Transport of tissue inhibitor of metalloproteinases‐1 through cartilage: Contributions of fluid flow and electrical migration

Abstract

The preservation of the structure of articular cartilage depends on the availability of inhibitors of matrix-degrading enzymes. Tissue inhibitor of metalloproteinases-1 is thought to be an important contributor to the integrity of the matrix of articular cartilage, but the mechanisms that regulate its availability within the tissue are poorly understood. These studies elucidate the contributions of diffusion, fluid flow, and electrical migration to the transport of iodinated recombinant human tissue inhibitor of metalloproteinases-1 through explants of adult bovine articular cartilage under conditions relevant to the loading of cartilage. With use of measured partition coefficients of the cartilage explants, the diffusivity of the inhibitor was 0.5-1.6 x 10(-7) cm2/sec. Fluid velocities that were induced by applying an electrical current across the cartilage disks increased the flux of the inhibitor by approximately 20 to more than 150-fold compared with the effect of diffusion alone for the range of current densities that were applied. We examined the contribution of electrophoretic migration by titrating the charge on the inhibitor during measurements of flux and found that flux in the presence of the applied current decreased as the inhibitor became more negatively charged. Enhancements in the flux of the inhibitor were observed relative to the flux during diffusion alone even under conditions in which electrophoretic migration opposed the flux due to fluid flow, suggesting that of the transport mechanisms tested, fluid flow was dominant. These results suggest that the physical phenomena present during physiologic loading conditions (e.g., fluid flows and streaming currents) can affect the transport of tissue inhibitor of metalloproteinases-1 through the matrix of cartilage.

Mechanobiology in the Third Dimension

“…92 Matrix proteolysis and deposition can also be affected by interstitial flow, as shown in articular cartilage under dynamic compression. 75,156 Thus, interstitial flow may strongly influence remodeling and morphogenesis in ways that do not require mechanosensing by the cell, although this area is nascent within the field of mechanobiology and needs more study.…”

A driving force for change: interstitial flow as a morphoregulator

“…Also, interstitial flow rather than solid stress is responsible for at least some of the mechanical stress-induced matrix production in cartilage [27], because dynamic rather than static compression was found to promote proteoglycan and collagen synthesis [28] and increase chondrocyte metabolism [29] (interstitial flow is always present in tissues undergoing dynamic compression). Dynamic compression stimulates directional deposition of proteoglycans and matrix fiber compaction in the direction of flow [26] and directs remodeling by enhancing the transport of tissue inhibitor of metalloproteinase-1 (TIMP-1) [30]. In bone, physical activity causes oscillatory compression that has been estimated to increase the convective transport of macromolecules up to 100 times more than what is possible with diffusion [31].…”

The Insulin-like Growth Factors (IGFs) I and II Bind to Articular Cartilage via the IGF-binding Proteins

“…The transport measurement system has been previously described in detail (14). Briefly, a two-compartment acrylic diffusion chamber (Fig.…”

“…Temperature was maintained at 20°C. Both compartments were open to ambient pressure, and portions of the downstream bath were recirculated at 1-3 ml/min through a modified flow-through 125 Iradioactivity detector (14). Downstream radioactivity as measured by the detector was continuously recorded at 6-s intervals by the computer.…”