Estrogen reduces bone sost mRNA and circulating sclerostin levels in postmenopausal women

Matthew Roforth, Koji Fujita, Susan Demaray, Ulrike McGregor, Salman Kirmani, Louise McCready, James Peterson, Matthew Drake, David Monroe, Sundeep Khosla

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Studies in postmenopausal women have shown that estrogen (E) reduces circulating sclerostin levels (JBMR 26:27, 2011). However, recent studies in mice(JBMR 28:618, 2013) found no significant effects of ovariectomy on serum sclerostin levels and lack of a relationship between circulating sclerostin and sost mRNA levels in various bones. To resolve this issue in humans, we measured serum sclerostin and bone sost mRNA levels in needle biopsies (1-2 mm diameter) from 20 postmenopausal women (71¡5 yr) treated with transdermal estradiol (0.05mg/d) for 3 weeks and 20untreated control women (73¡7 yr). Serum sclerostin levels were 29% lower (P =0.008) in the E-treated compared to the control women. Concomitantly, bone sost mRNA levels were reduced by 48% (P = 0.03) in the E-treated women. Interestingly ,bone sost mRNA levels were significantly correlated with serum sclerostin levels in the E-treated (r = 0.57, P = 0.008), but not in the control women (r = -0.25, P = 0.280). In addition, mRNA levels of the sclerostin domain-containing protein 1 (sostdc1), a sclerostin-related protein that is another Wnt/BMP inhibitor, were also reduced in the bones of the E-treated compared to the control women (by 54%, P = 0.01).We further extended these studies using customized, in-house QPCR analyses to examine the mRNA expression of genes in other pathways related to bone metabolism, as well as the expression of 71 genes linked to SNPs from GWAS studies (Nat Genet 44:491, 2012). Consistent with studies in mice showing that ovariectomy upregulated components of NFkB signaling, leading to impaired osteoblastic bone formation (Nat Med 15:682, 2009), we found significantly reduced mRNA levels of bothNFkB2andrelB, along with an overall trend (P = 0.028 by cluster analysis) for lower mRNA levels of multiple inflammatory markers in the bone biopsies of the E-treated compared to the control women. Of the 71 GWAS-related genes examined, 14 were modulated in vivo by E treatment. In summary, our studies demonstrate that, in humans, E reduces both bone sost mRNA and circulating sclerostin levels. Further, since bone loss following E deficiency is associated with impaired bone formation relative to bone resorption, our findings point to increases in two key inhibitors of Wnt/BMP signaling, sclerostin andsostdc1, along with increased NFkB signaling, as mediating this relative deficit in bone formation in E-deficient postmenopausal women.

Original languageUndefined/Unknown
JournalDepartment of Paediatrics and Child Health
Publication statusPublished - 1 Feb 2013

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