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- W2022073329 abstract "Prostaglandin estradiol (PGE2) stimulates bone resorption by a cyclic AMP (cAMP)-dependent mechanism that involves prostaglandin E receptors of the EP2 and EP4 subtypes. We tested a potent selective EP4 antagonist (EP4RA), which blocks PGE2 binding to EP4 receptors. We examined the effects of EP4RA on osteoclastogenesis in murine marrow cultures, on cAMP production in primary osteoblastic (POb) cell cultures, and on bone resorption in organ cultures. EP4RA (1 μmol/L) decreased the number of tartrate-resistant acid phosphatase-positive multinucleated cells (TRAP+ MNC) by 46%–48% in cultures treated with 0.1–1.0 μmol/L PGE2 and by 96% in cultures treated with 0.01 μmol/L PGE2. EP4RA also decreased TRAP+ MNC formation by 60% in 1,25-dihydroxyvitamin D (1,25D)-treated cultures and by 62% in parathyroid hormone (PTH)-treated cultures. A chemically related analog of EP4RA that lacks antagonist activity did not inhibit TRAP+ MNC formation. EP4RA decreased cAMP production in PGE2-treated POb by 44% but did not block cAMP response to PTH. EP4RA inhibited the increase in receptor activator of NF-κB ligand (RANKL) mRNA levels produced by PGE2. In fetal rat long bone cultures, EP4RA decreased 45Ca release from control, unstimulated cultures by 12%–25% and from PGE2-stimulated cultures by 22%–37%. Because EP4RA partially inhibited osteoclastogenesis not only in response to PGE2 but also in response to 1,25D and PTH, these results suggest that activation of the EP4 receptor may play a general role in osteoclastic bone resorption. EP4RA showed partial inhibition of PGE2-stimulated osteoclastogenesis at 1 μmol/L, but almost complete inhibition at 0.01 μmol/L PGE2. This could be due to the limited efficacy of the antagonist at high concentrations of PGE2, or an alternative pathway, such as activation of the EP2 receptor." @default.
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- W2022073329 date "1995-09-01" @default.
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- W2022073329 title "Tiludronate tablet (Skelid®) 400mg/d produces lengthy clinical remission of Paget's disease: follow up of a dose ranging study" @default.
- W2022073329 doi "https://doi.org/10.1016/8756-3282(95)97381-o" @default.
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