Collagens and their abnormalities in a wide spectrum of diseases.

Collagens are a family of extracellular matrix proteins that play a dominant role in maintaining the structural integrity of various tissues. Nineteen collagen types containing altogether more than 30 distinct polypeptide chains have now been identified, and their genes have been found to be dispersed among at least 12 chromosomes. Mutations in collagen genes or deficiencies in the activities of specific post-translational enzymes of collagen synthesis have been characterized in many heritable disorders such as osteogenesis imperfecta, several chondrodysplasias, several subtypes of the Ehlers-Danlos syndrome, the X-linked Alport syndrome and dystrophic forms of epidermolysis bullosa. In addition, collagen mutations have been found in certain common diseases, namely osteoporosis, osteoarthrosis and aortic aneurysms, and it is now evident that subsets of patients with these diseases have defects in types I, II or III collagen, respectively, as a predisposing factor. Mutations have so far been identified in only six of the more than 30 collagen genes, and thus research into collagen defects is only in its early stages. Transgenic mice have been shown to offer an excellent tool for investigating the consequences of mutations in collagen genes and identifying additional diseases caused by collagen defects. Excessive collagen accumulation also poses a common problem in medicine, leading to fibrosis with impairment of the normal functioning of the affected tissue. This has prompted attempts to develop drugs which inhibit collagen synthesis. Prolyl 4-hydroxylase would seem a particularly suitable target for antifibrotic therapy, and several compounds are now known that inhibit this enzyme. In particular, derivatives of pyridine 2,4-dicarboxylate have been shown to inhibit hepatic collagen accumulation in rats with two models of liver fibrosis.