Serotonin-reuptake inhibitors act centrally to cause bone loss in mice by counteracting a local anti-resorptive effect

Ortuño, María José; Robinson, Samuel T.; Subramanyam, Prakash; Paone, Riccardo; Huang, Yan-You; Guo, X. Edward; Colecraft, Henry M.; Mann, J. John; Ducy, Patricia

doi:10.1038/nm.4166

Cited by 84 publications

(89 citation statements)

References 62 publications

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“…There are some in vivo studies that examined the association between SSRIs and bone regeneration, which confirm the osteogenesis results of the present study .…”

Section: Discussionsupporting

confidence: 90%

The effects of fluoxetine on the human adipose‐derived stem cell proliferation and differentiation

Khademi

Ghavamabadi

Taghavi

et al. 2018

Fundamemntal Clinical Pharma

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Fluoxetine is one of the most commonly used antidepressants. Fluoxetine could prevent the mesenchymal stem cell differentiation in lung fetus of rat. Moreover, the mesenchymal stem cells are also present in adult tissues. Therefore, in the current study, we aimed to investigate the effects of fluoxetine (FLX) on both proliferation and adipogenic/osteogenic differentiation of human adipose‐derived stem cells (ADSCs). After culturing of human ADSCs, these cells were treated with two concentrations of FLX (10 and 20 μm). Then, cells were differentiated by adding osteogenic and adipogenic media. The effect of FLX on human ADSCs proliferation was evaluated by MTT assay. Fluoxetine role on adipogenic and osteogenic differentiation of human ADSCs was analyzed by oil red and alizarin red staining and RT‐PCR reaction. According to MTT assay, FLX showed a time‐ and concentration‐dependent proliferation response and eventually decreased human ADSCs proliferation. RT‐PCR analysis indicated that FLX significantly diminished the expression of osteogenesis‐related genes such as RUNX2 and alkaline phosphatase (ALP). Data also revealed a significant reduction in the expression of peroxisome proliferator‐activated receptor γ (PPARγ) and fatty acid‐binding protein (FABP) (specific genes of adipogenic lineage). In addition, FLX decreased mineralized matrix and the amount of lipid droplets in human ADSCs by staining methods. Our observation demonstrated that the effects of FLX may be time‐dependent. This drug possesses an increasing phase in proliferation and survival of human ADSCs (first 24 h) following a decreasing phase (after 48 h). Moreover, FLX could attenuate both osteogenic and adipogenic differentiation of human ADSCs.

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“…There are some in vivo studies that examined the association between SSRIs and bone regeneration, which confirm the osteogenesis results of the present study .…”

Section: Discussionsupporting

confidence: 90%

The effects of fluoxetine on the human adipose‐derived stem cell proliferation and differentiation

Khademi

Ghavamabadi

Taghavi

et al. 2018

Fundamemntal Clinical Pharma

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“…RIS antagonizes several serotonin receptors including Htr2c, which has been implicated in suppression of SNS-output to bone [29]. Downregulation of this receptor in the hypothalamus has also recently been shown to play a significant role in bone loss in response to the selective serotonin reuptake inhibitor (SSRI) fluoxetene [30]. Thus, inhibition of hypothalamic Htr2c signaling may be a common mechanism for bone changes in response to both RIS and SSRIs.…”

Section: Discussionmentioning

confidence: 99%

A novel role for dopamine signaling in the pathogenesis of bone loss from the atypical antipsychotic drug risperidone in female mice

Motyl

Beauchemin

Barlow

et al. 2017

Bone

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Atypical antipsychotic (AA) drugs, including risperidone (RIS), are used to treat schizophrenia, bipolar disorder, and autism, and are prescribed off-label for other mental health issues. AA drugs are associated with severe metabolic side effects of obesity and type 2 diabetes. Cross-sectional and longitudinal data also show that risperidone causes bone loss and increases fracture risk in both men and women. There are several potential mechanisms of bone loss from RIS. One is hypogonadism due to hyperprolactinemia from dopamine receptor antagonism. However, many patients have normal prolactin levels; moreover we demonstrated that bone loss from RIS in mice can be blocked by inhibition of β-adrenergic receptor activation with propranolol, suggesting the sympathetic nervous system (SNS) plays a pathological role. Further, when, we treated ovariectomized (OVX) and sham operated mice daily for 8 weeks with RIS or vehicle we demonstrated that RIS causes significant trabecular bone loss in both sham operated and OVX mice. RIS directly suppressed osteoblast number in both sham and OVX mice, but increased osteoclast number and surface in OVX mice alone, potentially accounting for the augmented bone loss. Thus, hypogonadism alone cannot explain RIS induced bone loss. In the current study, we show that dopamine and RIS are present in the bone marrow compartment and that RIS can exert its effects directly on bone cells via dopamine receptors. Our findings of both direct and indirect effects of AA drugs on bone are relevant for current and future clinical and translational studies investigating the mechanism of skeletal changes from AA drugs.

