Pharmacological Inhibition of Gut-derived Serotonin Synthesis is a Potential Bone Anabolic Treatment for Osteoporosis

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2010 Feb 9

PMID 20139991

Citations 142

Authors

Vijay K Yadav

Santhanam Balaji

Padmanaban S Suresh

X Sherry Liu

Xin Lu

Zhishan Li

X Edward Guo

J John Mann

Anil K Balapure

Michael D Gershon

Rudraiah Medhamurthy

Marc Vidal

Gerard Karsenty

Patricia Ducy

Affiliations

Soon will be listed here.

Abstract

Osteoporosis is a disease of low bone mass most often caused by an increase in bone resorption that is not sufficiently compensated for by a corresponding increase in bone formation. As gut-derived serotonin (GDS) inhibits bone formation, we asked whether hampering its biosynthesis could treat osteoporosis through an anabolic mechanism (that is, by increasing bone formation). We synthesized and used LP533401, a small molecule inhibitor of tryptophan hydroxylase-1 (Tph-1), the initial enzyme in GDS biosynthesis. Oral administration of this small molecule once daily for up to six weeks acts prophylactically or therapeutically, in a dose-dependent manner, to treat 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 new anabolic treatment for osteoporosis.

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