Shearing of synovial fluid activates latent TGF-β

Objective: TGF-beta 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-beta via integrin-mediated cellular contractions, or mechanical shearing of blood serum. Since TGF-beta 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-beta 1 of synovial fluid can be activated by shearing. Design: Synovial fluid from 26 bovine joints and three adult human joints was sheared at mean shear rates up to 4000 s(-1) for up to 15 h. Results: Unsheared synovial fluid was found to contain high levels of latent TGF-beta 1 (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-beta 1 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 h for either species, demonstrating long-term stability of the activated peptide. The unsheared control group continued to exhibit negligible levels of active TGF-beta 1 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. (C) 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.