Pathological studies on the tissue destruction by metalloproteinases

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CD151, a member of the tetraspanin family, was co-localized with MMP-7 in the chondrocytes of osteoarthritic cartilage, showing positive correlations of the CD151 immunoreactivity with Mankin scores and degree of chondrocyte cloning. Co-localization of the molecules in osteoarthritic chondrocytes resulted in pericellular activation of proMMP-7. These data suggest that CD151 is implicated in the destruction of articular cartilage and chondrocyte regeneration through the proMMP-7 activation in osteoarthritis. Among the proteinase-type ADAM8, 9, 10, 12, 15, 17, 20, 21, 28 and 30, ADAM12 was selectively expressed in the osteoarthritic chondrocytes and its immunoreactivity in osteoarthritic cartilage showed a direct correlation with degree of chondrocyte cloning. Cell proliferation and ADAM12 expression were induced by the chondrocyte treatment with TGF-β, and cell proliferation was inhibited with ADAM inhibitor, neutralizing anti-ADAM12 antibody or siRNA for ADAM12. The findings that ADAM 12 releases IGF-I from the IGF-PIGF-BP complex through digestion of IGF-BP suggest that ADAM12 is involved in chondrocyte proliferation through enhanced availability of IGF-I in osteoarthritis. Wound healing processes were analyzed in wild type, MMP-13-/-, MMP-9-/-and MMP-9/13-/-mice and compared each other. Re-epithelialization was delayed in MMP-9/13-/-, MMP-9-/-and MMP-13-/-mice compared with wild type mice in this order, and angiogenesis in the granulation tissue was retarded in MMP-9/13-/-and MMP-13-/-mice. These data suggest the important roles of both MMP-9 and MMP-13 in re-epithelialization and of MMP-13 in angiogenesis.