Osteogenetic effects of KY-273, a diphenylether derivative, in mesenchymal stem cells and ovariectomized rats.
Proceedings for Annual Meeting of The Japanese Pharmacological Society(2022)
摘要
Orally used bisphosphonates, bone resorption inhibitors, and PTH and anti-sclerostin antibodies for injection, which are both bone formation stimulators, are used for osteoporosis therapy. Oral osteogenetic drugs are desired but have not yet been developed. KY-273 selectively inhibited CDK8/19, whereas siRNA-mediated knockdown of CDK8/19 promoted osteoblast differentiation in mesenchymal stem cells (ST2 cells), suggesting osteogenetic effects of KY-273. In ST2 cells, KY-273 increased the mRNA expression and enzyme activity of ALP, and induced osteoblast mineralization. In ovariectomized (OVX) rats, KY-273 (10 mg/kg/day, p.o.) for 12 weeks gradually increased the cortical bone volume, outer diameter, simulated bone strength and the medullary volume (MV) in femoral epiphysics and diaphysis. The effects of KY-273 were compared with those of alendronate, a bisphpsphonate, and teriparatide, a parathyroid hormone, in OVX rats. KY-273 at 3 and 10 mg/kg/day for 8 weeks dose-dependently increased the femur cortical bone volume, MV and simulated bone strength without affecting the trabecular bone volume, accompanied by an increase in blood ALP3, a bone formation marker. Alendronate (3 mg/kg/day, p.o.) markedly increased trabecular bone and slightly increased the cortical bone volume without affecting MV, whereas teriparatide (3 and 10 microgram/kg/day, s.c.) markedly increased both trabecular and cortical bone volumes with reducing MV. The present study revealed that KY-273 has therapeutic effects against osteoporosis via the promotion of bone formation, the characteristics of which are different from those of alendronate or teriparatide.
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关键词
osteogenetic effects,mesenchymal stem cells,diphenylether derivative
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