Requirement of the inducible nitric oxide synthase pathway for IL-1-induced osteoclastic bone resorption

Hof, Rob J van 't; Armour, Kenneth J.; Smith, Lorna; Armour, Katharine E.; Wei, Xiaoguang; Liew, Foo Y.; Ralston, Stuart H.

doi:10.1073/pnas.130511497

Cited by 146 publications

(96 citation statements)

References 47 publications

(42 reference statements)

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“…Evidence from gene-knockout studies shows that bone formation and resorption are regulated by nitric oxide (NO): mice deficient in endothelial NO synthase (eNOS) or cyclic guanosine 3Ј,5Ј-monophosphate (cGMP)-dependent protein kinase (PKG) show bone abnormalities (Aguirre et al, 2001;Chae et al, 1997;Chikuda et al, 2004;Miyazawa et al, 2002;Otsuka et al, 1998;Talts et al, 1998) and inducible NO synthase (iNOS)-null mice show imbalances in bone osteogenenis (van't Hof et al, 2000). However, the mechanisms through which NO influences osteogenesis remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Cbfa-1 mediates nitric oxide regulation of MMP-13 in osteoblasts

Zaragoza

López-Rivera

García-Rama

et al. 2006

Journal of Cell Science

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During bone development, osteoblast differentiation requires remodeling of the extracellular matrix. Although underlying mechanisms have not been elucidated, evidence points to the participation of the nitric oxide (NO) and cyclic guanosine 3′,5′-monophosphate (cGMP) system. Here, we detected increased matrix metalloproteinase (MMP)-13 mRNA, protein and activity, as well as increased inducible NO synthase (iNOS) and NO production during the differentiation of MC3T3-E1 osteoblasts. Transcriptional activity of the MMP-13 promoter was augmented by NO, 8-bromo-cGMP (8-Br-cGMP), and by a dominant-positive form of protein kinase G (PKG1-α). The stimulatory effect on the MMP-13 promoter was partially inhibited by mutation of the osteoblast-specific element 2 (OSE-2) binding site. Core binding factor-1 (Cbfa-1) expression peaked at 7 days of differentiation, and was phosphorylated by PKG in vitro. Cbfa-1 was localized to cell nuclei, and its translocation was inhibited by the iNOS inhibitor 1400W. Immunohistological examination revealed that MMP-13 and Cbfa-1 expression levels are both reduced in 17-day-old embryos of iNOS-deficient mice. Silencing of Cbfa-1 mRNA blocked MMP-13 expression without interfering with endogenous NO production, confirming its role in NO-induced MMP-13 expression by MC3T3-E1 cells. The results described here suggest a mechanism by which NO regulates osteogenesis.

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Section: Introductionmentioning

confidence: 99%

Cbfa-1 mediates nitric oxide regulation of MMP-13 in osteoblasts

Zaragoza

López-Rivera

García-Rama

et al. 2006

Journal of Cell Science

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“…In addition, NO is known to serve as an essential and relatively specific downstream mediator in the signaling pathway of IL-1-induced bone resorption, and iNOS-deficient mice exhibit profound defects of IL-1-induced osteoclastic bone resorption. 38) These findings may indicate that inhibition of NO production by KBT is likely to suppress bone destruction indirectly. In this respect, NO is a new target for the treatment of RA, and KBT with inhibitory activity of NO production may be beneficial for the remedy of RA.…”

Section: Discussionmentioning

confidence: 93%

Suppressive Effect of Kanzo-bushi-to, a Kampo Medicine, on Collagen-Induced Arthritis

Ono

Mizukami

Ogihara

2004

Biological & Pharmaceutical Bulletin

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Kanzo-bushi-to (KBT) is a traditional Japanese herbal medicine (Kampo medicine), which is used in Japan to treat rheumatoid arthritis. In the present study, we investigated the suppressive effect of KBT on collagen-induced arthritis (CIA) and further studied the underlying mechanism. CIA was induced in male DBA/1J mice by immunization with bovine type II collagen, followed by a booster injection 21 d later. KBT was given at a dose of 430 mg/kg/d from three days before the first immunization to the end of the experiment. KBT suppressed CIA development effectively and further protected focal bone erosion and bone destruction as evidenced by the reduced histological score. Histochemical examination revealed that KBT decreased TRAP-positive cells at the synovium-bone interface and at the sites of focal bone erosion, coincident with the findings that RANKL/OPG mRNA ratio was significantly reduced by KBT treatment. KBT also decreased mRNA levels of M-CSF and iNOS in joints and of iNOS in peritoneal macrophages. In conclusion, KBT prevented osteoclast generation by decreasing RANKL/OPG ratio and M-CSF mRNA levels, resulting in reduction in bone erosion and destruction. In addition, KBT has anti-inflammatory effect such as the suppression of iNOS expression in peritoneal macrophages and joints of CIA mice. These finding suggests that KBT is a potential new therapeutic agent for the treatment of RA.Key words Kanzo-bushi-to; Kampo medicine; collagen-induced arthritis; bone destruction; osteoclast 1406Biol. Pharm. Bull. 27(9) 1406-1413 (2004 tis in an induced-arthritis model, CIA mice. 25) Especially, KBT decreased serum anti-type II collagen antibody levels significantly, 25) although such an effect was not seen in other Kampo medicines. These results suggest that the inhibition of arthritis by KBT is ascribed to anti-inflammatory and immunosuppressive effect. We therefore evaluated the effect of KBT on bone destruction in the joints of CIA model mice, as one of the most important aims of RA therapy is to block bone destruction. We provided here several lines of evidence that KBT effectively suppressed bone destruction in arthritic joints, accompaning the reduction of osteotropic factors.

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“…These 2 cytokines can also trigger the activation of NF-B, which leads to the production of additional inflammatory cytokines that will activate a cascade of events that cause joint inflammation and damage (24,25). Both iNOS and COX-2 are important mediators of IL-1-induced bone erosion and edema in the CIA model (26,27).…”

Section: Discussionmentioning

confidence: 99%