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Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis

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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 formation1. As gut-derived serotonin (GDS) inhibits bone formation2, 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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Figure 1: Analysis of LP533401 inhibition of TPH-1 activity.
Figure 2: LP533401 can prevent and rescue osteoporosis in ovariectomized mice.
Figure 3: LP533401 rescues osteoporosis in ovariectomized rats.
Figure 4: Effect of LP533401 on bone biomechanical strength.

Change history

  • 17 February 2010

    In the version of this article initially published online, the description in the figure legend for Figure 3d erroneously listed intermittent PTH as one of the treatment conditions. PTH treatment was used only in the experiments described in Figure 3a–c. As a result of this error, some of the figure callouts in the results section were misleading, and thus this section has also been edited for clarity. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank M.-T. Rached, Y.-Y. Huang, N. Suda and G. Ren for help in experiments and D. Landry (Organic Chemistry, Columbia University) for providing LP533401 for the initial stages of these experiments. Special thanks go to S. Kousteni and J. Martin for helpful suggestions. This work was supported by grants from the US National Institutes of Health (V.K.Y., G.K. and P.D.) and a Gideon and Sevgi Rodan fellowship from International Bone and Mineral Society (V.K.Y.).

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V.K.Y., G.K. and P.D. formulated the hypotheses and designed the studies. V.K.Y. performed mouse experiments and gene expression, biochemical and histological analyses. S.B. and M.V. performed and analyzed the bioinformatics molecular modeling. V.K.Y. performed the mutagenesis experiments. P.S.S. and R.M. performed rat experiments and analyzed humoral parameters in rats. X.S.L., X.L. and X.E.G. performed and analyzed microcomputed tomography and biomechanical testing experiments. Z.L. and M.D.G. analyzed gastrointestinal parameters. A.K.B. performed the in vitro serotonin synthesis inhibition experiments. J.J.M. analyzed brain serotonin contents. V.K.Y., G.K. and P.D. wrote the paper. All authors have approved the final version of the manuscript.

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Correspondence to Gerard Karsenty or Patricia Ducy.

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The authors declare no competing financial interests.

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Yadav, V., Balaji, S., Suresh, P. et al. Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis. Nat Med 16, 308–312 (2010). https://doi.org/10.1038/nm.2098

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