+1 Recommend
0 collections
      • Record: found
      • Abstract: found
      • Article: not found

      Inhibition of gut-derived serotonin synthesis: a potential bone anabolic treatment

      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          Osteoporosis is a low bone mass disease most often caused by an increase in bone resorption not compensated by a similar hike in bone formation 1. Since gut–derived serotonin (GDS) inhibits bone formation 2, we asked whether hampering its biosynthesis could treat osteoporosis through an anabolic mechanism. To that end we synthesized and used LP533401, a small molecule inhibitor of Tph1, the initial enzyme in GDS biosynthesis. Oral administration once daily for up to 6 weeks of this small molecule prevents the development of and fully rescues, in a dose–dependent manner, 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 novel anabolic treatment for osteoporosis.

          Related collections

          Most cited references 19

          • Record: found
          • Abstract: not found
          • Article: not found

          Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee.

            • Record: found
            • Abstract: found
            • Article: not found

            Therapeutic approaches to bone diseases.

            The strength and integrity of our bones depends on maintaining a delicate balance between bone resorption by osteoclasts and bone formation by osteoblasts. As we age or as a result of disease, this delicate balancing act becomes tipped in favor of osteoclasts so that bone resorption exceeds bone formation, rendering bones brittle and prone to fracture. A better understanding of the biology of osteoclasts and osteoblasts is providing opportunities for developing therapeutics to treat diseases of bone. Drugs that inhibit the formation or activity of osteoclasts are valuable for treating osteoporosis, Paget's disease, and inflammation of bone associated with rheumatoid arthritis or periodontal disease. Far less attention has been paid to promoting bone formation with, for example, growth factors or hormones, an approach that would be a valuable adjunct therapy for patients receiving inhibitors of bone resorption.
              • Record: found
              • Abstract: found
              • Article: not found

              Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass.

              Gonadal failure induces bone loss while obesity prevents it. This raises the possibility that bone mass, body weight, and gonadal function are regulated by common pathways. To test this hypothesis, we studied leptin-deficient and leptin receptor-deficient mice that are obese and hypogonadic. Both mutant mice have an increased bone formation leading to high bone mass despite hypogonadism and hypercortisolism. This phenotype is dominant, independent of the presence of fat, and specific for the absence of leptin signaling. There is no leptin signaling in osteoblasts but intracerebroventricular infusion of leptin causes bone loss in leptin-deficient and wild-type mice. This study identifies leptin as a potent inhibitor of bone formation acting through the central nervous system and therefore describes the central nature of bone mass control and its disorders.

                Author and article information

                Nat Med
                Nature medicine
                14 January 2010
                7 February 2010
                March 2010
                1 September 2010
                : 16
                : 3
                : 308-312
                [1 ]Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA
                [2 ]Department of Genetics, Harvard Medical School and Center for Cancer Systems Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
                [3 ]Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India
                [4 ]Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
                [5 ]Department of Cell Biology, Columbia University, New York, NY 10032, USA
                [6 ]Department of Psychiatry, Columbia University, New York, NY 10032, USA
                [7 ]Tissue and Cell Culture Unit, Central Drug Research Institute, Lucknow 226001, India
                [8 ]Department of Pathology, Columbia University, New York, NY 10032, USA
                Author notes

                These authors contributed equally to this work

                Author contributions

                V.K.Y, G.K. and P.D. formulated the hypotheses and designed the studies. V.K.Y. performed mice experiments, gene expression, biochemical and histological analysis. 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 microCT 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.


                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: K99 DK085328-01 ||DK



                Comment on this article