Rigid control of synthesis of collagen Types I and III by cells in culture

Abstract

THE constituents of the extracellular matrix have a fundamental role in the structure and function of all tissues. A major insight into the composition of this matrix came with the discovery^1–3 that interstitial collagen was not homogeneous, but rather composed of two species, termed Type I and Type III. Type I collagen (composed of two α1(I) chains and one α2 chain) usually forms densely packed fibrils (the cross-banded collagen commonly seen in electron micrographs). In comparison, Type III collagen (composed of three α1(III) chains) exists, in part, as reticulin, in which fine, randomly dispersed collagen fibrils are intimately associated with other connective tissue components^3,4. Appreciation of the possible functional significance of the heterogeneity of the interstitial collagens has come from the analysis of the ratio of Type I to Type III collagen in different tissues in health and disease. Most pliable tissues (skin, intestine, blood vessels, lung) have a I : III ratio of 2–3 to 1, while rigid tissues (bone, tendon) contain only Type I collagen^5,6. Studies of inflammation and wound healing have demonstrated that early granulation tissue (a material with little tensile strength) has a very low I : III ratio^4,7, while mature scar (a stiff tissue) has a high I : III ratio⁸. In addition, disorders associated with a loss of tissue compliance (arterosclerosis⁹, pulmonary fibrosis¹⁰) are associated with a shift in the normal I : III ratio toward relatively more Type I collagen. Taken together, these findings suggest that the structure and function of tissues are intimately associated with the relative amounts of the interstitial collagens, with Type I tightly packed and tough and Type III loosely associated and pliable. If the relative amounts of collagens I and III are as important as this data suggests, the maintenance of normal interstitial tissues must be critically dependent on cells in the local environment rigidily maintaining their differentiated state with respect to the synthesis and degradation of these collagen types. We describe here a study designed to evaluate this hypothesis, using a model system to assess the ‘tightness’ of cellular control of the synthesis of collagens I and III by a population of similar cells (fibroblasts in culture) over approximately 20 replicative cycles.