beta(2)-microglobulin induces MMP-1 but not TIMP-1 expression in human synovial fibroblasts

Background. beta(2)-Microglobulin (beta(2)m) amyloidosis is a destructive a rticular disease that causes significant morbidity in patients undergoing h emodialysis. The amyloid deposits contain beta(2)m, some of which is altere d with advanced glycation end products (AGE-beta(2)m). The deposits are loc ated principally in joint structures, with adjacent degradation of cartilag e and bone. We hypothesized that one of the mechanisms by which beta(2)m in duces joint destruction is to induce the release of matrix metalloproteinas e-1 (MMP-1), but not tissue inhibitor of metalloproteinase-1 (TIMP-1), from synovial fibroblasts. Methods. To test this hypothesis and determine the role of AGE-beta(2)m, we incubated human osteoarthritic synovial fibroblasts in the presence and ab sence of beta(2)m and AGE-beta(2)m and measured the release of interstitial collagenase (MMP-1) and/or TIMP-1 by enzyme-linked immunosorbent assay and Northern blot analysis. Results. beta(2)m and AGE-beta(2)m at 10 and 25 mu g/mL induced the release of MMP-1 from human osteoarthritic synovial fibro blasts at 24 hours. Tn c ontrast, there was no increased release of TIMP-1, leading to an increase i n the MMP-1/TIMP-1 ratio indicative of uncontrolled collagenolysis. A simil ar dose response was observed at 48 hours, except that AGE-beta(2)m had no effect over control cultures. MMP-1 mRNA expression by Northern blot analys is paralleled these findings. The source of the fibroblasts did not alter t he results. Finally, we demonstrated that doxycycline, a treatment for arth ritis, can inhibit the release of MMP-1 from synovial fibroblasts incubated with beta(2)m. Conclusion. beta(2)m, at physiologically relevant concentrations, induces t he release of MMP-1 without concomitant release of TIMP-1 from human synovi al fibroblasts, leading to uncontrolled collagenolysis. The alteration of b eta(2)m with AGE did not alter this effect at 24 hours, but blocked the eff ect at 48 hours. These findings may account for the tissue destruction seen in beta(2)m amyloidosis.