Exploring a novel class tryptophan hydroxylase 1 inhibitor derived from Sambucus williamsii Hance for the osteoporosis treatment

Objective: Gut-derived serotonin strongly inhibits bone formation by inhibiting osteoblast proliferation. Our previous study demonstrated that the lignan-rich fraction prepared from Sambucus willimasii Hance, a folk herbal medicine used to treat bone fractures and joint diseases in China, exerted bone-protective effects, and its actions were modulated by suppressing the synthesis of gut-derived serotonin via the inhibition of intestinal tryptophan hydroxylase 1 (TPH-1). However, there is no direct evidence for the action of lignans on TPH-1. This study aimed to verify the direct action of lignans on the TPH-1 and its influence on serotonin synthesis and bone properties. Methods: Molecular docking and surface plasmon resonance were performed to determine the affinities of lignans to TPH-1. The cell viability and the protein activity and expression of TPH-1 were measured in RBL2H3 cells. The serum serotonin level and bone mineral density upon lignan treatment in ovariectomized mice were determined. Result: The lignans showed high binding scores and binding affinities to TPH-1, inhibited the activity and protein expression of TPH-1, suppressed the serum serotonin levels in ovariectomized mice as well as promoted bone mineral density. Conclusion: This is the first study to report that lignans are novel TPH-1 inhibitors and that these lignans could be potential agents for the management of serotonin-related diseases, including osteoporosis.