Shear-Induced Activation of Latent TGF-ß1 in Synovial Fluid

INTRODUCTION: Transforming growth factor beta (TGF-β) is a ubiquitous multifunctional cytokine that modulates the growth, differentiation, and proliferation of most cell types. In cartilage, TGF-β has been shown to directly influence DNA and protein synthesis [1,2]. Additionally, TGF-β is believed to be present in synovial fluid [3,4] as well as released by chondrocytes as an autocrine regulator [2]. However, as with most biological tissues, the TGF-β of cartilage is released in a latent form, consisting of the latency-associated peptide (LAP), and latent TGF-β binding protein (LTBP) [5]. This latent TGF-β complex is unable to bind to cell surface receptors and therefore the protein must be released or activated into its mature protein form in order to mediate cellular activity. Traditionally, it is believed that in the native environment, TGF-β complexes are primarily activated through protease activity or pH regulation [6]. However, recently it has been discovered that mechanical forces such as cellular traction [7] or fluid shear stresses [8] can also serve as a means of releasing TGF-β from its latent state. The aforementioned discovery suggests that mechanical stimulation of joints may potentially influence cellular metabolism through the direct activation of TGF-β in synovial fluid. Therefore, the objective of this experimental study is to investigate this novel hypothesis by testing whether shearing of synovial fluid can activate TGF-β1, and by comparing concentrations of active and latent TGF-β1 in synovial fluid and articular cartilage.