Tissue remodeling in the intervertebral disc: Response to dynamic loading and growth factors

Disc degeneration is a chronic remodeling process that results in alterations of matrix composition and decreased cellularity. The objective of this work was to explore two important topics related to disc degeneration: (1) the role of mechanical loading in alterations of disc biology, and (2) the potential to repair degenerated discs. The first study tested the hypothesis that dynamic mechanical forces are important regulators of disc cellularity and matrix synthesis. The second study hypothesized that exogenous growth factors can stimulate regenerative remodeling in the degenerated disc in vivo.; To study dynamic forces, a murine model of dynamic loading was developed that used an external loading device to cyclically compress a single disc in the tail. Dynamic loading induced differential effects that depended on frequency and stress. The results suggested a tolerance to loading above which evidence of both an anabolic response (increased proteoglycan content and matrix gene expression) and a degenerative response (cell death) were found. Finite element modeling suggested that the responses might be due to variation of strain environment.; The effects of exogenous growth factors on degenerated discs were studied in vivo using a murine model of compression-induced degeneration. Degenerated discs were given single or multiple injections of GDF-5, TGF-β, IGF-1, bFGF, or saline as control and analyzed either one week or four weeks after treatment. In some growth factor treated discs, expansion of inner annular chondrocyte populations into the nucleus were observed. The results indicated that annular chondrocytes may be responsive to some growth factors in vivo, and that GDF-5 and TGF-β may be mitogens for annular chondrocytes.; In summary, this work provides new knowledge of the mechanisms of tissue remodeling in situ in the intervertebral disc. The results have implications in the prevention and treatment of disc degeneration. The responses to dynamic mechanical forces suggest that loading conditions may be optimized to promote maintenance of normal structure and function. The cellular response to growth factors observed in degenerated discs demonstrates the possibility of their use in new therapeutic modalities for repair.