Sex hormones and their receptors in bone homeostasis: insights from genetically modified mouse models

Vico, Laurence; Vanacker, Jean‐Marc

doi:10.1007/s00198-009-0963-5

Cited by 42 publications

(47 citation statements)

References 66 publications

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“…The current findings are consistent with a regulatory role for inhibin A in bone mass, although increased bone mass was found in TgFSH m females exhibiting levels of inhibin A well within the normal range. Likewise, the correlation between serum testosterone levels in TgFSH females exhibiting increased bone mass implicates a role for steroid-induced bone formation, presumably via local aromatization of androgen to estradiol and direct estradiol receptor mechanisms in the bone (27). The present study cannot distinguish between the effects of specific ovarian factors in vivo, such as sex steroids or inhibins.…”

Section: Discussionmentioning

confidence: 69%

Follicle-stimulating hormone increases bone mass in female mice

Allan

Kalak

Dunstan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Elevated follicle-stimulating hormone (FSH) activity is proposed to directly cause bone loss independent of estradiol deficiency in aging women. Using transgenic female mice expressing human FSH (TgFSH), we now reveal that TgFSH dose-dependently increased bone mass, markedly elevating tibial and vertebral trabecular bone volume. Furthermore, TgFSH stimulated a striking accrual of bone mass in hypogonadal mice lacking endogenous FSH and luteinizing hormone (LH) function, showing that FSH-induced bone mass occurred independently of background LH or estradiol levels. Higher TgFSH levels increased osteoblast surfaces in trabecular bone and stimulated de novo bone formation, filling marrow spaces with woven rather than lamellar bone, reflective of a strong anabolic stimulus. Trabecular bone volume correlated positively with ovarianderived serum inhibin A or testosterone levels in TgFSH mice, and ovariectomy abolished TgFSH-induced bone formation, proving that FSH effects on bone require an ovary-dependent pathway. No detectable FSH receptor mRNA in mouse bone or cultured osteoblasts or osteoclasts indicated that FSH did not directly stimulate bone. Therefore, contrary to proposed FSH-induced bone loss, our findings demonstrate that FSH has dose-dependent anabolic effects on bone via an ovary-dependent mechanism, which is independent of LH activity, and does not involve direct FSH actions on bone cells. ) were protected from bone loss despite estradiol deficiency, whereas haploinsufficient Fshb +/− females exhibited increased bone mass (9). By inference, it was proposed that elevated circulating FSH levels caused the bone loss observed in estrogen deficient peri-and postmenopausal women (9, 10). Mechanisms proposed for this putative FSH-induced bone loss included direct FSH stimulation of osteoclastic bone resorption via the FSHR (9) and FSH-induced TNFα production by bone marrow granulocytes and macrophages by as-yet-undefined pathways (11). However, elevated androgens in Fshb −/− and Fshr −/− female mice provide an alternate explanation for the preservation of bone mass in these estradiol-deficient mouse models (12). Although direct regulation of bone remodeling through FSH would have major clinical implications, such a mechanism has yet to exclude roles of FSH-regulated ovarianderived factors, which, on a biological basis, are more likely to control bone turnover, such as sex steroids (12-15) or inhibins (16, 17).In the current study, we have directly determined the effects of elevated FSH activity on bone mass and structure by using pituitary-independent, transgenic expression of human FSH (TgFSH) in female mice. Our TgFSH mouse model provides progressively rising circulating levels of FSH with age (18), with distinct transgenic lines allowing dose-dependent analysis of FSH actions in vivo (19)(20)(21). Using this FSH model, we have determined TgFSH actions on bone (i) in isolation of LH actions, using TgFSH expressed in hypogonadal (hpg) female mice lacking gonadotropinreleasing hormone (GnRH) and therefore endog...

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Section: Discussionmentioning

confidence: 69%

Follicle-stimulating hormone increases bone mass in female mice

Allan

Kalak

Dunstan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Hence, the greater bone size found in very long breastfeeding mothers may not be ascribed to the increased mechanical load during pregnancy, but probably due to the lactation-associated estrogen deficiency. Estrogen at high level promotes endocortical bone formation and inhibits periosteal formation [34][35][36], and this is considered to be one of the mechanisms underlying sexual dimorphism. Periosteal apposition is inversely associated with postmenopausal estrogen levels suggesting that periosteal apposition compensates for the decreased bone strength caused by the bone loss during menopause [37].…”

Section: Discussionmentioning

confidence: 99%

Lactation is associated with greater maternal bone size and bone strength later in life

Wiklund

Wang

et al. 2011

Osteoporos Int

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“…43,44 These experiments showed for the first time that the presence or absence of the estrogen receptor changes the way osteoblasts respond to mechanical signals. Further work showed that two other receptors with variable effects on cortical and trabecular bone growth, estrogen receptor-beta (ERb) and the androgen receptor (AR), [45][46][47] suppress ERa-mediated osteogenic responses to loading. 32,34,[48][49] However, ERa is expressed primarily in cortical bone, while ERb and AR are more numerous in trabecular bone.…”

Section: Estrogen Era and Mechanosensitivitymentioning

confidence: 99%

Estrogen, exercise, and the skeleton

Devlin¹

2011

Evolutionary Anthropology

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Patterns of variation in bone size and shape provide crucial data for reconstructing hominin paleobiology, including ecogeographic adaptation, life history, and functional morphology. Measures of bone strength, including robusticity (diaphyseal thickness relative to length) and cross-sectional geometric properties such as moments of area, are particularly useful for inferring behavior because bone tissue adapts to its mechanical environment. Particularly during skeletal growth, exercise-induced strains can stimulate periosteal modeling so that, to some extent, bone thickness reflects individual behavior. Thus, patterns of skeletal robusticity have been used to identify gender-based activity differences, temporal shifts in mobility, and changing subsistence strategies. Although there is no doubt that mechanical loading leaves its mark on the skeleton, less is known about whether individuals differ in their skeletal responses to exercise. For example, the potential effects of hormones or growth factors on bone-strain interactions are largely unexplored. If the hormonal background can increase or decrease the effects of exercise on skeletal robusticity, then the same mechanical loads might cause different degrees of bone response in different individuals. Here I focus on the role of the hormone estrogen in modulating exercise-induced changes in human bone thickness.

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Sex hormones and their receptors in bone homeostasis: insights from genetically modified mouse models

Cited by 42 publications

References 66 publications

Follicle-stimulating hormone increases bone mass in female mice

Follicle-stimulating hormone increases bone mass in female mice

Lactation is associated with greater maternal bone size and bone strength later in life

Estrogen, exercise, and the skeleton

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