Shearing of synovial fluid activates latent TGF-β

Abstract

Objective TGF-β is synthesized in an inactive latent complex that is unable to bind to membrane receptors, thus unable to induce a cellular biological response until it has been activated. In addition to activation by chemical mediators, recent studies have demonstrated that mechanical forces may activate latent TGF-β via integrin-mediated cellular contractions, or mechanical shearing of blood serum. Since TGF-β is present in synovial fluid in latent form, and since normal diarthrodial joint function produces fluid shear, this study tested the hypothesis that the native latent TGF-β1 of synovial fluid can be activated by shearing. Design Synovial fluid from 26 bovine joints and 3 adult human joints was sheared at mean shear rates up to 4000 s−1 for up to 15 hours. Results Unsheared synovial fluid was found to contain high levels of latent TGF-β1 (4.35±2.02 ng/mL bovine, 1.84±0.89 ng/mL human; mean±radius of 95% confidence interval) and low amounts (<0.05 ng/mL) of the active peptide. Synovial fluid concentrations of active TGF-β1 increased monotonically with shear rate and shearing duration, reaching levels of 2.64±1.22 ng/mL for bovine and 0.60±0.39 ng/mL for human synovial fluid. Following termination of shearing, there was no statistical change in these active levels over the next 8 hours for either species, demonstrating long-term stability of the activated peptide. The unsheared control group continued to exhibit negligible levels of active TGF-β1 at all times. Conclusions Results confirmed the hypothesis of this study and suggest that shearing of synovial fluid might contribute an additional biosynthetic effect of mechanical loading of diarthrodial joints.

Fibroblast-like synoviocyte mechanosensitivity to fluid shear is modulated by interleukin-1α

“…Other work on synovial joint biomechanics such as wear testing protocols specifying bovine serum as the lubricant (Harsha and Joyce 2011) point to the inclusion of serum as a relevant physiological parameter for in vitro model systems, as synovial fluid is an ultrafiltrate of plasma and includes growth factors found in serum (Denko, Boja et al 1996). Our team has studied the maintenance of native cartilage explants in synovial fluid (Albro, Durney et al 2014), and shown that shearing of native synovial fluid can activate growth factors such as latent TGF-beta that may modulate biological behavior of the surrounding joint tissues (Albro, Cigan et al 2012). Future work will include shear studies using native synovial fluid as the perfusion media to investigate FLS mechanosensitivity in a more physiologic model system.…”

Growth Factor-Mediated Migration of Bone Marrow Progenitor Cells for Accelerated Scaffold Recruitment

“…1,28,[81][82][83] To avoid an adverse effect of TGF-b1, one possibility is that moderate local activation of latent TGF-b1 found in native synovial fluid by chemical or mechanical forces may provide the necessary cues to stimulate migration if combined with PDGF-BB. 84,85 Alternatively, engineering approaches designed to locally deliver exogenous latent rather than active TGF-b1 have shown promising preliminary results in rats. 86 A strong local dose of a prochemotactic GF (e.g., PDGF-BB), however, may be sufficient to induce a chemotactic effect similar to that observed in vitro.…”

Association Between Shear Stress and Platelet-Derived Transforming Growth Factor-β1 Release and Activation in Animal Models of Aortic Valve Stenosis

“…11 Subsequently, Albro et al independently confirmed that shear stress can activate latent TGF-β1 in synovial fluid. 13 We recently reported that mice with targeted deletion of TGF-β1 in their megakaryocytes and platelets are partially protected from developing cardiac hypertrophy, fibrosis and systolic dysfunction, in response to constriction of the transverse aorta, a model that has increases WSS at the stenosis created and in the innominate artery. 14 Collectively, these data raise the possibility of an association between the activation of circulating latent TGF-β1 under high shear stress and the development of AS.…”