β2-microglobulin induces MMP-1 but not TIMP-1 expression in human synovial fibroblasts

Sharon M. Moe, Gurinder K. Singh, Anna M. Bailey

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Background. β2-Microglobulin (β2m) amyloidosis is a destructive articular disease that causes significant morbidity in patients undergoing hemodialysis. The amyloid deposits contain β2m, some of which is altered with advanced glycation end products (AGE-β2m). The deposits are located principally in joint structures, with adjacent degradation of cartilage and bone. We hypothesized that one of the mechanisms by which β2m induces joint destruction is to induce the release of matrix metalloproteinase-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- β2m, we incubated human osteoarthritic synovial fibroblasts in the presence and absence of β2m and AGE-β2m and measured the release of interstitial collagenase (MMP-1) and/or TIMP-1 by enzyme-linked immunosorbent assay and Northern blot analysis. Results. β2m and AGE-β2m at 10 and 25 μg/mL induced the release of MMP-1 from human osteoarthritic synovial fibroblasts at 24 hours. In contrast, there was no increased release of TIMP-1, leading to an increase in the MMP-1/TIMP-1 ratio indicative of uncontrolled collagenolysis. A similar dose response was observed at 48 hours, except that AGE-β2m had no effect over control cultures. MMP-1 mRNA expression by Northern blot analysis paralleled these findings. The source of the fibroblasts did not alter the results. Finally, we demonstrated that doxycycline, a treatment for arthritis, can inhibit the release of MMP-1 from synovial fibroblasts incubated with β2m. Conclusion. β2m, at physiologically relevant concentrations, induces the release of MMP-1 without concomitant release of TIMP-1 from human synovial fibroblasts, leading to uncontrolled collagenolysis. The alteration of β2m with AGE did not alter this effect at 24 hours, but blocked the effect at 48 hours. These findings may account for the tissue destruction seen in β2m amyloidosis.

Original languageEnglish (US)
Pages (from-to)2023-2034
Number of pages12
JournalKidney international
Volume57
Issue number5
DOIs
StatePublished - Jan 1 2000

Keywords

  • Amyloidosis
  • Collagenolysis
  • Dialysis amyloid
  • Matrix metalloproteinase
  • Synovium

ASJC Scopus subject areas

  • Nephrology

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