Role of prostaglandin E produced by osteoblasts in osteolysis due to bone metastasis.
Prostaglandin E2 (PGE2) is produced in bone mainly by osteoblasts and stimulates bone resorption. Osteolytic bone metastasis of cancers is accompanied by bone resorption. In this study, we examined the roles of PGE2 in osteolysis due to bone metastasis of breast cancer. Injection of human breast cancer cells, MDA-MB-231 (MDA-231), into nude mice causes severe osteolysis in the femur and tibia. The expression of cyclo-oxygenase-2 (COX-2) and the receptor activator of NF-kappaB ligand (RANKL), a key molecule in osteoclast differentiation, mRNAs was markedly elevated in bone with metastasis. When MDA-231 cells were cocultured with mouse calvaria, COX-2-induced PGE2 production and bone resorption progressed. The contact with MDA-231 cells could induce the expression of COX-2 and RANKL in osteoblasts by mechanisms involving MAP kinase and NF-kappaB. The blockage of PGE2 signal by indomethacin and EP4 antagonist abrogated the osteoclast formation induced by the breast cancer cells. Here, we show a PGE-dependent mechanism of osteolysis due to bone metastasis.
Ohshiba
Tomoyasu
T
Department of Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Miyaura
Chisato
C
Ito
Akira
A
D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary*; D001862:Bone Resorption; D001943:Breast Neoplasms / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018920:Coculture Techniques; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010006:Osteoblasts / Q000378:metabolism*; D010014:Osteolysis / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D011458:Prostaglandins E / Q000378:metabolism*; D053245:RANK Ligand; D011859:Radiography; D053246:Receptor Activator of Nuclear Factor-kappa B; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction / Q000502:physiology; D012886:Skull / Q000166:cytology / Q000378:metabolism; D013977:Tibia / Q000000981:diagnostic imaging / Q000473:pathology; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C545650:PTGER4 protein, human; D011458:Prostaglandins E; C545651:Ptger4 protein, mouse; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse