Osteoclast-stimulating activity of TIMP

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As both TIMP-1 and TIMP-2 have been reported to inhibit bone resorption, we examined whether TIMP-1 and/or TIMP-2 in fetal calf serum (FCS), with which culture media were supplemented, affected osteoclastic bone resorption in vitro. At first we looked at the effect of anti-TIMP monoclonal antibodies (alpha TIMP mAbs) on the bone resorption by osteclasts. When alpha TIMP-1 or alpha TIMP-2 mAb was added to the culture medium containing 10% FCS,bone resorption was significantly suppressed with alpha TIMP-2 mAb against our expectation, but little with alpha TIMP-1 mAb. Then we checked the effect of TIMP-1 and/or TIMP-2 delection from FCS on the bone resorption. The bone resorption was significantly suppressed in either TIMP-2-free FCS or TIMP-1-and TIMP-2-free FCS,but little in TIMP-1-free FCS.These results are consistent with those obtained by the addition of alpha TIMP mAbs. The bone-resorbing activity was almost fully restored by the addition of human recombinant TIMPs. The above results strongly suggest that TIMP-2 has a potent osteoclast-stimulating activity. To get a clue to the mechanism of TIMP-dependent bone resorption, we counted and compared the number of tartrate-resistant acid phosphatase (TRAP)-positive and multinuclear cells in each culture medium containing either 10% FCS or TIMP-1-and/or TIMP-2-free FCS.There was essentially no difference in the number among them suggesting that TIMP's role seems to be related to the functional expression of matured osteoclasts, but not to their maturation from progenitor cells.