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Effects of Deletion of ER? in Osteoblast-Lineage Cells on Bone Mass and Adaptation to Mechanical Loading Differ in Female and Male Mice.

ABSTRACT: Estrogen receptor alpha (ER?) has been implicated in bone's response to mechanical loading in both males and females. ER? in osteoblast lineage cells is important for determining bone mass, but results depend on animal sex and the cellular stage at which ER? is deleted. We demonstrated previously that when ER? is deleted from mature osteoblasts and osteocytes in mixed-background female mice, bone mass and strength are decreased. However, few studies exist examining the skeletal response to loading in bone cell-specific ER?KO mice. Therefore, we crossed ER? floxed (ER?(fl/fl)) and osteocalcin-Cre (OC-Cre) mice to generate animals lacking ER? in mature osteoblasts and osteocytes (pOC-ER?KO) and littermate controls (LC). At 10 weeks of age, the left tibia was loaded in vivo for 2 weeks. We analyzed bone mass through micro-CT, bone formation rate by dynamic histomorphometry, bone strength from mechanical testing, and osteoblast and osteoclast activity by serum chemistry and immunohistochemistry. ER? in mature osteoblasts differentially regulated bone mass in males and females. Compared with LC, female pOC-ER?KO mice had decreased cortical and cancellous bone mass, whereas male pOC-ER?KO mice had equal or greater bone mass than LC. Bone mass results correlated with decreased compressive strength in pOC-ER?KO female L(5) vertebrae and with increased maximum moment in pOC-ER?KO male femora. Female pOC-ER?KO mice responded more to mechanical loading, whereas the response of pOC-ER?KO male animals was similar to their littermate controls.

SUBMITTER: Melville KM

PROVIDER: S-EPMC4506717 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Effects of Deletion of ERα in Osteoblast-Lineage Cells on Bone Mass and Adaptation to Mechanical Loading Differ in Female and Male Mice.

Melville Katherine M KM Kelly Natalie H NH Surita Gina G Buchalter Daniel B DB Schimenti John C JC Main Russell P RP Ross F Patrick FP van der Meulen Marjolein C H MC

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20150522 8

Estrogen receptor alpha (ERα) has been implicated in bone's response to mechanical loading in both males and females. ERα in osteoblast lineage cells is important for determining bone mass, but results depend on animal sex and the cellular stage at which ERα is deleted. We demonstrated previously that when ERα is deleted from mature osteoblasts and osteocytes in mixed-background female mice, bone mass and strength are decreased. However, few studies exist examining the skeletal response to loadi ...[more]

PMID: 25707500

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Project description:Loss-of-function mutations in the Sost gene lead to high bone mass phenotypes. Pharmacological inhibition of Sost/sclerostin provides a new drug strategy for treating osteoporosis. Questions remain as to how physical activity may affect bone mass under sclerostin inhibition and if that effect differs between males and females. We previously observed in female Sost knockout (KO) mice an enhanced cortical bone formation response to a moderate level of applied loading (900 με at the tibial midshaft). The purpose of the present study was to examine cortical bone adaptation to the same strain level applied to male Sost KO mice. Strain-matched in vivo compressive loading was applied to the tibiae of 10-, 26- and 52-week-old male Sost KO and littermate control (LC) mice. The effect of tibial loading on bone (re)modeling was measured by microCT, 3D time-lapse in vivo morphometry, 2D histomorphometry and gene expression analyses. As expected, Sost deficiency led to high cortical bone mass in 10- and 26-week-old male mice as a result of increased bone formation. However, the enhanced bone formation associated with Sost deficiency did not appear to diminish with skeletal maturation. An increase in bone resorption was observed with skeletal maturation in male LC and Sost KO mice. Two weeks of in vivo loading (900 με at the tibial midshaft) induced only a mild anabolic response in 10- and 26-week-old male mice, independent of Sost deficiency. A decrease in the Wnt inhibitor Dkk1 expression was observed 3 h after loading in 52-week-old Sost KO and LC mice, and an increase in Lef1 expression was observed 8 h after loading in 10-week-old Sost KO mice. The current results suggest that long-term inhibition of sclerostin in male mice does not influence the adaptive response of cortical bone to moderate levels of loading. In contrast with our previous strain-matched study in females showing enhanced bone responses with Sost ablation, these results in males indicate that the influence of Sost deficiency on the cortical bone formation response to a moderate level of loading differs between males and females. Clinical studies examining antibodies to inhibit sclerostin may need to consider that the efficacy of additional physical activity regimens may be sex dependent.

Dataset Information

Effects of Deletion of ER? in Osteoblast-Lineage Cells on Bone Mass and Adaptation to Mechanical Loading Differ in Female and Male Mice.

Publications

Effects of Deletion of ERα in Osteoblast-Lineage Cells on Bone Mass and Adaptation to Mechanical Loading Differ in Female and Male Mice.

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