High bone mass phenotype is associated with impaired interferon signaling in skeletal (mesenchymal) stem cells: Potential mechanism for enhanced bone formation by Wnt singalling

Prior studies show that oxytocin (Oxt) and vasopressin (Avp) have opposing actions on the skeleton exerted through high-affinity G protein-coupled receptors. We explored whether Avp and Oxtr can share their receptors in the regulation of bone formation by osteoblasts. We show that the Avp receptor 1α (Avpr1α) and the Oxt receptor (Oxtr) have opposing effects on bone mass: Oxtr−/− mice have osteopenia, and Avpr1α−/− mice display a high bone mass phenotype. More notably, this high bone mass phenotype is reversed by the deletion of Oxtr in Oxtr−/−:Avpr1α−/− double-mutant mice. However, although Oxtr is not indispensable for Avp action in inhibiting osteoblastogenesis and gene expression, Avp-stimulated gene expression is inhibited when the Oxtr is deleted in Avpr1α−/− cells. In contrast, Oxt does not interact with Avprs in vivo in a model of lactation-induced bone loss in which Oxt levels are high. Immunofluorescence microscopy of isolated nucleoplasts and Western blotting and MALDI-TOF of nuclear extracts show that Avp triggers Avpr1α localization to the nucleus. Finally, a specific Avpr2 inhibitor, tolvaptan, does not affect bone formation or bone mass, suggesting that Avpr2, which primarily functions in the kidney, does not have a significant role in bone remodeling.

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Monosodium Glutamate-Sensitive Hypothalamic Neurons Contribute to the Control of Bone Mass

Endocrinology ◽

10.1210/en.2003-0369 ◽

2003 ◽

Vol 144 (9) ◽

pp. 3842-3847 ◽

Cited By ~ 43

Author(s):

Florent Elefteriou ◽

Shu Takeda ◽

Xiuyun Liu ◽

Dawna Armstrong ◽

Gerard Karsenty

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Bone Mass ◽

Monosodium Glutamate ◽

Hypothalamic Neurons ◽

High Bone Mass ◽

Independent Manner ◽

Normal Bone ◽

High Bone ◽

High Bone Mass Phenotype

Abstract Using chemical lesioning we previously identified hypothalamic neurons that are required for leptin antiosteogenic function. In the course of these studies we observed that destruction of neurons sensitive to monosodium glutamate (MSG) in arcuate nuclei did not affect bone mass. However MSG treatment leads to hypogonadism, a condition inducing bone loss. Therefore the normal bone mass of MSG-treated mice suggested that MSG-sensitive neurons may be implicated in the control of bone mass. To test this hypothesis we assessed bone resorption and bone formation parameters in MSG-treated mice. We show here that MSG-treated mice display the expected increase in bone resorption and that their normal bone mass is due to a concomitant increase in bone formation. Correction of MSG-induced hypogonadism by physiological doses of estradiol corrected the abnormal bone resorptive activity in MSG-treated mice and uncovered their high bone mass phenotype. Because neuropeptide Y (NPY) is highly expressed in MSG-sensitive neurons we tested whether NPY regulates bone formation. Surprisingly, NPY-deficient mice had a normal bone mass. This study reveals that distinct populations of hypothalamic neurons are involved in the control of bone mass and demonstrates that MSG-sensitive neurons control bone formation in a leptin-independent manner. It also indicates that NPY deficiency does not affect bone mass.

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A genomic and transcriptomic approach to the high bone mass phenotype: evidences of heterogeneity and of additive effects of TWIST1, IL6R, DLX3, and PPARG

Bone Abstracts ◽

10.1530/boneabs.1.pp277 ◽

2013 ◽

Author(s):

Patricia Sarrion ◽

Leonardo Mellibovsky ◽

Roser Urreizti ◽

Sergi Civit ◽

Neus Cols ◽

...

Keyword(s):

Bone Mass ◽

Additive Effects ◽

High Bone Mass ◽

High Bone ◽

High Bone Mass Phenotype

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Faculty Opinions recommendation of Cnot7-null mice exhibit high bone mass phenotype and modulation of BMP actions.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1089983.543155 ◽

2007 ◽

Author(s):

Joseph Bidwell

Keyword(s):

Bone Mass ◽

High Bone Mass ◽

High Bone ◽

High Bone Mass Phenotype

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Sex dimorphic regulation of osteoprogenitor progesterone in bone stromal cells

Journal of Molecular Endocrinology ◽

10.1530/jme-17-0076 ◽

2017 ◽

Vol 59 (4) ◽

pp. 351-363 ◽

Cited By ~ 3

Author(s):

Alexander Kot ◽

Zhendong A Zhong ◽

Hongliang Zhang ◽

Yu-An Evan Lay ◽

Nancy E Lane ◽

...

Keyword(s):

Mouse Model ◽

Bone Mass ◽

Gene Transcription ◽

Conditional Knockout ◽

Sequencing Analysis ◽

Wild Type ◽

High Bone Mass ◽

Matrix Interaction ◽

High Bone ◽

High Bone Mass Phenotype

Increasing peak bone mass is a promising strategy to prevent osteoporosis. A mouse model of global progesterone receptor (PR) ablation showed increased bone mass through a sex-dependent mechanism. Cre-Lox recombination was used to generate a mouse model of osteoprogenitor-specific PR inactivation, which recapitulated the high bone mass phenotype seen in the PR global knockout mouse mode. In this work, we employed RNA sequencing analysis to evaluate sex-independent and sex-dependent differences in gene transcription of osteoprogenitors of wild-type and PR conditional knockout mice. PR deletion caused marked sex hormone-dependent changes in gene transcription in male mice as compared to wild-type controls. These transcriptional differences revealed dysregulation in pathways involving immunomodulation, osteoclasts, bone anabolism, extracellular matrix interaction and matrix interaction. These results identified many potential mechanisms that may explain our observed high bone mass phenotype with sex differences when PR was selectively deleted in the MSCs.

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