REGULATORY MECHANISM FOR THE FORMATION OF TRIVALENT CROSS-LINK (HHL) OF TYPE I COLLAGENS IN ACQUIRED CONNECTIVE TISSUE DISEASES

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The etiology of acquired fibrosclerotic diseases remains unknown while the disease are characterized by excessive accumulation of extracellular matrices such as collagens. Previuous studies have demonstrated deposition of collagens and lesional activated fibroblasts produce more collagens. The qualitative changes of collagens, however, has not been investigated. In this project, we have focused on a mature type of trivalent cross-links, histidinohydroxylysinonorleucine (HHL), in type I collage and quntified HHL using a sensitive HPLC system that we have recently established. HHL provide type I collagens with stability and physiological properties.The molar ratio of HHL to type I collagen was significantly increased in the sclerotic skin samples from systemic sclerosis or morphea as compared with normal individuals or perilesional normal skin, respectively.The regulatory mechanism for the HHL formation in vivo is quite unknown. We are under investigation to elucidate factors that control the HHL formation using an in vitro three-dimensional culture system supplemented with L-ascorbic acid 2-phosphate. This culture system can provide fibroblasts with an optimal culture condition similar to in vivo condition. Preliminary experiments revealed that hypoxia or low serum concentration did not affect the activity of lysyl oxidase, a key enzyme that mediate the formation of reactive sites in collagen molecules.In conclusion, HHL may be involved in the development of fibrosclerotic diseases possibly by preventing collagens from degradation.