The serotonin 5‐HT_2Breceptor controls bone massviaosteoblast recruitment and proliferation

Abstract

The monoamine serotonin (5-HT), a well-known neurotransmitter, is also important in peripheral tissues. Several studies have suggested that 5-HT is involved in bone metabolism. Starting from our original observation of increased 5-HT(2B) receptor (5-HT(2B)R) expression during in vitro osteoblast differentiation, we investigated a putative bone phenotype in vivo in 5-HT(2B)R knockout mice. Of interest, 5-HT(2B)R mutant female mice displayed reduced bone density that was significant from age 4 months and had intensified by 12 and 18 months. This histomorphometrically confirmed osteopenia seems to be due to reduced bone formation because 1) the alkaline phosphatase-positive colony-forming unit capacity of bone marrow precursors was markedly reduced in the 5-HT(2B)R mutant mice from 4 to 12 months of age, 2) ex vivo primary osteoblasts from mutant mice exhibited reduced proliferation and delayed differentiation, and 3) calcium incorporation was markedly reduced in osteoblasts after 5-HT(2B)R depletion (produced genetically or by pharmacological inactivation). These findings support the hypothesis that the 5-HT(2B)R receptor facilitates osteoblast recruitment and proliferation and that its absence leads to osteopenia that worsens with age. We show here, for the first time, that the 5-HT(2B)R receptor is a physiological mediator of 5-HT in bone formation and, potentially, in the onset of osteoporosis in aging women.

Ineffective erythropoiesis with reduced red blood cell survival in serotonin-deficient mice

“…Indeed, pioneer work by Jean Lauder and coworkers (42,43) revealed that 5-HT regulates basic developmental processes, including cell proliferation, in mammalian and nonmammalian species. Also, identification and characterization of a 5-HT 2A signaling pathway by Sonier et al (9) demonstrated that 5-HT regulates proliferation of a human breast cancer cell line, and Collet et al (10) showed that decreased bone formation in aging female 5-HT 2B knockout mice was associated with reduced osteoblast proliferation.…”

“…Accordingly, and depending on its location, 5-HT may act as a neurotransmitter, a hormone, or a growth factor to regulate a wide range of cellular processes. Through activation of receptors of the 5-HT 2 subtype, 5-HT is known to have a mitogenic effect on a number of cell types, including vascular smooth muscle cells, trophoblast cells, osteoblasts, and cardiomyocytes (8)(9)(10)(11). Availability of 5-HT depends on the expression of the enzyme tryptophan hydroxylase (TPH), which catalyses the first and rate-limiting step in the biosynthesis of 5-HT (12).…”

Protein Kinase Cγ Mediates Regulation of Proliferation by the Serotonin 5-Hydroxytryptamine Receptor 2B

“…5-Hydroxytryptamine (5-HT, 2 serotonin) is well established as a neurotransmitter and a paracrine factor with over 90% of 5-HT produced by the gastrointestinal tract (1,2). There is now substantial evidence that, together with these established functions, 5-HT is involved in the control of cell proliferation through various 5-HT receptors, in particular the 5-hydroxytryptamine receptor 2B (5-HT 2B (3)(4)(5)(6)(7)(8)(9)). The 5-HT 2B receptor is G q/11 protein-coupled.…”

“…Activation of the 5-HT 2B receptor regulates cardiac function, smooth muscle contractility, vascular physiology, and mood control. Recently it was demonstrated that activation of the 5-HT 2B receptor also induces proliferation of neurons, retinal cells (3,4), hepatocytes (5), osteoblasts (8), and interstitial cells of Cajal (ICC) (9). ICC express the 5-HT 2B receptor, and activation by 5-HT induces proliferation of ICC (9).…”

Effect of advanced oxidation protein products on the proliferation and osteogenic differentiation of rat mesenchymal stem cells

“…Elevated levels of AOPPs are detected in many types of diseases, including osteoporosis (9)(10)(11)(12)(13)(14). Certain studies have demonstrated that oxidative stress leads to increased levels of AOPPs in osteoblastic MC3T3-E1 cells (15,16); AOPPs have been shown to inhibit the proliferation and differentiation of rat osteoblastic cells through NF-κB (17); these data suggest that AOPPs are associated with the progression of osteoporosis.…”