ST-1936

5-hydroxytryptamine 6 receptor (5-HT₆R) is a G protein-coupled receptor (GPCR), and its activation results in bone resorption and loss. In the present study, we investigated the signaling pathway induced by the activation of 5-HT₆R during osteoclastogenesis in bone marrow-derived macrophages (BMMs). ST1936-induced 5-HT₆R stimulation enhanced tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts during osteoclastogenesis, a process that was counteracted by SB258585, a specific 5-HT₆R antagonist, as well as by 5-HT₆R knockdown. The activation of 5-HT₆R increased the phosphorylation of ERK1/2, but not that of p38, JNK, and AKT in both BMMs and osteoclasts. 5-HT₆R-mediated ERK1/2 signaling also enhanced the formation of TRAP-positive multinucleated osteoclasts, increased the expression of osteoclast-related genes, and promoted F-actin ring formation, along with cathepsin K and integrin β3, which are essential for osteoclast differentiation and functional activity. Further investigation indicated that 5-HT₆R-induced ERK1/2 signaling inhibited apoptosis in osteoclasts. Taken together, the findings suggest that 5-HT₆R-induced ERK1/2 signaling plays an important role in osteoclastogenesis and function, shedding light on the unique roles that 5-HT₆R plays in bone.