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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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LP533401 rescues osteoporosis in ovariectomized rats(a–c) Histomorphometric analysis of L2 vertebra (a) and micro–computed tomography analysis of the proximal tibiae (b,c) collected from rat sham-operated (sham) vehicle treated control, ovariectomized (OVX) and treated with vehicle, intermittent injections of PTH or 250 mg per kg body weight per day of LP533401 (LP) from week 3 to 7 post–ovariectomy (n =8–10 animals each group).(d) Histomorphometric analysis of L2 vertebra and micro–computed tomography analysis of the proximal tibiae collected from rat sham-operated (sham) vehicle treated control, ovariectomized (OVX) and treated with vehicle, intermittent injections of PTH or LP533401 (25, 100 mg per kg body weight per day) from week 12 to 16 post–ovariectomy (n =8–10 animals each group).BV/TV, Bone volume over trabecular volume; Tb.N*, trabecular number; Tb.Th*, trabecular thickness; Tb.Sp*, trabecular spacing; Nb.Ob/T.Ar, osteoblast number over trabecular area; BFR, bone formation rate; OcS/BS, osteoclast surface over bone surface.All values are expressed as means ± SEM. * means the parameter is measured without a plate or rod model assumption, # p < 0.05 vs sham and ◇ p < 0.05 vs OVX (Veh).
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Figure 3: LP533401 rescues osteoporosis in ovariectomized rats(a–c) Histomorphometric analysis of L2 vertebra (a) and micro–computed tomography analysis of the proximal tibiae (b,c) collected from rat sham-operated (sham) vehicle treated control, ovariectomized (OVX) and treated with vehicle, intermittent injections of PTH or 250 mg per kg body weight per day of LP533401 (LP) from week 3 to 7 post–ovariectomy (n =8–10 animals each group).(d) Histomorphometric analysis of L2 vertebra and micro–computed tomography analysis of the proximal tibiae collected from rat sham-operated (sham) vehicle treated control, ovariectomized (OVX) and treated with vehicle, intermittent injections of PTH or LP533401 (25, 100 mg per kg body weight per day) from week 12 to 16 post–ovariectomy (n =8–10 animals each group).BV/TV, Bone volume over trabecular volume; Tb.N*, trabecular number; Tb.Th*, trabecular thickness; Tb.Sp*, trabecular spacing; Nb.Ob/T.Ar, osteoblast number over trabecular area; BFR, bone formation rate; OcS/BS, osteoclast surface over bone surface.All values are expressed as means ± SEM. * means the parameter is measured without a plate or rod model assumption, # p < 0.05 vs sham and ◇ p < 0.05 vs OVX (Veh).

Mentions: The rat is the rodent model of choice for post–menopausal osteoporosis and intermittent injections of parathyroid hormone (PTH), the standard to which any novel bone anabolic agent must be compared 10. Hence, we ovariectomized rats at 12 weeks of age and left them untreated for 3 or 12 more weeks so that they develop a severe osteopenia (Fig. 3 and Supplementary Fig. 5). Sham–operated or ovariectomized rats were then treated for 4 weeks with either vehicle, a relatively high dose of PTH (80 μg per kg per day, subcutaneous)11, or increasing amounts of LP533401 (25, 100 or 250 mg per kg per day, orally).


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)

LP533401 rescues osteoporosis in ovariectomized rats(a–c) Histomorphometric analysis of L2 vertebra (a) and micro–computed tomography analysis of the proximal tibiae (b,c) collected from rat sham-operated (sham) vehicle treated control, ovariectomized (OVX) and treated with vehicle, intermittent injections of PTH or 250 mg per kg body weight per day of LP533401 (LP) from week 3 to 7 post–ovariectomy (n =8–10 animals each group).(d) Histomorphometric analysis of L2 vertebra and micro–computed tomography analysis of the proximal tibiae collected from rat sham-operated (sham) vehicle treated control, ovariectomized (OVX) and treated with vehicle, intermittent injections of PTH or LP533401 (25, 100 mg per kg body weight per day) from week 12 to 16 post–ovariectomy (n =8–10 animals each group).BV/TV, Bone volume over trabecular volume; Tb.N*, trabecular number; Tb.Th*, trabecular thickness; Tb.Sp*, trabecular spacing; Nb.Ob/T.Ar, osteoblast number over trabecular area; BFR, bone formation rate; OcS/BS, osteoclast surface over bone surface.All values are expressed as means ± SEM. * means the parameter is measured without a plate or rod model assumption, # p < 0.05 vs sham and ◇ p < 0.05 vs OVX (Veh).
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Related In: Results  -  Collection

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Figure 3: LP533401 rescues osteoporosis in ovariectomized rats(a–c) Histomorphometric analysis of L2 vertebra (a) and micro–computed tomography analysis of the proximal tibiae (b,c) collected from rat sham-operated (sham) vehicle treated control, ovariectomized (OVX) and treated with vehicle, intermittent injections of PTH or 250 mg per kg body weight per day of LP533401 (LP) from week 3 to 7 post–ovariectomy (n =8–10 animals each group).(d) Histomorphometric analysis of L2 vertebra and micro–computed tomography analysis of the proximal tibiae collected from rat sham-operated (sham) vehicle treated control, ovariectomized (OVX) and treated with vehicle, intermittent injections of PTH or LP533401 (25, 100 mg per kg body weight per day) from week 12 to 16 post–ovariectomy (n =8–10 animals each group).BV/TV, Bone volume over trabecular volume; Tb.N*, trabecular number; Tb.Th*, trabecular thickness; Tb.Sp*, trabecular spacing; Nb.Ob/T.Ar, osteoblast number over trabecular area; BFR, bone formation rate; OcS/BS, osteoclast surface over bone surface.All values are expressed as means ± SEM. * means the parameter is measured without a plate or rod model assumption, # p < 0.05 vs sham and ◇ p < 0.05 vs OVX (Veh).
Mentions: The rat is the rodent model of choice for post–menopausal osteoporosis and intermittent injections of parathyroid hormone (PTH), the standard to which any novel bone anabolic agent must be compared 10. Hence, we ovariectomized rats at 12 weeks of age and left them untreated for 3 or 12 more weeks so that they develop a severe osteopenia (Fig. 3 and Supplementary Fig. 5). Sham–operated or ovariectomized rats were then treated for 4 weeks with either vehicle, a relatively high dose of PTH (80 μg per kg per day, subcutaneous)11, or increasing amounts of LP533401 (25, 100 or 250 mg per kg per day, orally).

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