Dynamic mechanical compression of devitalized articular cartilage does not activate latent TGF-ß.

A growing body of research has highlighted the role that mechanical forces play in the activation of latent TGF-ß in biological tissues. In synovial joints, it has recently been demonstrated that the mechanical shearing of synovial fluid, induced during joint motion, rapidly activates a large fraction of its soluble latent TGF-ß content. Based on this observation, the primary hypothesis of the current study is that the mechanical deformation of articular cartilage, induced by dynamic joint motion, can similarly activate the large stores of latent TGF-ß bound to the tissue extracellular matrix (ECM). Here, devitalized deep zone articular cartilage cylindrical explants (n=84) were subjected to continuous dynamic mechanical loading (low strain: ±2% or high strain: ±7.5% at 0.5Hz) for up to 15h or maintained unloaded. TGF-ß activation was measured in these samples over time while accounting for the active TGF-ß that remains bound to the cartilage ECM. Results indicate that TGF-ß1 is present in cartilage at high levels (68.5±20.6ng/mL) and resides predominantly in the latent form (>98% of total). Under dynamic loading, active TGF-ß1 levels did not statistically increase from the initial value nor the corresponding unloaded control values for any test, indicating that physiologic dynamic compression of cartilage is unable to directly activate ECM-bound latent TGF-ß via purely mechanical pathways and leading us to reject the hypothesis of this study. These results suggest that deep zone articular chondrocytes must alternatively obtain access to active TGF-ß through chemical-mediated activation and further suggest that mechanical deformation is unlikely to directly activate the ECM-bound latent TGF-ß of various other tissues, such as muscle, ligament, and tendon.

Accumulation of exogenous activated TGF-ß 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 ß (TGF-ß). This discovery raised the possibility of a physiological process consisting of latent TGF-ß supply to SF, activation via shearing, and transport of TGF-ß into the cartilage matrix. Therefore, the two primary objectives of this investigation were to characterize the secretion rate of latent TGF-ß into SF, and the transport of active TGF-ß across the articular surface and into the cartilage layer. Experiments on tissue explants demonstrate that high levels of latent TGF-ß1 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-ß to SF. Furthermore, upon exposure of cartilage to active TGF-ß1, the peptide accumulates in the superficial zone (SZ) due to the presence of an overwhelming concentration of nonspecific TGF-ß binding sites in the extracellular matrix. Although this response leads to high levels of active TGF-ß 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-ß: the synovium and articular cartilage secrete latent TGF-ß into the SF and, upon activation, TGF-ß transports back into the cartilage layer, binding exclusively to the SZ.

In-vivo clinical validation of cardiac deformation and strain measurements from 4D ultrasound.

An important goal in clinical cardiology is the non-invasive quantification of regional cardiac deformation. While many methods have been proposed for the estimation of 3D left ventricular deformation and strains derived from 4D ultrasound, currently there is a lack of in vivo clinical validation of these algorithms on humans. In this paper, we describe the experiments used in validating cardiac deformation and strain estimates of 4D ultrasound using correlation-based optical flow tracking on two different COPD patients with normal left ventricular function. Validation of the algorithm was done by 1) validation of cardiac volume across multiple scans of the same patient and 2) validation of the repeatability of cardiac displacement and strain results from multiple scan acquisitions of the same patient. The preliminary results are encouraging with our algorithm producing consistent cardiac volume and strain results across multiple acquisitions. Furthermore, our derived 4D cardiac strains showed qualitatively correct results. We also observed particularly interesting results in the radial displacements of the posterior and lateral walls of our COPD patients.