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Abstract
Postmenopausal osteoporosis is characterized by declining estrogen levels, and estrogen replacement therapy has been proven beneficial for preventing bone loss in affected women. While the physiological functions of estrogen in bone, primarily the inhibition of bone resorption, have been studied extensively, the effects of pharmacological estrogen administration are still poorly characterized. Since elevated levels of follicle-stimulating hormone (FSH) have been suggested to be involved in postmenopausal bone loss, we investigated whether the skeletal response to pharmacological estrogen administration is mediated in a FSH-dependent manner. Therefore, we treated wildtype and FSHβ-deficicent (Fshb−/−) mice with estrogen for 4 weeks and subsequently analyzed their skeletal phenotype. Here we observed that estrogen treatment resulted in a significant increase of trabecular and cortical bone mass in both, wildtype and Fshb−/− mice. Unexpectedly, this FSH-independent pharmacological effect of estrogen was not caused by influencing bone resorption, but primarily by increasing bone formation. To understand the cellular and molecular nature of this osteo-anabolic effect we next administered estrogen to mouse models carrying cell specific mutant alleles of the estrogen receptor alpha (ERα). Here we found that the response to pharmacological estrogen administration was not affected by ERα inactivation in osteoclasts, while it was blunted in mice lacking the ERα in osteoblasts or in mice carrying a mutant ERα incapable of DNA binding. Taken together, our findings reveal a previously unknown osteo-anabolic effect of pharmacological estrogen administration, which is independent of FSH and requires DNA-binding of ERα in osteoblasts.
Highlights
Osteoporosis results from an imbalance between bone formation and bone resorption, thereby causing bone loss and increased fracture risk [1]
Fshb2/2 mice displayed a marked atrophy of the uterus and ovaries, which was fully normalized by estrogen treatment (Fig. 1A)
Serum measurements revealed that estrogen levels were non-significantly decreased in Fshb2/2 mice, but significantly increased approximately 10-fold in the both groups following estrogen treatment (Fig. 1A)
Summary
Osteoporosis results from an imbalance between bone formation and bone resorption, thereby causing bone loss and increased fracture risk [1]. One of the major risk factors of osteoporosis in women is menopause, when ovarian atrophy results in a decline of serum estrogen levels and increased bone resorption [2]. Since ovarian failure is accompanied by an increase in pituitaryderived hormones, it was alternatively proposed that FSH (folliclestimulating hormone), and not necessarily estrogen itself, is involved in hypogonadism-induced bone loss [6,7]. This hypothesis was supported by the findings that hypogonadic mice lacking either the FSH receptor (Fshr2/2) or the FSH ß-subunit (Fshb2/2) failed to develop the expected osteopenia, and that FSH administration activated osteoclast differentiation in vitro [8]
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