Regulation of adult bone turnover by sex steroids

Frenkel, Baruch; Hong, A.; Baniwal, Sanjeev K.; Coetzee, Gerhard A.; Ohlsson, Claes; Khalid, Omar; Gabet, Yankel

doi:10.1002/jcp.22159

Cited by 130 publications

(97 citation statements)

References 73 publications

(120 reference statements)

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“…Nevertheless, gender differences in bone phenotypes of Scarb1-null mice may not rely on the GC/ACTH axis alterations. We next investigated whether E 2 , a powerful bone growth modulator (Frenkel et al 2010), was affected in Scarb1-null females. Total E 2 levels were normal in Scarb1-null females, therefore discarding the disruption of this hormonal axis as a major factor for the gender-specific bone alterations.…”

Section: Discussionmentioning

confidence: 99%

Gender- and region-specific alterations in bone metabolism in Scarb1-null female mice

Martineau

Martin-Falstrault

Brissette

et al. 2014

Journal of Endocrinology

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A positive correlation between plasma levels of HDL and bone mass has been reported by epidemiological studies. As scavenger receptor class B, type I (SR-BI), the gene product of Scarb1, is known to regulate HDL metabolism, we recently characterized bone metabolism in Scarb1-null mice. These mice display high femoral bone mass associated with enhanced bone formation. As gender differences have been reported in HDL metabolism and SR-BI function, we investigated gender-specific bone alterations in Scarb1-null mice by microtomography and histology. We found 16% greater relative bone volume and 39% higher bone formation rate in the vertebrae from 2-month-old Scarb1-null females. No such alteration was seen in males, indicating gender-and region-specific differences in skeletal phenotype. Total and HDL-associated cholesterol levels, as well as ACTH plasma levels, were increased in both Scarb1-null genders, the latter being concurrent to impaired corticosterone response to fasting. Plasma levels of estradiol did not differ between null and WT females, suggesting that the estrogen metabolism alteration is not relevant to the higher vertebral bone mass in female Scarb1-null mice. Constitutively, high plasma levels of leptin along with 2.5-fold increase in its expression in white adipose tissue were measured in female Scarb1-null mice only. In vitro exposure of bone marrow stromal cells to ACTH and leptin promoted osteoblast differentiation as evidenced by increased gene expression of osterix and collagen type I alpha. Our results suggest that hyperleptinemia may account for the gender-specific high bone mass seen in the vertebrae of female Scarb1-null mice.

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Section: Discussionmentioning

confidence: 99%

Gender- and region-specific alterations in bone metabolism in Scarb1-null female mice

Martineau

Martin-Falstrault

Brissette

et al. 2014

Journal of Endocrinology

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“…For this, we used three mouse models that recapitulate different pathological situations associated with increased osteoclast activation: post-menopause osteoporosis 14 , chronic inflammation 15 and cancer metastasis to the bone 16 .…”

Section: C21 Reversibly Disrupts Podosome Organization In Osteoclastsmentioning

confidence: 99%

“…Dock5 inhibition prevents ovariectomy-induced bone loss. We first assessed the effect of C21 on post-menopause osteoporosis, which is caused by oestrogen loss 14 and can be reproduced in mice following bilateral ovariectomy (OVX) 17 . We first tested a preventive effect of C21 on bone loss by injecting daily doses of C21 or vehicle to OVX to young adult mice for 4 weeks (Fig.…”

Section: C21 Reversibly Disrupts Podosome Organization In Osteoclastsmentioning

confidence: 99%

Pharmacological inhibition of Dock5 prevents osteolysis by affecting osteoclast podosome organization while preserving bone formation

et al. 2015

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Osteoporosis is caused by excessive activity of bone-degrading osteoclasts over bone-forming osteoblast. Standard antiosteolytic treatments inhibit bone resorption by inducing osteoclast loss, with the adverse effect of hindering also bone formation. Formation of the osteoclast sealing zone requires Dock5, a guanine nucleotide exchange factor for the small GTPase Rac, and C21, a chemical inhibitor of Dock5, decreases bone resorption by cultured osteoclasts. Here we show that C21 directly inhibits the exchange activity of Dock5 and disrupts osteoclast podosome organization. Remarkably, C21 administration protects mice against bone degradation in models recapitulating major osteolytic diseases: menopause, rheumatoid arthritis and bone metastasis. Furthermore, C21 administration does not affect bone formation and is not toxic. Our results validate the pharmacological inhibition of Dock5 as a novel therapeutic route for fighting osteolytic diseases while preserving bone formation.

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“…(1,(3)(4)(5) The expression of RANKL and OPG in osteoblasts, in turn, is controlled by both systemic and local factors, which include different cytokines, hormones such as parathyroid hormone (PTH), and changes in the biomechanical load. (6)(7)(8) However, little is known about endogenous mechanisms regulating the RANKL/OPG equilibrium within the osteoblast itself. Nuclear receptors comprise a superfamily of ligand-activated transcription factors regulating multiple homeostatic processes such as fat and glucose metabolism.…”

mentioning

confidence: 99%

Liver X receptors orchestrate osteoblast/osteoclast crosstalk and counteract pathologic bone loss

Kleyer

Scholtysek

Bottesch

et al. 2012

Journal of Bone and Mineral Research

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Osteoporosis is characterized by enhanced differentiation of bone-resorbing osteoclasts, resulting in a rapid loss of functional trabecular bone. Bone-forming osteoblasts and osteoblast-derived osteocytes perform a key role in the regulation of osteoclast development by providing both the pro-osteoclastogenic cytokine receptor activator of NF-kB ligand (RANKL) and its natural decoy receptor osteoprotegerin (OPG). By regulating the RANKL/OPG ratio, osteoblasts hence determine the rate of both osteoclast differentiation and bone turnover. Here, we describe a novel role for liver X receptors (LXRs) during the crosstalk of bone-forming osteoblasts and boneresorbing osteoclasts. By using a system of osteoblast/osteoclast cocultures, we identify LXRs as regulator of RANKL expression and the RANKL/OPG ratio in osteoblasts. Activation of LXRs drastically reduced the RANKL/OPG ratio and interfered with osteoblast-mediated osteoclast differentiation in vitro. During an ovariectomy (OVX)-induced model of postmenopausal osteoporosis, the application of an LXR agonist shifted the RANKL/OPG ratio in vivo, ameliorated the enhanced osteoclast differentiation, and provided complete protection from OVX-induced bone loss. These results reveal an unexpected involvement of LXRs in the regulation of bone turnover and highlight a potential role for LXRs as novel targets in the treatment of osteoporosis and related diseases. ß

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Regulation of adult bone turnover by sex steroids

Cited by 130 publications

References 73 publications

Gender- and region-specific alterations in bone metabolism in Scarb1-null female mice

Gender- and region-specific alterations in bone metabolism in Scarb1-null female mice

Pharmacological inhibition of Dock5 prevents osteolysis by affecting osteoclast podosome organization while preserving bone formation

Liver X receptors orchestrate osteoblast/osteoclast crosstalk and counteract pathologic bone loss

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