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Estrogen receptor-? expression in neuronal cells affects bone mass.

ABSTRACT: It has generally been assumed that bone mass is controlled by endocrine mechanisms and the local bone environment. Recent findings demonstrate that central pathways are involved in the regulation of bone mass. Estrogen is involved in the regulation of bone homeostasis and the CNS is also a target for estrogen actions. The aim of this study was to investigate in vivo the role of central estrogen receptor-? (ER?) expression for bone mass. Nestin-Cre mice were crossed with ER?(flox) mice to generate mice lacking ER? expression specifically in nervous tissue (nestin-ER?(-/-)). Bone mineral density was increased in both the trabecular and cortical bone compartments in nestin-ER?(-/-) mice compared with controls. Femoral bone strength was increased in nestin-ER?(-/-) mice, as demonstrated by increased stiffness and maximal load of failure. The high bone mass phenotype in nestin-ER?(-/-) mice was mainly caused by increased bone formation. Serum leptin levels were elevated as a result of increased leptin expression in white adipose tissue (WAT) and slightly increased amount of WAT in nestin-ER?(-/-) mice. Leptin receptor mRNA levels were reduced in the hypothalamus but not in bone. In conclusion, inactivation of central ER? signaling results in increased bone mass, demonstrating that the balance between peripheral stimulatory and central inhibitory ER? actions is important for the regulation of bone mass. We propose that the increased bone mass in nestin-ER?(-/-) mice is mediated via decreased central leptin sensitivity and thereby increased secretion of leptin from WAT, which, in turn, results in increased peripheral leptin-induced bone formation.

SUBMITTER: Ohlsson C

PROVIDER: S-EPMC3271867 | biostudies-other | 2012 Jan

REPOSITORIES: biostudies-other

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Estrogen receptor-α expression in neuronal cells affects bone mass.

Ohlsson Claes C Engdahl Cecilia C Börjesson Anna E AE Windahl Sara H SH Studer Erik E Westberg Lars L Eriksson Elias E Koskela Antti A Tuukkanen Juha J Krust Andree A Chambon Pierre P Carlsten Hans H Lagerquist Marie K MK

Proceedings of the National Academy of Sciences of the United States of America 20120103 3

It has generally been assumed that bone mass is controlled by endocrine mechanisms and the local bone environment. Recent findings demonstrate that central pathways are involved in the regulation of bone mass. Estrogen is involved in the regulation of bone homeostasis and the CNS is also a target for estrogen actions. The aim of this study was to investigate in vivo the role of central estrogen receptor-α (ERα) expression for bone mass. Nestin-Cre mice were crossed with ERα(flox) mice to generat ...[more]

PMID: 22215598

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Project description:BACKGROUND:The study investigated the associations of rs9340799:A?>?G (XbaI) and rs2234693:T?>?C (PvuII) polymorphisms in the estrogen receptor 1 gene (ESR1) with femoral neck (BMD-FN) and lumbar spine bone mineral density (BMD-LS), biochemical markers of bone turnover, calcium and phosphate levels, fracture prevalence, and a response to two types of anti-osteoporotic therapy in postmenopausal women from southern Slovakia. METHODS:We analysed 343 postmenopausal Slovak women (62.40?±?0.46 years). The influence of rs9340799 (AA vs. AG?+?GG) and rs2234693 (TT vs. TC?+?CC) genotypes on BMD and biochemical markers was evaluated by covariance analysis adjusted for age and BMI. Binary logistic regression was used to evaluate the genotype effect on fracture prevalence. Pharmacogenetic part of the study included women who received a regular therapy of HT (17ß estradiol with progesterone; 1 mg/day for both; N?=?76) or SERMs/raloxifene (60 mg/day; N?=?64) during 48 months. The genotype-based BMD change was assessed by variance analysis for repeated measurements. RESULTS:Women with AA genotype of rs9340799 had higher BMD-FN (+?0.12?±?0.57 of T-score) and BMD-LS (+?0.17?±?0.08 of T-score) in comparison with AG?+?GG. The rs2234693 polymorphism did not affect any of the monitored parameters. No effect of any ESR1 polymorphisms was found on fracture prevalence. Both types of anti-osteoporotic therapy had a positive effect on BMD improvement in FN and LS sites. Considering the effect of the ESR1 gene within the HT, the subjects with rs9340799/AA genotype showed worse response than those with GG genotype (-?0.26?±?0.10 of BMD-FN T-score; -?0.35?±?0.10 of BMD-LS T-score) and also with AG genotype (-?0.22?±?0.08 of BMD-LS T-score). The rs2234693/TT genotype responded poorer in BMD-LS in comparison with TC (-?0.22?±?0.08 of T-score) and CC (-?0.35?±?0.09 of T-score). The effect of the ESR1 gene on raloxifene therapy was reported only in BMD-LS. Subjects with rs9340799/AA genotype had a?-?0.30?±?0.11 of T-score worse response compared to AG genotype. The rs2234693/TT genotype showed -?0.39?±?0.11 and?-?0.46?±?0.15 lower T-scores in comparison with TC and CC genotypes, respectively. CONCLUSIONS:The rs9340799 polymorphism may contribute to decreased BMD in postmenopausal women from southern Slovakia; however, this is not related to higher fracture prevalence. Concurrently, both polymorphisms affected a response to analysed anti-osteoporotic therapies.

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Estrogen receptor-? expression in neuronal cells affects bone mass.

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Estrogen receptor-α expression in neuronal cells affects bone mass.

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