Editing Serotonin (section)

====Bone metabolism====
In mice and humans, alterations in serotonin levels and signalling have been shown to regulate bone mass.<ref name="pmid20200960">{{cite journal | vauthors = Frost M, Andersen TE, Yadav V, Brixen K, Karsenty G, Kassem M | title = Patients with high-bone-mass phenotype owing to Lrp5-T253I mutation have low plasma levels of serotonin | journal = Journal of Bone and Mineral Research | volume = 25 | issue = 3 | pages = 673–675 | date = March 2010 | pmid = 20200960 | doi = 10.1002/jbmr.44 | s2cid = 24280062 | doi-access = free }}</ref><ref name="pmid19197289">{{cite journal | vauthors = Rosen CJ | title = Breaking into bone biology: serotonin's secrets | journal = Nature Medicine | volume = 15 | issue = 2 | pages = 145–146 | date = February 2009 | pmid = 19197289 | doi = 10.1038/nm0209-145 | s2cid = 5489589 }}</ref><ref name="pmid19594297">{{cite journal | vauthors = Mödder UI, Achenbach SJ, Amin S, Riggs BL, Melton LJ, Khosla S | title = Relation of serum serotonin levels to bone density and structural parameters in women | journal = Journal of Bone and Mineral Research | volume = 25 | issue = 2 | pages = 415–422 | date = February 2010 | pmid = 19594297 | pmc = 3153390 | doi = 10.1359/jbmr.090721 }}</ref><ref name="pmid21351148">{{cite journal | vauthors = Frost M, Andersen T, Gossiel F, Hansen S, Bollerslev J, van Hul W, Eastell R, Kassem M, Brixen K | title = Levels of serotonin, sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high-bone-mass phenotype due to a mutation in Lrp5 | journal = Journal of Bone and Mineral Research | volume = 26 | issue = 8 | pages = 1721–1728 | date = August 2011 | pmid = 21351148 | doi = 10.1002/jbmr.376 | doi-access = free }}</ref> Mice that lack brain serotonin have [[osteopenia]], while mice that lack gut serotonin have high bone density. In humans, increased blood serotonin levels have been shown to be a significant negative predictor of low bone density. Serotonin can also be synthesized, albeit at very low levels, in the bone cells. It mediates its actions on bone cells using three different receptors. Through [[5-HT1B receptor|5-HT<sub>1B</sub> receptors]], it negatively regulates bone mass, while it does so positively through [[5-HT2B receptor|5-HT<sub>2B</sub> receptors]] and [[5-HT2C receptor|5-HT<sub>2C</sub> receptors]]. There is very delicate balance between physiological role of gut serotonin and its pathology. Increase in the extracellular content of serotonin results in a complex relay of signals in the osteoblasts culminating in FoxO1/ Creb and ATF4 dependent transcriptional events.<ref name="pmid22945629">{{cite journal | vauthors = Kode A, Mosialou I, Silva BC, Rached MT, Zhou B, Wang J, Townes TM, Hen R, DePinho RA, Guo XE, Kousteni S | title = FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin | journal = The Journal of Clinical Investigation | volume = 122 | issue = 10 | pages = 3490–3503 | date = October 2012 | pmid = 22945629 | pmc = 3461930 | doi = 10.1172/JCI64906 }}</ref> Following the 2008 findings that gut serotonin regulates bone mass, the mechanistic investigations into what regulates serotonin synthesis from the gut in the regulation of bone mass have started. [[PIEZO1|Piezo1]] has been shown to sense RNA in the gut and relay this information through serotonin synthesis to the bone by acting as a sensor of single-stranded RNA (ssRNA) governing 5-HT production. Intestinal epithelium-specific deletion of mouse ''Piezo1'' profoundly disturbed gut peristalsis, impeded experimental colitis, and suppressed serum 5-HT levels. Because of systemic 5-HT deficiency, conditional knockout of ''Piezo1'' increased bone formation. Notably, fecal ssRNA was identified as a natural Piezo1 ligand, and ssRNA-stimulated 5-HT synthesis from the gut was evoked in a MyD88/TRIF-independent manner. Colonic infusion of RNase A suppressed gut motility and increased bone mass. These findings suggest gut ssRNA as a master determinant of systemic 5-HT levels, indicating the ssRNA-Piezo1 axis as a potential prophylactic target for treatment of bone and gut disorders. Studies in 2008, 2010 and 2019 have opened the potential for serotonin research to treat bone mass disorders.<ref name="pmid20139991">{{cite journal | vauthors = Yadav VK, Balaji S, Suresh PS, Liu XS, Lu X, Li Z, Guo XE, Mann JJ, Balapure AK, Gershon MD, Medhamurthy R, Vidal M, Karsenty G, Ducy P | title = Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis | journal = Nature Medicine | volume = 16 | issue = 3 | pages = 308–312 | date = March 2010 | pmid = 20139991 | pmc = 2836724 | doi = 10.1038/nm.2098 }}</ref><ref name="pmid32640190">{{cite journal | vauthors = Sugisawa E, Takayama Y, Takemura N, Kondo T, Hatakeyama S, Kumagai Y, Sunagawa M, Tominaga M, Maruyama K | title = RNA Sensing by Gut Piezo1 Is Essential for Systemic Serotonin Synthesis | journal = Cell | volume = 182 | issue = 3 | pages = 609–624.e21 | date = August 2020 | pmid = 32640190 | doi = 10.1016/j.cell.2020.06.022 | doi-access = free }}</ref>