Regulation of Matrix Metalloproteinases (MMP-2, -3, -9, and -13) by Interleukin-1 and Interleukin-6 in Mouse Calvaria: Association of MMP Induction with Bone Resorption*

Abstract

Interleukin-1 (IL-1) greatly induces osteoclast formation and stimulates bone resorption of mouse calvaria in culture. In the presence of soluble IL-6 receptor (sIL-6R), IL-6 similarly induces osteoclast formation, but the potency of IL-6 in inducing bone resorption in organ culture is weaker than that of IL-1. To study the differences in bone-resorbing activity between IL-1 and IL-6, we examined the effects of the two cytokines on the induction of matrix metalloproteinases (MMPs). In mouse calvarial cultures, IL-1 markedly enhanced the messenger RNA (mRNA) expression of MMP-13 (collagenase 3), MMP-2 (gelatinase A), MMP-9 (gelatinase B), and MMP-3 (stromelysin 1), which associated with increases in bone matrix degradation. A hydroxamate inhibitor of MMPs significantly suppressed bone-resorbing activity induced by IL-1. Gelatin zymography showed that both pro- and active-forms of MMP-2 and MMP-9 were detected in the conditioned medium collected from calvarial cultures, and IL-1 markedly stimulated both pro- and active-forms of the two gelatinases. IL-6 with sIL-6R also stimulated mRNA expression and biological activities of these MMPs, but the potency was much weaker than that of IL-1. Conditioned medium collected from IL-1-treated calvariae degraded native type I collagen, but 3/4- and 1/4-length collagen fragments were not detected, suggesting that both collagenases and gelatinases synergistically degraded type I collagen into smaller fragments. In mouse osteoblastic cells, the expression ofMMP-2, MMP-3, and MMP-13 mRNAs could be detected, and they were markedly enhanced by IL-1alpha 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. These results demonstrate that the potency of induction of MMPs by IL-1 and IL-6 is closely linked to the respective bone-resorbing activity, suggesting that MMP-dependent degradation of bone matrix plays a key role in bone resorption induced by these cytokines.

MKK3/6—p38 MAPK negatively regulates murine MMP-13 gene expression induced by IL-1β and TNF-α in immortalized periodontal ligament fibroblasts

“…In support of MMP-13 potential role in destructive periodontal disease, increased levels of MMP-13 have been detected in diseased human periodontal tissues (Kiili et al, 2002;Uitto et al, 1998;Tervahartiala et al, 2000;Ejeil et al, 2003). In vivo and in vitro data suggests that MMP-13 expression may be associated with alveolar bone resorption in humans (Ma et al, 2000) and mice (Kusano et al, 1998). In vitro, MMP-13 expression was induced in gingival fibroblasts by TGF-h (Leivonen et al, 2002;Ravanti et al, 1999).…”

Tensile strength suppresses the osteogenesis of periodontal ligament cells in inflammatory microenvironments

“…By contrast, inflammatory stimuli additionally induced factors that facilitate bone resorption, including matrix metalloproteinases (MMPs) in PDL fibroblasts (18) and the anterior cruciate ligament (19). In vitro (20) and in vivo (21,22) studies have demonstrated that alveolar bone resorption is closely associated with MMP production. Notably, inflammatory cytokines appear to trigger cellular responses that facilitate bone apposition and bone resorption.…”

Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis

“…MMP9 has been shown to be critical for the development of arthritis as MMP9 KO mice develop less inflammation and joint destruction in the serum transfer model [42]. MMP9 has also been shown to modulate several aspects of osteoclast function, including enhancement of cell migration, potentiation of cell fusion, and increased bone metabolism [43–46]. Altogether, our data indicate that Wnt5a promotes osteoclast formation, and suggests a possible role of Wnt5a in development of other bone resorption disorders.…”