Regulation of procollagen genes. From forces to factors

摘要

Collagens are the most abundant vertebrate proteins. Their primary role is to provide a supportive scaffolding to which cells attach but other actions in cell communication and cell function are now recognized. The work of pioneers of collagen researeh, of whom G N Ramachandran is a giant, have provided us with a detailed understanding of collagens' structure and function. In many of the inherited disorders (i.e., osteogenesis imperfecta) specific molecular lesions have been identified in collagen genes but in the common diseases, such as fibrotic disorders or theumatoid arthritis, it is an imbalance in the rates of synthesis and breakdown which are critical. In vivo studies have shown that collagen turnover occurs at rapid rates in body tissues and that fibroblasts are dynamic cells actively synthesizing and degrading collagens. These cells are central to normal wound repair and the pathogenesis of fibrotic diseases. Theyorganise and respond to their extracellular milieu and produce cytokines which exert autocrine and paracrine effects. They react to a variety of stimuli, including feedback from procollagen breakdown products, mechanical forces and polypeptide mediators. Mediators which regulate procollagen tumover, include the TGFP family of homodimeric peptides which act via partially described signaling systems involving G-protein linked pathways. Elements of the coagulation cascade, including the serine protease thrombin, also promote collagen production and it is likely that these agents are part of a primitive system of haemostasis and tissue repair. For example, thr