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

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

Effects of estrogen on bone mRNA levels of sclerostin and other genes relevant to bone metabolism in postmenopausal women

Context: Studies in postmenopausal women have shown that estrogen reduces circulating sclerostin levels, but effects of estrogen on skeletal sclerostin mRNA levels are unknown.Objective: The objective of the study was to evaluate the effects of short-term estrogen treatment on bone mRNA levels of sclerostin and other genes relevant to bone metabolism.Design, setting, and patients: Needle bone biopsies were obtained from 20 postmenopausal women treated with transdermal estrogen for 3 weeks and 20 untreated controls. Quantitative PCR analyses were used to examine the expression of sclerostin and other genes related to bone metabolism, including 71 additional genes linked to bone density/fracture from genome-wide association studies.Results: Estrogen treatment was associated with lower bone sclerostin mRNA levels (by 48%, P\u3c.05) and with lower (by 54%, P\u3c.01) mRNA levels of the sclerostin-related protein, sclerostin domain-containing protein 1 (SOSTDC1), which is also a Wnt/bone morphogenetic protein inhibitor. Consistent with studies in mice showing that ovariectomy increased nuclear factor-κB (NF-κB) activation, we found that estrogen treatment was associated with a significant reduction in inflammatory genes as a group (P=.028), with bone mRNA levels of NFKB2 and RELB (both encoding proteins in the NF-κB transcription factor complex) being significantly reduced individual genes. Eight of the 71 genome-wide association study-related genes examined were modulated by estrogen (P\u3c.05, false discovery rate\u3c0.10).Conclusion: In humans, estrogen-induced decreases in two key inhibitors of Wnt/bone morphogenetic protein signaling, sclerostin and SOSTDC1, along with reductions in NF-κB signaling, may be responsible for at least part of the protective effects of estrogen on bone