Regulatory mechanism of CCN2 production by serotonin (5-HT) via 5-HT2A and 5-HT2B receptors in chondrocytes

• Published in: PloS one Vol. 12; no. 11; p. e0188014
• Main Authors: Hori, Ayaka, Nishida, Takashi, Takashiba, Shogo, Kubota, Satoshi, Takigawa, Masaharu
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.11.2017; Public Library of Science (PLoS)
• Subjects: AKT protein; Arthritis; Biochemistry; Biology and Life Sciences; Blood pressure; Blood vessels; Bones; Cartilage; Cartilage (articular); Cell cycle; Chondrocytes; Connective tissue growth factor; Connective tissues; Dental schools; Dentistry; Growth factors; Growth plate; Immunoglobulins; JNK protein; Kinases; MAP kinase; Medicine; Medicine and Health Sciences; mRNA; Pharmaceutical sciences; Phosphorylation; Protein kinase C; Proteins; Receptors; Regeneration; Regulatory mechanisms (biology); Serotonin; Serotonin S2 receptors; Tissues; University graduates; Urban regeneration; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0188014

Serotonin (5-hydroxytryptamine: 5-HT) is recognized as a neurotransmitter in the central nerve system and as a regulator of systemic blood pressure in the peripheral tissues. Recently, it was reported that 5-HT2 receptors (5-HT2Rs) were expressed in cartilage tissues lacking both vessels and neurons, suggesting possible novel functions of 5-HT during cartilage development and regeneration. Our previous data indicated that CCN family protein 2/connective tissue growth factor (CCN2/CTGF) plays a central role in cartilage development and regeneration. Therefore, the aim of this study was to investigate the effect of 5-HT on the production of CCN2 in chondrocytes. Firstly, we showed that the mRNAs of 5-HT2R subtypes 5-HT2AR and 5-HT2BR, were expressed in a human chondrocytic cell line, HCS-2/8; however, 5-HT2CR mRNA was not detected. In addition, exogenously added 5-HT did not affect the 5-HT2AR and 5-HT2BR expressions. Next, we demonstrated that CCN2 production was increased by treatment with a 5-HT2AR agonist and the combination of 5-HT and 5-HT2BR antagonist. In contrast, treatment with a 5-HT2BR agonist and the combination of 5-HT and 5-HT2AR antagonist decreased CCN2 production. Furthermore, we showed that phosphorylation of Akt and p38 MAPK were increased by treatment with 5-HT2AR agonist, and that phosphorylation of PKCε, PKCζ, ERK1/2 and JNK were increased by treatment with 5-HT2BR agonist. Finally, we found that 5-HT2AR was localized in the growth plate, whereas 5-HT2BR was localized in the articular cartilage. These findings suggest that 5-HT promotes CCN2 production through the 5-HT2AR in growth plates, and that it represses CCN2 production through the 5-HT2BR in articular cartilage for harmonized development of long bones.