Accumulation of Exogenous Activated TGF-β in the Superficial Zone of Articular Cartilage

It was recently demonstrated that mechanical shearing of synovial fluid (SF), induced during joint motion, rapidly activates latent transforming growth factor beta (TGF-beta). This discovery raised the possibility of a physiological process consisting of latent TGF-beta supply to SF, activation via shearing, and transport of TGF-beta into the cartilage matrix. Therefore, the two primary objectives of this investigation were to characterize the secretion rate of latent TGF-beta into SF, and the transport of active TGF-beta across the articular surface and into the cartilage layer. Experiments on tissue explants demonstrate that high levels of latent TGF-beta 1 are secreted from both the synovium and all three articular cartilage zones (superficial, middle, and deep), suggesting that these tissues are capable of continuously replenishing latent TGF-beta to SF. Furthermore, upon exposure of cartilage to active TGF-beta 1, the peptide accumulates in the superficial zone (SZ) due to the presence of an overwhelming concentration of nonspecific TGF-beta binding sites in the extracellular matrix. Although this response leads to high levels of active TGF-beta in the SZ, the active peptide is unable to penetrate deeper into the middle and deep zones of cartilage. These results provide strong evidence for a sequential physiologic mechanism through which SZ chondrocytes gain access to active TGF-beta: the synovium and articular cartilage secrete latent TGF-beta into the SF and, upon activation, TGF-beta transports back into the cartilage layer, binding exclusively to the SZ.