Osteoblastic MMPs are important actors of bone remodeling. We showed previously that osteoblast specific overexpression of TIMP1, an inhibitor of MMPs, prevents the bone loss induced by ovariectomy mainly through inhibition of bone resorption. We hypothesized that inhibition of the MMP3 could be implicated in the protective effect of TIMP1 and that MMP3 polymorphisms located in the proximal promoter of MMP3 gene could be associated to post-menopausal bone loss in women.
We evaluated the effect of MMP3 invalidation on bone mass in mice and after ovariectomy. MMP3 knockout (KO) mice exhibited significantly higher bone mineral density (BMD) compared to WT mice. MMP3 invalidation leads, alike TIMP1 overexpression, to a protective effect against bone loss induced by ovariectomy: BMD is not significantly different between ovariectomized and sham-ovariectomized MMP3 KO mice. Furthermore, plasmatic D-PYR was lower in sham-operated compared to ovariectomized MMP3 KO mice suggesting involvement of MMP3 in bone resorption.
We identified several polymorphisms within the 2 kb proximal MMP3 promoter that could result in modification of gene expression. We generated plasmids containing increasing fragments of the human MMP3 promoter containing one or more polymorphisms, cloned upstream of the luciferase gene. We used a DNA collection, established with approval of ethical committee, from a cohort of 548 post-menopausal women. Only women who had a complete bone phenotype characterization and who had no anti-osteoporotic treatment or concomitant disease were considered. Our analyses showed that three polymorphisms (rs522616, rs302590 and rs3025058) are associated to an up-regulation of MMP3 promoter activity. Moreover, women carrying the variant 5A/5A (rs3025058) showed higher Z-score at the femoral neck compared to the other genotypes.
In conclusion, our data indicates that invalidation of MMP3 protects against bone loss in mice. Moreover, SNPs located in its promoter affect MMP3 gene expression and are associated to bone density in post-menopausal women.
17 May 2014 - 20 May 2014