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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.

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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.

References

  1. Rodan, G.A. & Martin, T.J. Therapeutic approaches to bone diseases. Science 289, 1508–1514 (2000).

    Article  CAS  Google Scholar 

  2. Yadav, V.K. et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135, 825–837 (2008).

    Article  CAS  Google Scholar 

  3. Liu, Q. et al. Discovery and characterization of novel tryptophan hydroxylase inhibitors that selectively inhibit serotonin synthesis in the gastrointestinal tract. J. Pharmacol. Exp. Ther. 325, 47–55 (2008).

    Article  CAS  Google Scholar 

  4. Shi, Z.C. et al. Modulation of peripheral serotonin levels by novel tryptophan hydroxylase inhibitors for the potential treatment of functional gastrointestinal disorders. J. Med. Chem. 51, 3684–3687 (2008).

    Article  CAS  Google Scholar 

  5. Yadav, V.K. et al. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite and energy expenditure. Cell 138, 976–989 (2009).

    Article  CAS  Google Scholar 

  6. Wang, L., Erlandsen, H., Haavik, J., Knappskog, P.M. & Stevens, R.C. Three-dimensional structure of human tryptophan hydroxylase and its implications for the biosynthesis of the neurotransmitters serotonin and melatonin. Biochemistry 41, 12569–12574 (2002).

    Article  CAS  Google Scholar 

  7. Manolagas, S.C., Kousteni, S. & Jilka, R.L. Sex steroids and bone. Recent Prog. Horm. Res. 57, 385–409 (2002).

    Article  CAS  Google Scholar 

  8. Gershon, M.D. & Tack, J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 132, 397–414 (2007).

    Article  CAS  Google Scholar 

  9. Bilezikian, J.P. et al. Targeting bone remodeling for the treatment of osteoporosis: summary of the proceedings of an ASBMR workshop. J. Bone Miner. Res. 24, 373–385 (2009).

    Article  Google Scholar 

  10. Frolik, C.A. et al. Anabolic and catabolic bone effects of human parathyroid hormone (1–34) are predicted by duration of hormone exposure. Bone 33, 372–379 (2003).

    Article  CAS  Google Scholar 

  11. Parfitt, A.M. et al. Bone histomorphometry: standardization of nomenclature, symbols and units. Report of the ASBMR Histomorphometry Committee. J. Bone Miner. Res. 2, 595–610 (1987).

    Article  CAS  Google Scholar 

  12. Andersson, N. et al. Pharmacological treatment of osteopenia induced by gastrectomy or ovariectomy in young female rats. Acta Orthop. Scand. 75, 201–209 (2004).

    Article  Google Scholar 

  13. Feldkamp, L.A., Goldstein, S.A., Parfitt, A.M., Jesion, G. & Kleerekoper, M. The direct examination of three-dimensional bone architecture in vitro by computed tomography. J. Bone Miner. Res. 4, 3–11 (1989).

    Article  CAS  Google Scholar 

  14. Gundersen, H.J., Boyce, R.W., Nyengaard, J.R. & Odgaard, A. The Conneulor: unbiased estimation of connectivity using physical disectors under projection. Bone 14, 217–222 (1993).

    Article  CAS  Google Scholar 

  15. Hodsman, A.B. et al. Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocr. Rev. 26, 688–703 (2005).

    Article  CAS  Google Scholar 

  16. Vegni, F.E., Corradini, C. & Privitera, G. Effects of parathyroid hormone and alendronate alone or in combination in osteoporosis. N. Engl. J. Med. 350, 189–192, author reply 189–192 (2004).

    Article  CAS  Google Scholar 

  17. Frost, M. et al. Patients with high bone mass have low plasma levels of serotonin. J. Bone Miner. Res. (in the press).

  18. Morris, G.M. et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem. 30, 2785–2791 (2009).

    Article  CAS  Google Scholar 

  19. Ducy, P. et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100, 197–207 (2000).

    Article  CAS  Google Scholar 

  20. Takeda, S. et al. Leptin regulates bone formation via the sympathetic nervous system. Cell 111, 305–317 (2002).

    Article  CAS  Google Scholar 

  21. Hildebrand, T., Laib, A., Muller, R., Dequeker, J. & Ruegsegger, P. Direct three-dimensional morphometric analysis of human cancellous bone: microstructural data from spine, femur, iliac crest and calcaneus. J. Bone Miner. Res. 14, 1167–1174 (1999).

    Article  CAS  Google Scholar 

  22. Chen, J.J. et al. Maintenance of serotonin in the intestinal mucosa and ganglia of mice that lack the high affinity serotonin transporter (SERT): abnormal intestinal motility and the expression of cation transporters. J. Neurosci. 21, 6348–6361 (2001).

    Article  CAS  Google Scholar 

  23. Mann, J.J. et al. Relationship between central and peripheral serotonin indexes in depressed and suicidal psychiatric inpatients. Arch. Gen. Psychiatry 49, 442–446 (1992).

    Article  CAS  Google Scholar 

  24. Lane, N.E. et al. Glucocorticoid-treated mice have localized changes in trabecular bone material properties and osteocyte lacunar size that are not observed in placebo-treated or estrogen-deficient mice. J. Bone Miner. Res. 21, 466–476 (2006).

    Article  CAS  Google Scholar 

  25. Turner, C.H. & Burr, D.B. Basic biomechanical measurements of bone: a tutorial. Bone 14, 595–608 (1993).

    Article  CAS  Google Scholar 

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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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