Tissue Inhibitors of Metalloproteinases (TIMP-1 and TIMP-2) Stimulate Osteoclast Differentiation

Abstract

Tissue inhibitor of metalloproteinases-1 (TIMP-1) and TIMP-2, originally known as intrinsic inhibitors of matrix metalloproteinases (MMPs), are now known as constitutive components in serum and have potent cell growth-promoting activity. In this study, we examined the effects of TIMPs in FCS on osteoclast-like (OCL) cell formation in mouse bone marrow culture. The OCL cell formation is totally dependent on the presence of PGE₂ or 1α25 (OH)₂D₃ or IL-1α. The effects of these factors were, however, not completely but greatly suppressed by deleting TIMP-1 and TIMP-2 from FCS in culture. But the suppression was almost fully recovered by the readdition of the same amount of recombinant (r) TIMPs which were detected in 10% FCS. As low molecular weight MMP inhibitors could not substitute rTIMPs for the recovery, TIMP activity on the OCL cell formation seemed to be independent from their MMP inhibitory activity. These results strongly suggest a secondary but potent stimulating activity of TIMPs on OCL cell formation. In conclusion, TIMPs in serum play an important role in osteoclastgenesis in mouse bone marrow culture.