Regulation of procollagen genes. From forces to factors
Geoffrey John Laurent Robin J McAnulty Rachel Chambers Carmel B Keerthisingam
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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 research, 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 rheumatoid 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. They organise 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 turnover; include theTGFβ family of homodimeric peptides which act via partially described signaling systems involving G-protein linked pathways. Elements of the coagulation cascade, including the serine proteasethrombin, also promote collagen production and it is likely that these agents are part of a primitive system of haemostasis and tissue repair. For example, thrombin promotes procollagen production and gene expression via a recently characterized proteolytically activated receptor (PAR-1). Inhibitory molecules, such asprostaglandin E2, are also vital to collagen homeostasis and there is evidence that loss of this inhibitory control occurs in fibrotic conditions. The existence of multiple mediators regulating collagen deposition provides important questions and challenges for the future. For example, which are the key regulatory moleculesin vivo and in which physiological and pathological settings are they playing roles? We also need to ascertain whether or not the different mediators are acting via common signaling pathways, or common transcription factors that may be appropriate targets to promote or inhibit collagen deposition? Answers to these questions are being sought using disparate technologies. For example, techniques of molecular genetics are being applied to the above diseases and should be instructive in the identification of key mediators in disease. The use of genetically manipulated animals, such as gene knock-outs and gene over-expressors will continue to be useful in defining the important mediators that regulate collagen deposition in normal developmental growth and disease states.
Geoffrey John Laurent1 Robin J McAnulty1 Rachel Chambers1 Carmel B Keerthisingam1
Volume 135, 2023
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