Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis.
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.
Yadav
Vijay K
VK
Department of Genetics and Development, Columbia University Medical Center, New York, New York, USA.
Balaji
Santhanam
S
Suresh
Padmanaban S
PS
Liu
X Sherry
XS
Lu
Xin
X
Li
Zhishan
Z
Guo
X Edward
XE
Mann
J John
JJ
Balapure
Anil K
AK
Gershon
Michael D
MD
Medhamurthy
Rudraiah
R
Vidal
Marc
M
Karsenty
Gerard
G
Ducy
Patricia
P
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D041981:Gastrointestinal Tract / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology; D010024:Osteoporosis / Q000188:drug therapy*; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D012701:Serotonin / Q000096:biosynthesis*; D018490:Serotonin Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors*
C548240:LP533401; D011743:Pyrimidines; D018490:Serotonin Agents; D012701:Serotonin; D014365:Tryptophan Hydroxylase; C504570:tph1 protein, rat