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.
Highlights
Serotonin is important in brain functions and involved in neurological diseases
We investigated the relative expression of 5-HT6R in bone compared to brain, and examined its role in in vitro osteoblast differentiation and in vivo bone regeneration and bone development via peripheral serotonin system
Our results showed that 5-HT6R showed relatively higher expression in bone compared to brain (Fig. 1A)
Summary
In an effort to elucidate how peripheral serotonin system regulates bone formation, we first examined the relative expression of repective 5-HTRs between the bone and brain. Rh-BMP-2-induced ALP activity and mineralized nodule formation in primary osteoblasts were suppressed dramatically by ST1936 (Fig. 2C–F) These results suggested that the BMP-2 signaling pathway has an important role in 5-HT6R-mediated differentiation and function of osteoblasts. The knockdown of Jab[1] attenuated 5-HT6R agonist induced–Runx[2] suppression (Fig. D) as well as osteoblast differentiation as evidenced by ALP staining (Fig. 3E) and activity (F) and differentiation markers, ALP, OCN, and bone sialoprotein (BSP) (Fig. 3G–I) These data suggest that 5-HT6R inhibits bone formation via Jab1-mediated BMP2 signaling. Our results showed that the 5-HT6R antagonist significantly reversed the 5-HT6R agonist–suppressed expression of Runx[2] (Fig. 4I) and osteoblast-related genes, OCN and BSP (Fig. 4J,K) Taken together, these in vivo results demonstrated that 5-HT6R is a critical receptor to regulate bone formation in peripheral serotonin-mediated system. These findings suggest that 5-HT6R is a potential therapeutic target for bone repair and bone diseases, and will provide basic understanding on how peripheral serotonin-mediated system regulates bone formation
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