Journal
JOURNAL OF BONE AND MINERAL RESEARCH
Volume 26, Issue 9, Pages 2002-2011Publisher
WILEY
DOI: 10.1002/jbmr.439
Keywords
SEROTONIN; TPH1 INHIBITOR; ANABOLIC TREATMENT; OSTEOPOROSIS; BONE FORMATION
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Funding
- National Institute of Aging [AG032959]
- Grants-in-Aid for Scientific Research [23890053] Funding Source: KAKEN
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In a proof-of-concept study it was shown that decreasing synthesis of gut serotonin through a small molecule inhibitor of Tph1 could prevent and treat ovariectomy-induced osteoporosis in young mice and rats. In this study, we define the minimal efficacy of this Tph1 inhibitor, demonstrate that its activity is improved with the duration of treatment, and show that its anabolic effect persists on interruption. Importantly, given the prevalence of osteoporosis in the aging population, we then show that Tph1 inhibition rescues ovariectomy-induced bone loss in aged mice. It also cures the low bone mass of Lrp5-deficient mice through a sole anabolic effect. Lastly, we provide evidence that inhibition of gut serotonin synthesis can work in concert with an antiresorptive agent to increase bone mass in ovariectomized mice. This study provides a more comprehensive view of the anabolic efficacy of Tph1 inhibitors and further establishes the spectrum of their therapeutic potential in the treatment of bone-loss disorders. (C) 2011 American Society for Bone and Mineral Research.
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