JTT-305, an orally active calcium-sensing receptor antagonist, stimulates transient parathyroid hormone release and bone formation in ovariectomized rats
| Autor: | Mikio Hayashi, Yuji Ishida, Takashi Nakagawa, Yoshihisa Okamoto, Yushi Matsuo, Shuichi Kimura |
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| Rok vydání: | 2011 |
| Předmět: |
medicine.medical_specialty
Anabolism Ovariectomy Osteoporosis Parathyroid hormone Administration Oral Benzoates Anabolic Agents Propanolamines Rats Sprague-Dawley Osteogenesis Internal medicine Chlorocebus aethiops medicine Animals Humans Pharmacology Bone mineral Chemistry Parathyroid chief cell medicine.disease Recombinant Proteins Rats Endocrinology Parathyroid Hormone COS Cells Ovariectomized rat Female Calcium-sensing receptor Receptors Calcium-Sensing hormones hormone substitutes and hormone antagonists |
| Zdroj: | European journal of pharmacology. 668(1-2) |
| ISSN: | 1879-0712 |
| Popis: | Intermittent administration of parathyroid hormone (PTH) has a potent anabolic effect on bone in humans and animals. Calcium-sensing receptor (CaSR) antagonists stimulate endogenous PTH secretion through CaSR on the surface of parathyroid cells and thereby may be anabolic agents for osteoporosis. JTT-305 is a potent oral short-acting CaSR antagonist and transiently stimulates endogenous PTH secretion. The objective of the present study was to investigate the effects of JTT-305 on PTH secretion and bone in ovariectomized rats. Female rats, immediately after ovariectomy (OVX), were orally administered vehicle or JTT-305 (0.3, 1, or 3 mg/kg) for 12 weeks. The serum PTH concentrations were transiently elevated with increasing doses of JTT-305. In the proximal tibia, JTT-305 prevented OVX-induced decreases in both the cancellous and total bone mineral density (BMD) except for the 0.3mg/kg dose. At the 3mg/kg dose, JTT-305 increased the mineralizing surface and bone formation rate in histomorphometry. The efficacy of JTT-305 at the 3mg/kg dose on the BMD corresponded to that of exogenous rat PTH1-84 injection at doses between 3 and 10 μg/kg. In conclusion, JTT-305 stimulated endogenous transient PTH secretion and bone formation, and consequently prevented bone loss in OVX rats. These results suggest that JTT-305 is orally active and has the potential to be an anabolic agent for the treatment of osteoporosis. |
| Databáze: | OpenAIRE |
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