Research for the medical treatment of rheumatoid arthritis by endogenous inhibitor of aggrecanase

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Aggrecan is greatly responsible for bad-bearing and shock-absorbing junction of the joint cartilage. In degradative articular diseases such as rheumatoid arthritis(RA) and osteoarthritis(OA), loss of extracellular matrices occurs resulting in the destruction of joint cartilage. Aggrecan proteolysis is one of the early events leading to the breakdown of the extracellular matrix. Matrix metalloproteinases have been reported to be the key enzymes in cartilage degeneration. Recent studies show that aggrecanase-1 and aggrecanase-2 are members of the ADAMTS(a disintegrin and metalloproteinase with thrombospondin motifs) family, and these enzymes are considered to play a pivotal role in the abrasion of cartilage aggrecan in RA or OA. Tissue inhibitor of matrix metalloproteinase-3(TIMP-3) is a potent inhibitor of aggrecanase-1 and -2, but whether TIMP-3 is the only inhibitor of aggrecanases remains unknown. The identification of a specific endogenous aggrecanase inhibitor therefore would be of critical importance in considering new medication for degradative joint diseases. The aims of the current study were to identify the endogenous inhibitor of aggrecanase-1 and to characterize the mechanism of interaction between aggrecanase-1 and its endogenous inhibitor We performed the yeast two-hybrid screen using the catalytic domain of human aggrecanase-1 as a bait, and an EGY48 yeast strain containing the bait plasmid was transformed with a human liver cDNA library plasmid. We identified alpha-1-antitrypsin and alpha-1-antichymotrypsin, members of plasma serine proteinase inhibitors, as preys.