The emerging role of serotonin (5-hydroxytryptamine) in the skeleton and its mediation of the skeletal effects of low-density lipoprotein receptor-related protein 5 (LRP5)

Warden, Stuart J.; Robling, Alexander G.; Haney, Elizabeth M; Turner, Charles H.; Bliziotes, Michael

doi:10.1016/j.bone.2009.06.029

Cited by 84 publications

(73 citation statements)

References 54 publications

(122 reference statements)

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“…Pharmacological inhibition of gut-derived serotonin promotes bone formation and prevents bone loss in OVX mice (62,63). If confirmed, these findings may possibly provide a novel therapeutic approach in osteoporosis therapy, in addition to target LRP5/6 in osteoblasts for promoting bone formation in osteopenic disorders (64).…”

Section: Therapies In Pipelinementioning

confidence: 71%

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

Marie¹,

Kassem²

2011

European Journal of Endocrinology

187

143

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Objective: Age-related bone loss is associated with significant changes in bone remodeling characterized by decreased trabecular and periosteal bone formation relative to bone resorption, resulting in bone fragility and increased risk of fractures. Prevention or reversal of age-related decrease in bone mass and increase in bone fragility has been based on inhibition of bone resorption using anticatabolic drugs. The current challenge is to promote osteoblastogenesis and bone formation to prevent age-related bone deterioration. Methods: A limited number of approved therapeutic molecules are available to activate bone formation. Therefore, there is a need for anabolic drugs that promote bone matrix apposition at the endosteal, endocortical, and periosteal envelopes by increasing the number of osteoblast precursor cells and/or the function of mature osteoblasts. In this study, we review current therapeutics promoting bone formation and anabolic molecules targeting signaling pathways involved in osteoblastogenesis, based on selected full-text articles searched on Medline search from 1990 to 2010. Results and discussion: We present current therapeutic approaches focused on intermittent parathyroid hormone and Wnt signaling agonists/antagonists. We also discuss novel approaches for prevention and treatment of defective bone formation and bone loss associated with aging and osteoporosis. These strategies targeting osteoblastic cell functions may prove to be useful in promoting bone formation and improving bone strength in the aging population.

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Section: Therapies In Pipelinementioning

confidence: 71%

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

Marie¹,

Kassem²

2011

European Journal of Endocrinology

187

143

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“…The functional impact of 5-HT signaling in the skeleton is still very much debated because both enhancing and inhibitory effects on bone formation have been depicted in response to serotonin (1). Such diverse effects may be explained by the concurrent expression of several 5-HT receptor subtypes (4, 6, 10, 11) and downstream couplings, which may vary according to the differentiation state of bone-forming cells.…”

Section: Discussionmentioning

confidence: 99%

“…Proper skeletal development and bone homeostasis notably necessitate a tight regulation of mineralization. Over the past few years, growing attention has been paid to the involvement of serotonin (5-hydroxytryptamine, 5-HT) 2 in bone biology (1). Indeed, beyond its role as a neurotransmitter in brain (2), platelet-stored 5-HT broadly participates to the homeostasis of various tissues.…”

mentioning

confidence: 99%

Serotonergic 5-HT2B Receptor Controls Tissue-nonspecific Alkaline Phosphatase Activity in Osteoblasts via Eicosanoids and Phosphatidylinositol-specific Phospholipase C

