Estrogen receptor-α 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-α (ERα) expression for bone mass. Nestin-Cre mice were crossed with ERα flox mice to generate mice lacking ERα expression specifically in nervous tissue (nestin-ERα). Bone mineral density was increased in both the trabecular and cortical bone compartments in nestin-ERα −/− mice compared with controls. Femoral bone strength was increased in nestin-ERα −/− mice, as demonstrated by increased stiffness and maximal load of failure. The high bone mass phenotype in nestin-ERα −/− 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-ERα −/− mice. Leptin receptor mRNA levels were reduced in the hypothalamus but not in bone. In conclusion, inactivation of central ERα signaling results in increased bone mass, demonstrating that the balance between peripheral stimulatory and central inhibitory ERα actions is important for the regulation of bone mass. We propose that the increased bone mass in nestin-ERα −/− 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.

Estrogen receptor-α in osteocytes is important for trabecular bone formation in male mice

“…In addition, it was recently proposed that neuronal ERα modulates bone mass in female mice (29). The most compelling evidence for a role of cell-specific ERα for bone metabolism is the results from two separate in vivo studies inactivating ERα either in mature osteoclasts (14) or monocytes/osteoclast precursors (13).…”

“…CT scans of the femur and tibia were performed by using pQCT XCT RESEARCH M (v4.5B; Norland) as described previously (12,33). The μCT analyses were performed on the lumbar vertebra (L 5 ) using a model 1072 scanner (Skyscan) (29,34,35). Further details are provided in SI Materials and Methods.…”

Estrogen-BDNF signalling in neuronal cells: toward a brain-centric approach to the cure of aging and osteoporosis

“…An attempt to compare central and peripheral action of estrogens has been addressed, administrating estradiol intracerebroventricularly and subcutaneously, but it failed because estradiol easily pass the blood -brain barrier accrual. 14 To further investigate this point, Ohlsson et al 1 generated Nestin-Cre mice in which ER-is selectively ablated in the nervous system of female animals. This genetic manipulation led to a significant reduction of ER-in the hypothalamous and no compensatory effects in the expression of ER-in other tissues.…”

“…Ohlsson et al 1 attribute the skeletal phenotype of nestin-ER − / − to the peripheral effect of leptin on bone. To state so, the author presents the following sequence of evidences:…”

“…Ohlsson et al 1 in a recently published PNAS paper explored the possible role of central estrogens receptor (ER-) signalling on bone mass and found that the deletion of ER-signalling in nestin-ER − / − mice brain results in high bone mass phenotype. The authors propose that the balance between the well-known peripheral stimulatory ER action and the newly discovered central inhibitory ER-action determine bone mass with the contribution of the anabolic effect of peripheral leptin on bone.…”