold enhancements in the secretion rate of the synovial biolubricant, PRG4, from SZ cartilage and synovium explants. Further, aTGF-ß inhibition in cartilage over 1-month culture leads to a pronounced loss of GAG content (30-35% decrease) and tissue softening (60-65% EY reduction). Overall, this work advances a novel perspective on the regulation of TGF-ß in the synovial joint and its role in maintaining synovial joint health.
