Adult Tph2 knockout mice without brain serotonin have moderately elevated spine trabecular bone but moderately low cortical bone thickness

Brommage, Robert; Liu, Jeff; Doree, Deon; Yu, Wangsheng; Powell, David R.; Yang, Qi

doi:10.1038/bonekey.2015.87

Cited by 18 publications

(12 citation statements)

References 39 publications

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“…Components of the serotonin signaling pathway are present on osteoclasts, osteoblasts, and osteocytes 20 . However, there is little consensus on the role of serotonin in the regulation of bone mass 21–23 . Pups exposed to fluoxetine throughout pregnancy and lactation had elevated concentrations of serum serotonin compared to control pups.…”

Section: Discussionmentioning

confidence: 99%

In utero and lactational exposure to the Selective Serotonin Reuptake Inhibitor fluoxetine compromises pup bones at weaning

Weaver

Xie

Charles

et al. 2019

Sci Rep

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Selective Serotonin Reuptake Inhibitors (SSRIs) such as fluoxetine are widely prescribed to pregnant and breastfeeding women, yet the effects of peripartum SSRI exposure on neonatal bone are not known. In adult populations, SSRI use is associated with compromised bone health, and infants exposed to in utero SSRIs have a smaller head circumference and are shorter, suggesting possible effects on longitudinal growth. Yet no study to date has examined the effects of peripartum SSRIs on long bone growth or mass. We used microCT to determine the outcomes of in utero and lactational SSRI exposure on C57BL6 pup bone microarchitecture. We found that peripartum exposure to 20 mg/kg fluoxetine reduced femoral bone mineral density and bone volume fraction, negatively impacted trabecular and cortical parameters, and resulted in shorter femurs on postnatal day 21. Although SSRIs are considered the first-choice antidepressant for pregnant and lactating women due to a low side effect profile, SSRI exposure may compromise fetal and neonatal bone development.

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Section: Discussionmentioning

confidence: 99%

In utero and lactational exposure to the Selective Serotonin Reuptake Inhibitor fluoxetine compromises pup bones at weaning

Weaver

Xie

Charles

et al. 2019

Sci Rep

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“…Gut is the major site of serotonin production, through the actions of the enzyme tryptophan hydroxylase (TPH1). Some microbes produce serotonin and several studies demonstrate that gut microbiota induce host serotonin production in the gut 7,45 , however the majority of reports suggest that the absence of gut serotonin production in Tph1 −/− mice has little effect on bone physiology 46–48 . Therefore, whether induction of serotonin is involved in microbiota modulation of bone phenotype still needs further investigation.…”

Section: Mechanisms Underlying Microbiota-mediated Effects On Bonementioning

confidence: 99%

Gut Microbiome and Bone: to Build, Destroy, or Both?

Yan

Charles

2017

Curr Osteoporos Rep

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Purpose of the Review The gut microbiota can be considered a hidden organ that plays essential roles in host homeostasis. Exploration of the effects of microbiota on bone have just begun. Complimentary studies using germ-free mice, antibiotic and probiotic treatments reveal a complicated relationship between microbiota and bone. Here we review recent reports addressing the effect of gut microbiota on bone health, discuss potential reasons for discrepant findings, and explore potential mechanisms for these effects. Recent findings Manipulation of microbiota by colonization of germ free mice, antibiotics or probiotic supplementation significantly alters bone remodeling, bone development and growth, as well as bone mechanical strength. Different experimental models reveal context dependent effects of gut microbiota on bone. Summary By examining phenotypic effects, experimental context and proposed mechanisms, revealed by recent reports, we hope to provide comprehensive and fresh insights into the many facets of microbiota and bone interactions.

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“…However, an association among LRP5 deficiency, circulating 5HT and bone loss has not been reproduced in mice with osteocyte-specific expression of inducible Lrp5 mutations that cause high and low bone mass phenotypes in humans [ 3 ]. Further, association between circulating serotonin and bone mass has not been unequivocally confirmed in different mouse knockout models (global knockouts of TPH1 and TPH2, LRP5) [ 4 – 6 ]. De Vernejoul and colleagues revisited the bone phenotype in mice with genetic deletion of peripheral 5HT-synthesizing enzyme tryptophan hydroxylase-1 ( TPH1 -/- ) and showed that osteoclasts synthesize 5HT which acts to induce osteoclast precursor differentiation in a local micro-serotoninergic system via a mechanism of RANKL-induced osteoclast formation [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Constitutively Elevated Blood Serotonin Is Associated with Bone Loss and Type 2 Diabetes in Rats

et al. 2016

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Reduced peripheral serotonin (5HT) in mice lacking tryptophan hydroxylase (TPH1), the rate limiting enzyme for 5HT synthesis, was reported to be anabolic to the skeleton. However, in other studies TPH1 deletion either had no bone effect or an age dependent inhibition of osteoclastic bone resorption. The role of 5HT in bone therefore remains poorly understood. To address this issue, we used selective breeding to create rat sublines with constitutively high (high-5HT) and low (low-5HT) platelet 5HT level (PSL) and platelet 5HT uptake (PSU). High-5HT rats had decreased bone volume due to increased bone turnover characterized by increased bone formation and mineral apposition rate, increased osteoclast number and serum C-telopeptide level. Daily oral administration of the TPH1 inhibitor (LX1032) for 6 weeks reduced PSL and increased the trabecular bone volume and trabecular number of the spine and femur in high-5HT rats. High-5HT animals also developed a type 2 diabetes (T2D) phenotype with increased: plasma insulin, glucose, hemoglobin A1c, body weight, visceral fat, β-cell pancreatic islets size, serum cholesterol, and decreased muscle strength. Serum calcium accretion mediated by parathyroid hormone slightly increased, whereas treatment with 1,25(OH)2D3 decreased PSL. Insulin reduction was paralleled by a drop in PSL in high-5HT rats. In vitro, insulin and 5HT synergistically up-regulated osteoblast differentiation isolated from high-5HT rats, whereas TPH1 inhibition decreased the number of bone marrow-derived osteoclasts. These results suggest that constitutively elevated PSL is associated with bone loss and T2D via a homeostatic interplay between the peripheral 5HT, bone and insulin.

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Adult Tph2 knockout mice without brain serotonin have moderately elevated spine trabecular bone but moderately low cortical bone thickness

Cited by 18 publications

References 39 publications

In utero and lactational exposure to the Selective Serotonin Reuptake Inhibitor fluoxetine compromises pup bones at weaning

In utero and lactational exposure to the Selective Serotonin Reuptake Inhibitor fluoxetine compromises pup bones at weaning

Gut Microbiome and Bone: to Build, Destroy, or Both?

Constitutively Elevated Blood Serotonin Is Associated with Bone Loss and Type 2 Diabetes in Rats

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