A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor–deficient mice

Sims, Natalie A.; Clément-Lacroix, Philippe; Minet, Dominique; Fraslon-Vanhulle, Caroline; Gaillard-Kelly, Martine; Resche-Rigon, Matthieu; Baron, Roland

doi:10.1172/jci17246

Cited by 105 publications

(129 citation statements)

References 34 publications

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“…Bone histomorphometry was performed on lumbar vertebrae as described previously. (31,32) Histomorphometric measurements were made on sections of lumbar vertebrae (L 3 ) using the OsteoMeasure Analysis System (Osteometrics, Atlanta, GA, USA) according to standard criteria. (33) For osteoclast activity TRACP assay, bones were fixed in 10% paraformaldehyde (PFA), and decalcification was achieved by 10% EDTA immersion for 2 weeks.…”

Section: Calcium Imagingmentioning

confidence: 99%

Maslinic acid suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss by regulating RANKL-mediated NF-κB and MAPK signaling pathways

Yang

et al. 2010

Journal of Bone and Mineral Research

119

100

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Activation of NF-kB and MAPK/activator protein 1 (AP-1) signaling pathways by receptor activator NF-kB ligand (RANKL) is essential for osteoclast activity. Targeting NF-kB and MAPK/AP-1 signaling to modulate osteoclast activity has been a promising strategy for osteoclast-related diseases. In this study we examined the effects of maslinic acid (MA), a pentacyclic triterpene acid that is widely present in dietary plants, on RANKL-induced osteoclastogenesis, osteoclast function, and signaling pathways by in vitro and in vivo assay systems. In mouse bone marrow monocytes (BMMs) and RAW264.7 cells, MA inhibited RANKL-induced osteoclastogenesis in a dosedependent manner within nongrowth inhibitory concentration, and MA decreased osteoclastogenesis-related marker gene expression, including TRACP, MMP9, c-Src, CTR, and cathepsin K. Specifically, MA suppressed osteoclastogenesis and actin ring formation at early stage. In ovariectomized mice, administration of MA prevented ovariectomy-induced bone loss by inhibiting osteoclast activity. At molecular levels, MA abrogated the phosphorylation of MAPKs and AP-1 activity, inhibited the IkBa phosphorylation and degradation, blocked NF-kB/p65 phosphorylation, nuclear translocation, and DNA-binding activity by downregulating RANK expression and blocking RANK interaction with TRAF6. Together our data demonstrate that MA suppresses RANKL-induced osteoclastogenesis through NF-kB and MAPK/AP-1 signaling pathways and that MA is a promising agent in the treatment of osteoclast-related diseases such as osteoporosis. ß

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Section: Calcium Imagingmentioning

confidence: 99%

Maslinic acid suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss by regulating RANKL-mediated NF-κB and MAPK signaling pathways

Yang

et al. 2010

Journal of Bone and Mineral Research

119

100

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“…The biological effects of estradiol (E2) are mainly mediated by the nuclear estrogen receptors (ERs), ERα encoded by the Esr1 gene, and ERβ encoded by the Esr2 gene. The bonesparing effect of estrogen in both males and females is primarily mediated via ERα (6)(7)(8), although the effect of ERα activation in bone might be slightly modulated by ERβ in female mice (9)(10)(11)(12).…”

mentioning

confidence: 99%

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

Windahl

Börjesson

Farman

et al. 2013

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

122

113

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The bone-sparing effect of estrogen in both males and females is primarily mediated via estrogen receptor-α (ERα), encoded by the Esr1 gene. ERα in osteoclasts is crucial for the trabecular bonesparing effect of estrogen in females, but it is dispensable for trabecular bone in male mice and for cortical bone in both genders. We hypothesized that ERα in osteocytes is important for trabecular bone in male mice and for cortical bone in both males and females. Dmp1-Cre mice were crossed with ERα flox/flox mice to generate mice lacking ERα protein expression specifically in osteocytes (Dmp1-ERα −/− ). Male Dmp1-ERα −/− mice displayed a substantial reduction in trabecular bone volume (−20%, P < 0.01) compared with controls. Dynamic histomorphometry revealed reduced bone formation rate (−45%, P < 0.01) but the number of osteoclasts per bone surface was unaffected in the male Dmp1-ERα −/− mice. The male Dmp1-ERα −/− mice had reduced expression of several osteoblast/osteocyte markers in bone, including Runx2, Sp7, and Dmp1 (P < 0.05). Gonadal intact Dmp1-ERα −/− female mice had no significant reduction in trabecular bone volume but ovariectomized Dmp1-ERα −/− female mice displayed an attenuated trabecular bone response to supraphysiological E2 treatment. Dmp1-ERα −/− mice of both genders had unaffected cortical bone. In conclusion, ERα in osteocytes regulates trabecular bone formation and thereby trabecular bone volume in male mice but it is dispensable for the trabecular bone in female mice and the cortical bone in both genders. We propose that the physiological trabecular bone-sparing effect of estrogen is mediated via ERα in osteocytes in males, but via ERα in osteoclasts in females.

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“…The biological effects of estradiol (E2) are mainly mediated by the nuclear estrogen receptors (ERs), ERα and ERβ (4,7). The bone-sparing effect of estrogen is mediated primarily via ERα (4,8,9).…”

mentioning

confidence: 99%

The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

Movérare‐Skrtic

Börjesson

Farman

et al. 2014

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

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Significance Estrogen exerts important effects in the skeleton, which are primarily mediated via estrogen receptor (ER)α, which stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand-binding domain. Previous studies demonstrate that ERα ligands might act as agonists, partial agonists, or antagonists. We demonstrate that the ERα antagonist ICI 182,780 (ICI) acts in a tissue-dependent manner in mice lacking ERαAF-2, resulting in no effect, agonistic activity, or inverse agonistic activity. Importantly, ICI exerted a pronounced inverse agonistic activity in the growth plate of mice lacking ERαAF-2. We propose that ERα lacking AF-2 is constitutively active in the absence of ligand in the growth plate, enabling ICI to act as an inverse agonist.

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A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor–deficient mice

Cited by 105 publications

References 34 publications

Maslinic acid suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss by regulating RANKL-mediated NF-κB and MAPK signaling pathways

Maslinic acid suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss by regulating RANKL-mediated NF-κB and MAPK signaling pathways

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

The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

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