Serotonin inhibits osteoblast differentiation and bone regeneration in rats

Background: Although increasing evidence indicates that serotonin (SER; 5-hydroxytrypamine [5-HT]) is involved in the regulation of bone metabolism, conflicting data exist regarding whether SER promotes or inhibits osteoblast differentiation and bone formation. Regeneration of functional bone is required for proper osseointegration of dental implants. Noticeably, the use of selective SER reuptake inhibitors was recently associated with the failure of osseointegrated dental implants. The present study examines the direct role of peripheral SER on the regulation of bone regeneration. Methods: The effect of SER on osteoblast differentiation and bone regeneration was examined using rat calvarial cell cultures in vitro and a rat critical-sized calvarial defect model in vivo. Results: Rat calvarial cells expressed SER receptors Htr1 (5-HT1) and Htr2 (5-HT2), which are known to transmit signals in bone cells. In vitro, SER significantly reduced osteogenic differentiation and mineralization of rat calvarial cells with concomitant reduction of osteoblast marker genes including alkaline phosphatase (Alpl), osterix (Sp7), and osteocalcin (Bglap). Histologic and radiologic analyses using the rat critical-sized calvarial defect model revealed that the existence of SER significantly inhibited β-phase tricalcium phosphate-induced bone regeneration. Conclusion: Results suggest that SER in the local bone microenvironment might play a negative role in osteoblast differentiation and bone formation in rats.