Estrogen receptor-α signaling in osteoblast progenitors stimulates cortical bone accrual
Maria Almeida, … , Charles A. O’Brien, Stavros C. Manolagas
Maria Almeida, … , Charles A. O’Brien, Stavros C. Manolagas
Published December 10, 2012
Citation Information: J Clin Invest. 2013;123(1):394-404. https://doi.org/10.1172/JCI65910.
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Research Article Bone biology

Estrogen receptor-α signaling in osteoblast progenitors stimulates cortical bone accrual

Abstract

The detection of estrogen receptor-α (ERα) in osteoblasts and osteoclasts over 20 years ago suggested that direct effects of estrogens on both of these cell types are responsible for their beneficial effects on the skeleton, but the role of ERα in osteoblast lineage cells has remained elusive. In addition, estrogen activation of ERα in osteoclasts can only account for the protective effect of estrogens on the cancellous, but not the cortical, bone compartment that represents 80% of the entire skeleton. Here, we deleted ERα at different stages of differentiation in murine osteoblast lineage cells. We found that ERα in osteoblast progenitors expressing Osterix1 (Osx1) potentiates Wnt/β-catenin signaling, thereby increasing proliferation and differentiation of periosteal cells. Further, this signaling pathway was required for optimal cortical bone accrual at the periosteum in mice. Notably, this function did not require estrogens. The osteoblast progenitor ERα mediated a protective effect of estrogens against endocortical, but not cancellous, bone resorption. ERα in mature osteoblasts or osteocytes did not influence cancellous or cortical bone mass. Hence, the ERα in both osteoblast progenitors and osteoclasts functions to optimize bone mass but at distinct bone compartments and in response to different cues.

Authors

Maria Almeida, Srividhya Iyer, Marta Martin-Millan, Shoshana M. Bartell, Li Han, Elena Ambrogini, Melda Onal, Jinhu Xiong, Robert S. Weinstein, Robert L. Jilka, Charles A. O’Brien, Stavros C. Manolagas

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Figure 6

The unliganded ERα potentiates the Wnt/β-catenin signaling pathway.

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The unliganded ERα potentiates the Wnt/β-catenin signaling pathway. Br...
BrdU incorporation and AP activity in periosteal cell cultures pooled from 3 mice from each of the (A) ERαf/f;Prx1-cre and ERαf/f littermate groups and (B) the ERαf/f;Osx1-cre and Osx1-cre littermate groups, preincubated for 1 hour with vehicle or E2 (10–8 M), followed by incubation without or with Wnt3 (25 ng/ml) for 3 days. (C) ERα mRNA levels determined by quantitative PCR in C2C12 cells transduced with lentiviruses encoding a nontarget shRNA (sh-control) or sh-ERα. (D) AP activity in cells treated as in A. (E) Luciferase activity in C2C12 cells transfected with a TCF-luc reporter construct and pretreated as in A, followed by treatment without or with Wnt3 (12.5 ng/ml) for 24 hours. Bars represent mean and SD. *P < 0.05 by 1-way ANOVA with Bonferroni’s test; #P < 0.05 by Student’s t test.