Baudry

Bitard

Mouillet-Richard

et al. 2010

Journal of Biological Chemistry

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In previous studies, we observed that mice knocked out for the serotonin-2B receptor (5-HT 2B R) show defects in bone homeostasis. The present work focuses on the downstream targets relaying the anabolic function of this receptor in osteoblasts. A functional link between the 5-HT 2B R and the activity of the tissue-nonspecific alkaline phosphatase (TNAP) is established using the C1 osteoprogenitor cell line. During C1 osteogenic differentiation, both 5-HT 2B R and TNAP mRNA translations are delayed with respect to extracellular matrix deposition. Once the receptor is expressed, it constitutively controls TNAP activity at a post-translational level along the overall period of mineral deposition. Indeed, pharmacological inhibition of the 5-HT 2B R intrinsic activity or shRNA-mediated 5-HT 2B R knockdown prevents TNAP activation, but not its mRNA translation. In contrast, agonist stimulation of the receptor further increases TNAP activity during the initial mineralization phase. Building upon our previous observations that the 5-HT 2B R couples with the phospholipase A2 pathway and prostaglandin production at the beginning of mineral deposition, we show that the 5-HT 2B R controls leukotriene synthesis via phospholipase A2 at the terminal stages of C1 differentiation. These two 5-HT 2B R-dependent eicosanoid productions delineate distinct time windows of TNAP regulation during the osteogenic program. Finally, prostaglandins or leukotrienes are shown to relay the post-translational activation of TNAP via stimulation of the phosphatidylinositol-specific phospholipase C. In agreement with the above findings, primary calvarial osteoblasts from 5-HT 2B R-null mice exhibit defects in TNAP activity.Imbalances in bone formation or resorption frequently result in pathological situations, such as osteoporosis, osteopenia, or osteomalacia. Proper skeletal development and bone homeostasis notably necessitate a tight regulation of mineralization. Over the past few years, growing attention has been paid to the involvement of serotonin (5-hydroxytryptamine, 5-HT) 2 in bone biology (1). Indeed, beyond its role as a neurotransmitter in brain (2), platelet-stored 5-HT broadly participates to the homeostasis of various tissues. For instance, 5-HT regulates cardiovascular, smooth muscle, and endocrine functions (for review, see Ref.3).In the periphery, 5-HT is synthesized exclusively by enterochromaffin cells of the gut and stored by platelets. Thus, because they express the serotonin transporter and diverse serotonergic receptors (4 -6), osteoblasts may be directly influenced by circulating 5-HT. In agreement with this idea, inhibition of the serotonin transporter reduces bone formation (7, 8). Moreover, patients receiving selective serotonin reuptake inhibitor antidepressants appear to be at risk for osteoporosis (9). Five types of serotonergic receptors have been depicted in osteoblast primary cultures or osteoblastic cell lines: 5-HT 1A , 5-HT 1B , 5-HT 1D , 5-HT 2A , and 5-HT 2B (4, 6, 10, 11). For instance, focusing on the 5-HT ...

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“…In vitro studies showed that mice with a null mutation in the 5‐HTT gene or mice treated with SSRIs exhibit reduced BMD, altered skeletal architecture, and reduced bone mechanical properties (Bliziotes 2010; Warden et al. 2010). …”

Section: Introductionmentioning

confidence: 99%

Bone density and depressive disorder: a meta‐analysis

Schweiger

Hüppe

et al. 2016

Brain and Behavior

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BackgroundThe aim of this study was to evaluate the evidence of low bone mineral density (BMD) in depression. Low BMD is a major risk factor for osteoporotic fractures and frailty.MethodsThe searched database was Pubmed, Meta‐analysis included human studies in men and women fulfilling the following criteria: (1) assessment of BMD in the lumbar spine, the femur or the total hip; (2) comparison of BMD between depressed individuals and the healthy control group; (3) measurement of BMD using dual‐energy X‐ray absorptiometry (DEXA); and (4) data on the mean, standard deviation, or standard error of BMD.ResultsTwenty‐one studies were identified, encompassing 1842 depressed and 17,401 nondepressed individuals. Significant negative composite weighted mean effect sizes were identified for the lumbar spine (d = −0.15, 95%CL −0.22 to −0.08), femur (d = −0.34, 95%CL −0.64 to −0.05), and total hip (d = −0.14, 95%CL −0.23 to −0.05) indicating low BMD in depression. Examining men and women shows low bone density in the lumbar spine and femur in women and low bone density in the hip in men. The differences between men and women with MDD and the comparison group tended to be higher when examined by expert interviewers. Low bone density was found in all age groups.ConclusionsBone mineral density is reduced in patients with depressive disorders. The studies provide little evidence for potential relevant mediating factors.

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The emerging role of serotonin (5-hydroxytryptamine) in the skeleton and its mediation of the skeletal effects of low-density lipoprotein receptor-related protein 5 (LRP5)

Cited by 84 publications

References 54 publications

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

Serotonergic 5-HT2B Receptor Controls Tissue-nonspecific Alkaline Phosphatase Activity in Osteoblasts via Eicosanoids and Phosphatidylinositol-specific Phospholipase C

Bone density and depressive disorder: a meta‐analysis

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