Significance of anti-calpastatin antibodies in rheumatic diseases and their effect on osteoclast

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I. Role of calpain in osteoclast activity and effect of anti-calpastatin antibodies in rheumatic diseases:Osteoclasts prepared from newborn rabbit femur were caltured on the thin-sliced ivory, and the effect of calpain on the bone absorption of osteoclasts was examined. The bone absorption activity decreased up to 50% of control by adding human calpastatin and calpain inhibitory peptide and increased 37-45% by mouse monoclonal anti-calpastatin antibodies. IgG from some RA patient sera with anti-calpastatin antibodies also increased the activity up to 32%. Thus, calpain/calpastatin system affects the osteoclast activity and may be associated with joint destruction in RA patients.II. Effect of calpain inhibitors on anti-collagen monoclonal antibody-induced mouse arthritis:Since calpain is thought to be a neutral proteinase that affects cartilage destruction and inflammation, the inhibition of calpain activity might be a new therapeutic strategy of RA. Therefore, we intended to treat RA model mouse by calpain inhibitors. Various calpain inhibitors (calpastatin, leupeptin, calpeptin and E-64-d) inhibited the development of anti-collagen monoclonal antibody cocktail-induced mouse arthritis, and in particular the high dose E-64-d (9mg/kg) showed the significant inhibition of arthritis as strong as dexamethasone.III. Development of quatitative mesurement of anti-calpastatin antibodies in rheumatic dseases:We previously reported that autoantibodies to calpastatin were detected in patients with rhuematic diseases. In this study, quantitative ELISA was developed by using purified human recombinant calpastatin that was expressed from the full-length cDNA encoding for human calpastatin. Anti-calpastatin antibodies were detected in RA with the highest frequency (43%), whereas also detected in SLE (30%), scleroderma (30%) and PM/DM (24%).