REGULATION OF MATRIX METALLOPROTEINASES (MMP-2, MMP-3, MMP-9, AND MMP-13) BY INTERLEUKIN-1 AND INTERLEUKIN-6 IN MOUSE CALVARIA - ASSOCIATION OF MMP INDUCTION WITH BONE-RESORPTION

Interleukin-l (IL-1) greatly induces osteoclast formation and stimulat es bone resorption of mouse calvaria in culture. In the presence of so luble IL-6 receptor (sIL-6R), IL-6 similarly induces osteoclast format ion, but the potency of IL-6 in inducing bone resorption in organ cult ure is weaker than that of IL-1. To study the differences in bone-reso rbing activity between IL-1 and IL-6, we examined the effects of the t wo cytokines on the induction of matrix metalloproteinases (MMPs). In mouse calvarial cultures, IL-1 markedly enhanced the messenger RNA (mR NA) expression of MMP-13 (collagenase 3), MMP-2 (gelatinase A), MMP-9 (gelatinase B), and MMP-3 (stromelysin 1), which associated with incre ases in bone matrix degradation. A hydroxamate inhibitor of MMPs signi ficantly suppressed bone-resorbing activity induced by IL-1. Gelatin z ymography showed that both pro-and active-forms of MMP-2 and MMP-9 wer e detected in the conditioned medium collected from calvarial cultures , and IL-1 markedly stimulated both pro-and active-forms of the two ge latinases. IL-6 with sIL-6R also stimulated mRNA expression and biolog ical activities of these MMPs, but the potency was much weaker than th at of IL-1. Conditioned medium collected from IL-l-treated calvariae d egraded native type I collagen, but 3/4- and 1/4-length collagen fragm ents were not detected, suggesting that both collagenases and gelatina ses synergistically degraded type I collagen into smaller fragments. I n mouse osteoblastic cells, the expression of MMP-2, MMP-3, and MMP-13 mRNAs could be detected, and they were markedly enhanced by IL-1 alph a on days 2 and 5. IL-6 with sIL-6R also induced expression of MMP-13 and MMP-2 mRNAs on day 2, but the expression was rather transient. The se results demonstrate that the potency of induction of MMPs by IL-1 a nd IL-6 is closely linked to the respective bone-resorbing activity, s uggesting that MMP-dependent degradation of bone matrix plays a key ro le in bone resorption induced by these cytokines.