Inhibition of gut-derived serotonin synthesis: a potential bone anabolic treatment

Abstract

Osteoporosis is a low bone mass disease most often caused by an increase in bone resorption not compensated by a similar hike in bone formation 1. Since gut–derived serotonin (GDS) inhibits bone formation 2, we asked whether hampering its biosynthesis could treat osteoporosis through an anabolic mechanism. To that end we synthesized and used LP533401, a small molecule inhibitor of Tph1, the initial enzyme in GDS biosynthesis. Oral administration once daily for up to 6 weeks of this small molecule prevents the development of and fully rescues, in a dose–dependent manner, osteoporosis in ovariectomized rodents because of an isolated increase in bone formation. These results provide a proof of principle that inhibiting GDS biosynthesis could become a novel anabolic treatment for osteoporosis.