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 5

Deletion of ERα decreases proliferation and differentiation of osteoblast progenitors from the periosteum.

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Deletion of ERα decreases proliferation and differentiation of osteoblas...
(A) Mineralized matrix visualized and quantified following Alizarin Red staining and (B) osteocalcin levels in the medium of periosteal cell cultures pooled from 3 mice treated with vehicle (veh) or rhBMP-2 (25 ng/ml) for 21 days (triplicate cultures). Original magnification, ×63 (bottom row). (C) BrdU incorporation and (D) caspase-3 activity in periosteal cells cultured for 3 day (6 wells). AFU, arbitrary fluorescence units. (E) mRNA levels of the indicated genes determined by quantitative PCR in periosteal cells cultured with ascorbic acid for 14 days (triplicate cultures). (F) Mineralized matrix quantified following Alizarin Red staining in periosteal cells cultured with vehicle or E2 (10–8 M) in the presence of ascorbic acid for 21 days (triplicate cultures). Bars represent mean and SD. *P < 0.05 by 2-way ANOVA; #P < 0.05 by Student’s t test.