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

Yadav VK, Balaji S, Suresh PS, Liu XS, Lu X, Li Z, Guo XE, Mann JJ, Balapure AK, Gershon MD, Medhamurthy R, Vidal M, Karsenty G, Ducy P - Nat. Med. (2010)

Bottom Line: 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.We synthesized and used LP533401, a small molecule inhibitor of tryptophan hydroxylase-1 (Tph-1), the initial enzyme in GDS biosynthesis.These results provide a proof of principle that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Development, Columbia University Medical Center, New York, New York, USA.

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 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.

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Analysis of LP533401 inhibition of Tph1 activity(a–b) In vitro (a) and in vivo (b) dose response of inhibition of serotonin synthesis by LP533401.(c) Crystal structure of human TPH1 bound to 7,8–dihydro–L–biopterin co–factor (HBI, in magenta) and Fe(III) (in blue) (PDB ID: 1mlw). Amino acid side-chains interacting with HBI are in white and those binding the metal ion are in cyan.(d) Left panel, crystal structure of human TPH1 docked to the generated 3D model of LP533401. LP533401 is in magenta and the metal ion is in blue. The side-chains of amino acid residues interacting with LP533401 and metal ion are in white and cyan respectively. The residues interacting with LP533401 include Val232, Tyr235, Leu236, Pro238, Phe241, His251, Ala309 and Tyr312. Right panel, Zoom image for the binding of LP533401 to TPH1. The structure figures have been made using PyMOL (http://www.pymol.org/).(e) In vitro activity of wild–type or mutated (Y235S, F241V) TPH1 in the presence of LP533401 (0.01 μM).All values are expressed as means ± SEM. * p < 0.05 vs vehicle.
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Figure 1: Analysis of LP533401 inhibition of Tph1 activity(a–b) In vitro (a) and in vivo (b) dose response of inhibition of serotonin synthesis by LP533401.(c) Crystal structure of human TPH1 bound to 7,8–dihydro–L–biopterin co–factor (HBI, in magenta) and Fe(III) (in blue) (PDB ID: 1mlw). Amino acid side-chains interacting with HBI are in white and those binding the metal ion are in cyan.(d) Left panel, crystal structure of human TPH1 docked to the generated 3D model of LP533401. LP533401 is in magenta and the metal ion is in blue. The side-chains of amino acid residues interacting with LP533401 and metal ion are in white and cyan respectively. The residues interacting with LP533401 include Val232, Tyr235, Leu236, Pro238, Phe241, His251, Ala309 and Tyr312. Right panel, Zoom image for the binding of LP533401 to TPH1. The structure figures have been made using PyMOL (http://www.pymol.org/).(e) In vitro activity of wild–type or mutated (Y235S, F241V) TPH1 in the presence of LP533401 (0.01 μM).All values are expressed as means ± SEM. * p < 0.05 vs vehicle.

Mentions: We used the available chemical description to synthesize LP533401 and verified its structural identity by multiple analyses4 (Supplementary Fig. 1). To evaluate LP533401 efficacy in inhibiting serotonin biosynthesis we treated Tph1–expressing cells (RBL2H3 cells) for 3 days with increasing amounts of LP533401 (0.1-1 μM). LP533401 completely inhibited serotonin production in these cells at a dose of 1 μM (Fig. 1a). Moreover, there was a dose–dependent decrease in serum serotonin levels in WT mice fed with LP533401 (Fig. 1b). This decrease in serum serotonin levels reached 30% of control values when using 250 mg per kg body weight per day of the compound although no change in brain serotonin content was observed (Supplementary Fig. S2). This latter point is important since brain– and gut–derived serotonin exert opposite influences on bone formation5.


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

Yadav VK, Balaji S, Suresh PS, Liu XS, Lu X, Li Z, Guo XE, Mann JJ, Balapure AK, Gershon MD, Medhamurthy R, Vidal M, Karsenty G, Ducy P - Nat. Med. (2010)

Analysis of LP533401 inhibition of Tph1 activity(a–b) In vitro (a) and in vivo (b) dose response of inhibition of serotonin synthesis by LP533401.(c) Crystal structure of human TPH1 bound to 7,8–dihydro–L–biopterin co–factor (HBI, in magenta) and Fe(III) (in blue) (PDB ID: 1mlw). Amino acid side-chains interacting with HBI are in white and those binding the metal ion are in cyan.(d) Left panel, crystal structure of human TPH1 docked to the generated 3D model of LP533401. LP533401 is in magenta and the metal ion is in blue. The side-chains of amino acid residues interacting with LP533401 and metal ion are in white and cyan respectively. The residues interacting with LP533401 include Val232, Tyr235, Leu236, Pro238, Phe241, His251, Ala309 and Tyr312. Right panel, Zoom image for the binding of LP533401 to TPH1. The structure figures have been made using PyMOL (http://www.pymol.org/).(e) In vitro activity of wild–type or mutated (Y235S, F241V) TPH1 in the presence of LP533401 (0.01 μM).All values are expressed as means ± SEM. * p < 0.05 vs vehicle.
© Copyright Policy
Related In: Results  -  Collection

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Figure 1: Analysis of LP533401 inhibition of Tph1 activity(a–b) In vitro (a) and in vivo (b) dose response of inhibition of serotonin synthesis by LP533401.(c) Crystal structure of human TPH1 bound to 7,8–dihydro–L–biopterin co–factor (HBI, in magenta) and Fe(III) (in blue) (PDB ID: 1mlw). Amino acid side-chains interacting with HBI are in white and those binding the metal ion are in cyan.(d) Left panel, crystal structure of human TPH1 docked to the generated 3D model of LP533401. LP533401 is in magenta and the metal ion is in blue. The side-chains of amino acid residues interacting with LP533401 and metal ion are in white and cyan respectively. The residues interacting with LP533401 include Val232, Tyr235, Leu236, Pro238, Phe241, His251, Ala309 and Tyr312. Right panel, Zoom image for the binding of LP533401 to TPH1. The structure figures have been made using PyMOL (http://www.pymol.org/).(e) In vitro activity of wild–type or mutated (Y235S, F241V) TPH1 in the presence of LP533401 (0.01 μM).All values are expressed as means ± SEM. * p < 0.05 vs vehicle.
Mentions: We used the available chemical description to synthesize LP533401 and verified its structural identity by multiple analyses4 (Supplementary Fig. 1). To evaluate LP533401 efficacy in inhibiting serotonin biosynthesis we treated Tph1–expressing cells (RBL2H3 cells) for 3 days with increasing amounts of LP533401 (0.1-1 μM). LP533401 completely inhibited serotonin production in these cells at a dose of 1 μM (Fig. 1a). Moreover, there was a dose–dependent decrease in serum serotonin levels in WT mice fed with LP533401 (Fig. 1b). This decrease in serum serotonin levels reached 30% of control values when using 250 mg per kg body weight per day of the compound although no change in brain serotonin content was observed (Supplementary Fig. S2). This latter point is important since brain– and gut–derived serotonin exert opposite influences on bone formation5.

Bottom Line: 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.We synthesized and used LP533401, a small molecule inhibitor of tryptophan hydroxylase-1 (Tph-1), the initial enzyme in GDS biosynthesis.These results provide a proof of principle that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Development, Columbia University Medical Center, New York, New York, USA.

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 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.

Show MeSH
Related in: MedlinePlus