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First published online April 24, 2006
doi: 10.1242/10.1242/jcs.02895

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

¹ Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain
² Centro de Investigaciones Biológicas (CSIC), Instituto `Reina Sofía' de Investigaciones Nefrológicas, Ramiro de Maeztu 9, 28040 Madrid, Spain
³ Departamento de Fisiología, Facultad de Medicina, Universidad de Alcalá, Ctra de Barcelona, Km 33.5, 28871 Madrid, Spain

^* Author for correspondence (e-mail: czaragoza{at}cnic.es)

Accepted 18 January 2006

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-). 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.

Key words: Matrix metalloproteinases, MMP-13, Nitric oxide, iNOS, Osteoblasts, cGMP/PKG, Bone development

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