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Nitric Oxide Promotes Infectious Bone Resorption by Enhancing Cytokine‐Stimulated Interstitial Collagenase Synthesis in Osteoblasts
Author(s) -
Lin SzeKwan,
Kok SangHeng,
Kuo Mark YenPing,
Lee MingShu,
Wang ChihChiang,
Lan WanHong,
Hsiao Michael,
Goldring Steven R,
Hong ChiYuan
Publication year - 2003
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.2003.18.1.39
Subject(s) - bone resorption , nitric oxide , collagenase , resorption , cytokine , chemistry , osteoblast , interstitial collagenase , medicine , endocrinology , biochemistry , in vitro , enzyme
This experiment was undertaken to determine the role of macrophage‐derived nitric oxide (NO) in mediating lipopolysaccharide (LPS)‐induced bone resorption by using an in vitro co‐culture system and an in vivo model of infectious bone resorption. Our results demonstrated that LPS stimulated the expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF)‐α mRNAs and nitrite synthesis in the J774 mouse macrophage cell line but not in the UMR‐106 (rat) and MC3T3‐E1 (mouse) osteoblast cell lines. Conditioned media (CM) from LPS‐stimulated J774 triggered only low to moderate levels of iNOS mRNAs in MC3T3‐E1 and a trivial effect in UMR‐106. On the other hand, CM induced matrix metalloproteinase‐1 (MMP‐1) gene expression in both osteoblast cell lines. The NOS inhibitor N G ‐monomethyl‐ L ‐arginine ( L ‐NMMA) did not alter this effect in MC3T3‐E1 and UMR‐106, whereas TNF‐α antibody diminished the CM‐induced MMP‐1 gene expression in both cell lines. Interestingly, SNAP, a NO donor, although by itself is not a MMP‐1 stimulator for UMR‐106, augmented the TNF‐α‐stimulated MMP‐1 mRNA production in UMR‐106. In a J774/UMR‐106 co‐culture system, LPS stimulated significant MMP‐1 gene expression in UMR‐106, and this upregulation was abolished by L ‐NMMA and TNF‐α antibodies. Immunohistochemical analysis in a rat model of infectious bone resorption (periapical lesion) showed co‐distributions of iNOS + macrophages and MMP‐1 + osteoblasts around the osteolytic areas. Administration of L ‐NMMA markedly reduced the extent of bone loss and the percentage of MMP‐1‐synthesizing osteoblasts. These data suggest that NO derived from macrophages after LPS stimulation may enhance bone loss by augmenting the cytokine‐induced MMP‐1 production in osteoblasts.