title: Peripheral serotonin-mediated system suppresses bone development and regeneration via serotonin 6 G-protein-coupled receptor.
abstract: Serotonin is important in brain functions and involved in neurological diseases. It is also drawn considerable attention in bone disease since it mainly produced by the gut. Serotonin 6 G-protein-coupled receptor (5-HT6R) is clinical targets for the treatment of neurological diseases. However, 5-HT6R as a therapeutic target in bone has not been reported. Herein, we found that 5-HT6R showed higher expression in bone, and its expression was increased during bone remodeling and osteoblast differentiation. The activation of 5-HT6R by ST1936 caused the inhibition of ALP activity and mineralization in primary osteoblast cultures, which was antagonized by SB258585, an antagonist and by the knockdown of 5-HT6R. Further investigation indicated that 5-HT6R inhibited osteoblast differentiation via Jab1 in BMP2 signaling but not PKA and ERK1/2. In vivo studies showed that the activation of 5-HT6R inhibited bone regeneration in the calvarial defect mice and also delayed bone development in newborn mice; this response was antagonized by SB258585. Therefore, our findings indicate a key role of 5-HT6R in bone formation through serotonin originating in the peripheral system, and suggest that it is a novel therapeutic target for drug development in the bone repair and bone diseases.
authors: Department of Oral and Maxillofacial Pathology, School of Dentistry, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors: Hyung-Mun
authors: HM
authors: Yun
authors: Department of Oral &Maxillofacial Regeneration, Graduate School, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors: Kyung-Ran
authors: KR
authors: Park
authors: College of Pharmacy and MRC, Chungbuk National University, 12 Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk 361-763, Korea.
authors: Jin Tae
authors: JT
authors: Hong
authors: Department of Oral and Maxillofacial Pathology, School of Dentistry and Research Center for Tooth &Periodontal Regeneration (MRC), Kyung Hee University, Seoul 130-701, Republic of Korea.
authors: Eun-Cheol
authors: EC
authors: Kim
mesh_terms: D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D001861:Bone Regeneration / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D012886:Skull / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism
chemical_list: D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; C097216:serotonin 6 receptor; D012701:Serotonin