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“…This is in contrast to our previous results in vivo FLX exposure increased mammary gland cAMP concentrations on day 10 of lactation, after approximately 14 days of treatment with FLX (20). It is possible that duration and timing of treatment (acute vs. chronic) with these compounds can result in different effects on the mammary gland or other tissues, which we and other have previously shown (48,56). Interestingly, in the human breast cancer cell line, MDA-MB-231, a similar observation was found regarding decrease in cAMP with an increase in 5HT and a switch from growth inhibition to stimulation was attributed to the altered cAMP dynamics (57).…”

Section: Discussionmentioning

confidence: 76%

Serotonin stimulated parathyroid hormone related protein induction in the mammary epithelia by transglutaminase-dependent serotonylation

Sheftel

Hernández

2020

Preprint

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Mammary-derived serotonin [5HT] has been implicated in breast-to-bone communication during lactation by increasing parathyroid hormone related-peptide [PTHrP] in the mammary gland. It is well-established that PTHrP acts on the bone to liberate calcium for the milk during lactation; however, the mechanism of 5HT's regulation of PTHrP has not been fully elucidated. Recently, serotonylation, has been shown to be involved in a variety of physiological processes. Therefore, we investigated whether serotonylation is involved in 5HT's regulation of PTHrP in the mammary gland. Using lactogenic differentiated mouse mammary epithelial cells, we studied the effect of increased intracellular 5HT using the antidepressant, fluoxetine [FLX], or 5-hydroxytryptophan ([5HTP] 5HT precursor) with or without transglutaminase inhibition on PTHrP induction and activity and the potential serotonylation target protein, RhoA.Treatment with FLX or 5HTP significantly increased intracellular 5HT concentration and subsequently increased PTHrP gene expression which was reduced with transglutaminase inhibition. Further, we demonstrated that transglutaminase becomes more active with lactogenic differentiation and with 5HTP or FLX treatment. We examined RhoA, Rac1, and Rab4 as potential serotonylation target proteins and have concluded RhoA is likely a serotonylation target protein. Our data suggest that 5HT regulates PTHrP induction in part through the process of serotonylation during lactation. Introduction:Serotonin (5-hydroxytryptamine [5HT]), an established monoamine and neurotransmitter, is synthesized from L-tryptophan in a 2-step conversion requiring a hydroxylation step and a decarboxylation step. The hydroxylation is performed by the rate-limiting enzyme, tryptophan hydroxylase [TPH], producing 5-hydroxytryptophan [5HTP], which is decarboxylated by aromatic Lamino acid decarboxylase producing 5HT (1). 5HT is then released into the blood and stored by platelets, which lack the TPH1 enzyme. Degradation of 5HT occurs through oxidation by monoamine oxidase into 5-hydroxyindolacetic acid which is excreted in the urine. In humans and in mice, there are two TPH enzymes: TPH2 which converts L-tryptophan to 5HTP in the central nervous system and TPH1 which converts L-tryptophan to 5HTP in the periphery (2-4). 5HT and TPH1/2 are unable to cross the blood brain barrier, resulting in compartmentalization of 5HT (2,5). While 5HT is well-known as a central neurotransmitter altering behavior and mood, over 95% of 5HT is produced in the periphery in the gut enterochromaffin cells. During lactation, it has been has demonstrated that the mammary gland contributes approximately 50% of circulating 5HT (6,7).Mammary-derived 5HT is important in regulating maternal calcium homeostasis and breast-tobone communication via the synthesis and secretion of the parathyroid hormone related protein [PTHrP] in the mammary gland during lactation (8-10). PTHrP is secreted from the mammary epithelial cells and then acts on the bone to liberate calcium for milk synthe...

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Serotonin-reuptake inhibitors act centrally to cause bone loss in mice by counteracting a local anti-resorptive effect

Cited by 84 publications

References 62 publications

The effects of fluoxetine on the human adipose‐derived stem cell proliferation and differentiation

The effects of fluoxetine on the human adipose‐derived stem cell proliferation and differentiation

A novel role for dopamine signaling in the pathogenesis of bone loss from the atypical antipsychotic drug risperidone in female mice

Serotonin stimulated parathyroid hormone related protein induction in the mammary epithelia by transglutaminase-dependent serotonylation

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