Estrogen and the skeleton

Osteoclastogenesis is under the control of posttranscriptional and transcriptional events. However, posttranscriptional regulation of osteoclastogenesis is incompletely understood. CNOT3 is a component of the CCR4 family that regulates mRNA stability, but its function in bone is not known. Here, we show that Cnot3 deficiency by deletion of a single allele induces osteoporosis. Cnot3 deficiency causes an enhancement in bone resorption in association with an elevation in bone formation, resulting in high-turnover type bone loss. At the cellular level, Cnot3 deficiency enhances receptor activator of NF-κB ligand (RANKL) effects on osteoclastogenesis in a cell-autonomous manner. Conversely, Cnot3 deficiency does not affect osteoblasts directly. Cnot3 deficiency does not alter RANKL expression but enhances receptor activator of NF-κB (RANK) mRNA expression in bone in vivo. Cnot3 deficiency promotes RANK mRNA stability about twofold in bone marrow cells of mice. Cnot3 knockdown also increases RANK mRNA expression in the precursor cell line for osteoclasts. Anti-CNOT3 antibody immunoprecipitates RANK mRNA. Cnot3 deficiency stabilizes luciferase reporter expression linked to the 3′-UTR fragment of RANK mRNA. In contrast, Cnot3 overexpression destabilizes the luciferase reporter linked to RANK 3′-UTR. In aged mice that exhibit severe osteoporosis, Cnot3 expression levels in bone are reduced about threefold in vivo. Surprisingly, Cnot3 deficiency in these aged mice further exacerbates osteoporosis, which also occurs via enhancement of osteoclastic activity. Our results reveal that CNOT3 is a critical regulator of bone mass acting on bone resorption through posttranscriptional down-regulation of RANK mRNA stability, at least in part, even in aging-induced osteoporosis.RNA stability | osteopenia

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“…This article is a PNAS Direct Submission. 1 To whom correspondence may be addressed. E-mail: ezura.mph@mri.tmd.ac.jp or noda.…”

Section: Resultsmentioning

confidence: 99%

“…The pathophysiology of osteoporosis is based on the imbalance between bone resorption and bone formation (1). These two arms are regulated by the activities of osteoclasts and osteoblasts, respectively (2).…”

mentioning

confidence: 99%

Stability of mRNA influences osteoporotic bone mass via CNOT3

Watanabe

Morita

Hayata

et al. 2014

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

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“…In humans, direct evidence for hormone-mediated sex-specific bone remodeling patterns of the pelvis is not yet available. Nevertheless, studies on long bone morphology indicate that sexual skeletal dimorphism develops via complex interactions between sex-specific steroid hormone levels, sex-biased gene expression, and gender differences in sensitivity to bone-loading conditions and to hormones such as the growth hormone/insulin-like growth factor 1 (IGF1) axis (42)(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

Developmental evidence for obstetric adaptation of the human female pelvis

Huseynov

Zollikofer

Coudyzer

et al. 2016

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

163

143

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The bony pelvis of adult humans exhibits marked sexual dimorphism, which is traditionally interpreted in the framework of the "obstetrical dilemma" hypothesis: Giving birth to large-brained/ large-bodied babies requires a wide pelvis, whereas efficient bipedal locomotion requires a narrow pelvis. This hypothesis has been challenged recently on biomechanical, metabolic, and biocultural grounds, so that it remains unclear which factors are responsible for sex-specific differences in adult pelvic morphology. Here we address this issue from a developmental perspective. We use methods of biomedical imaging and geometric morphometrics to analyze changes in pelvic morphology from late fetal stages to adulthood in a knownage/known-sex forensic/clinical sample. Results show that, until puberty, female and male pelves exhibit only moderate sexual dimorphism and follow largely similar developmental trajectories. With the onset of puberty, however, the female trajectory diverges substantially from the common course, resulting in rapid expansion of obstetrically relevant pelvic dimensions up to the age of 25-30 y. From 40 y onward females resume a mode of pelvic development similar to males, resulting in significant reduction of obstetric dimensions. This complex developmental trajectory is likely linked to the pubertal rise and premenopausal fall of estradiol levels and results in the obstetrically most adequate pelvic morphology during the time of maximum female fertility. The evidence that hormones mediate female pelvic development and morphology supports the view that solutions of the obstetrical dilemma depend not only on selection and adaptation but also on developmental plasticity as a response to ecological/nutritional factors during a female's lifetime.pelvis | development | evolution | obstetrical dilemma | sex steroids

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“…19,20 Peak bone mass is reached early in adult life and from this point both men and women start to lose bone mass more or less depending on a combination of intrinsic and extrinsic factors. 21,22 This process can be aggravated by a lack of physical exercise, 23 prolonged treatment with corticoids, 24 estrogen deficiency, especially in postmenopausal women, 25 presence of other chronic diseases, and by aging. 20 Recent evidence has pointed out that autophagy, a cell survival pathway, plays an important role in the maintenance of bone homeostasis, [26][27][28] and changes in this pathway have been related to osteoporosis.…”

Section: Introductionmentioning

confidence: 99%

Osteoporosis and autophagy: What is the relationship?

Florencio‐Silva

Sasso

Simões

et al. 2017

Rev. Assoc. Med. Bras.

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Autophagy is a survival pathway wherein non-functional proteins and organelles are degraded in lysosomes for recycling and energy production. Therefore, autophagy is fundamental for the maintenance of cell viability, acting as a quality control process that prevents the accumulation of unnecessary structures and oxidative stress. Increasing evidence has shown that autophagy dysfunction is related to several pathologies including neurodegenerative diseases and cancer. Moreover, recent studies have shown that autophagy plays an important role for the maintenance of bone homeostasis. For instance, in vitro and animal and human studies indicate that autophagy dysfunction in bone cells is associated with the onset of bone diseases such as osteoporosis. This review had the purpose of discussing the issue to confirm whether a relationship between autophagy dysfunction and osteoporosis exits.

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Estrogen and the skeleton

Cited by 694 publications

References 54 publications

Stability of mRNA influences osteoporotic bone mass via CNOT3

Stability of mRNA influences osteoporotic bone mass via CNOT3

Developmental evidence for obstetric adaptation of the human female pelvis

Osteoporosis and autophagy: What is the relationship?

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