UC San Diego

Articular cartilage function as a low friction, wear- resistant, load-bearing material in joints depends on the molecular composition and structure of the extracellular tissue matrix. The proteoglycan component provides the tissue with a fixed negative charge, which imparts a swelling pressure. The crosslinked collagen network resists the swelling tendency of the proteoglycans, and provides the tissue with tensile integrity. During growth of articular cartilage in vivo, composition and function evolve dramatically and both chemical and mechanical stimuli have profound regulatory effects. However, it is unknown how immature tissue evolves into its adult form, and if and how various types of chemical stimuli modulate this process. The overall hypothesis proposed here is that cartilage growth results from a chemically regulated dynamic imbalance between the swelling pressure of glycosaminoglycans (GAG) and the restraining function of the collagen network. Manipulation of matrix content, metabolism, and assembly distinctly altered the growth phenotype of immature articular cartilage, as assessed by culture-associated variations in tissue geometry, composition, and function. In vitro growth of cartilage explants was regulated differentially by growth factors. Overall, cartilage explants grew in volume, as GAG content, an indicator of swelling pressure, increased and tensile modulus and strength, indicators of collagen network integrity, decreased. The propensity of cartilage tissue to grow was additionally enhanced during growth in presence of an inhibitor of collagen crosslink formation, and reduced during growth of explants which were depleted of GAG prior to culture. Thus, factors that lead to growth of cartilage explants in vitro involve a shift in the balance between the swelling pressure of the proteoglycans and the restraining ability of the collagen network, toward an overall expansive effect resulting from the swelling pressure. The tensile integrity of articular cartilage was modulated through depletion of certain extracellular matrix components; however the extent of this modulation was dependent on the maturity of the source tissue. Certain resident matrix components of articular cartilage were implicated in the development of tensile integrity. An understanding of cartilage growth mechanisms may ultimately allow the development of methods to guide appropriate growth of cartilage tissue grafts for emerging tissue engineering and cartilage repair therapies