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Estrogen receptor-? signaling in osteoblast progenitors stimulates cortical bone accrual.

ABSTRACT: The detection of estrogen receptor-? (ER?) 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 ER? in osteoblast lineage cells has remained elusive. In addition, estrogen activation of ER? 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 ER? at different stages of differentiation in murine osteoblast lineage cells. We found that ER? in osteoblast progenitors expressing Osterix1 (Osx1) potentiates Wnt/?-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 ER? mediated a protective effect of estrogens against endocortical, but not cancellous, bone resorption. ER? in mature osteoblasts or osteocytes did not influence cancellous or cortical bone mass. Hence, the ER? in both osteoblast progenitors and osteoclasts functions to optimize bone mass but at distinct bone compartments and in response to different cues.

SUBMITTER: Almeida M

PROVIDER: S-EPMC3533305 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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

Almeida Maria M Iyer Srividhya S Martin-Millan Marta M Bartell Shoshana M SM Han Li L Ambrogini Elena E Onal Melda M Xiong Jinhu J Weinstein Robert S RS Jilka Robert L RL O'Brien Charles A CA Manolagas Stavros C SC

The Journal of clinical investigation 20121210 1

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 sk ...[more]

PMID: 23221342

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Project description:Introduction Sirtuin 1 (SIRT1) is a key player in aging and metabolism and regulates bone mass and architecture. Sexual dimorphism in skeletal effects of SIRT1 has been reported, with an unfavorable phenotype primarily in female mice. Methods To investigate the mechanisms of gender differences in SIRT1 skeletal effect, we investigated femoral and vertebral cortical and cancellous bone in global Sirt1 haplo-insufficient 129/Sv mice aged 2,7,12 months lacking Sirt1 exons 5,6,7 (Sirt1+/Δ) and their wild type (WT) counterparts. Results In females, femoral bone mineral content, peak cortical thickness, and trabecular bone volume (BV/TV%), number and thickness were significantly lower in Sirt1+/Δ compared to WT mice. Increased femoral cortical porosity was observed in 7-month-old Sirt1+/Δ compared to WT female mice, accompanied by reduced biomechanical strength. No difference in vertebral indices was detected between Sirt1+/Δ and WT female mice. SIRT1 decreased with aging in WT female mice and was lower in vertebrae and femur in 18- and 30- versus 3-month-old 129/Sv and C57BL/6J female mice, respectively. Decreased bone estrogen receptor alpha (ERα) was observed in Sirt1+/Δ compared to WT female mice and was significantly higher in Sirt1 over-expressing C3HT101/2 murine mesenchymal stem cells. In males no difference in femoral indices was detected in Sirt1+/Δ versus WT mice, however vertebral BV/TV%, trabecular number and thickness were higher in Sirt1+/Δ vs. WT mice. No difference in androgen receptor (AR) was detected in bone in Sirt1+/Δ vs. WT male mice. Bone SIRT1 was significantly lower in male compared to female WT mice, suggesting that SIRT1 maybe more significant in female than male skeleton. Discussion These findings demonstrate that 50% reduction in SIRT1 is sufficient to induce the hallmarks of skeletal aging namely, decreased cortical thickness and increased porosity in female mice, highlighting the role of SIRT1 as a regulator of cortical bone quantity and quality. The effects of SIRT1 in cortical bone are likely mediated in part by its regulation of ERα. The age-associated decline in bone SIRT1 positions SIRT1 as a potential therapeutic target to ameliorate age-related cortical bone deterioration in females. The crosstalk between ERα, AR and SIRT1 in the bone microenvironment remains to be further investigated.

Dataset Information

Estrogen receptor-? signaling in osteoblast progenitors stimulates cortical bone accrual.

Publications

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

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