Regulation of procollagen genes. From forces to factors

Collagens are the most abundant vertebrate proteins. Their primary role is to provide a supportive scaffolding to which cells attach but other actions in eel communication and cell function are now recognized. The work of pio neers of collagen research, of whom G N Ramachandran is a giant, have provi ded 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 rheumatoid arthritis, it is an imb alance in the rates of synthesis and breakdown which are critical. In vivo studies have shown that collagen turnover occurs at rapid rates in body tis sues and that fibroblasts are dynamic cells actively synthesizing and degra ding collagens. These cells are central to normal wound repair and the path ogenesis of fibrotic diseases. They organise and respond to their extracell ular milieu and produce cytokines which exert autocrine and paracrine effec ts. They react to a variety of stimuli, including feedback from procollagen breakdown products, mechanical forces and polypeptide mediators. Mediators which regulate procollagen turnover; include the TGF beta family of homodi meric peptides which act via partially described signaling systems involvin g G-protein linked pathways. Elements of the coagulation cascade, including the serine protease thrombin, also promote collagen production and it is l ikely that these agents are part of a primitive system of haemostasis and t issue repair. For example, thrombin promotes procollagen production and gen e expression via a recently characterized proteolytically activated recepto r (PAR-I). Inhibitory molecules, such as prostaglandin E2, are also vital t o collagen homeostasis and there is evidence that loss of this inhibitory c ontrol occurs in fibrotic conditions. The existence of multiple mediators r egulating collagen deposition provides important questions and challenges f or the future. For example, which are the key regulatory molecules in vivo and in which physiological and pathological settings are they playing roles ? We also need to ascertain whether or not the different mediators are acti ng via common signaling pathways,;or common transcription factors that may be appropriate targets to promote or inhibit collagen deposition? Answers t o these questions are being sought using disparate technologies, For exampl e, techniques of molecular genetics are being applied to the above diseases and should be instructive in the identification of key mediators in diseas e. The use of genetically manipulated animals, such as gene knock-outs and gene over-expressors will continue to be useful in defining the important m ediators that regulate collagen deposition in normal developmental growth a nd disease states.