title: IL-1alpha stimulation of osteoclast survival through the PI 3-kinase/Akt and ERK pathways.
abstract: Osteoclasts, cells that resorb bone, die once fully differentiated. Several factors including interleukin-1 (IL-1) have been shown to regulate the survival of mature osteoclasts. However, information on the mechanism underlying the regulation of osteoclast survival has been limited. In this study, we investigated the mechanism for the IL-1-stimulated survival of osteoclasts. Treatment of purified osteoclasts with IL-1alpha led to activation of the serine-threonine kinases Akt and ERK. Blocking the activation of Akt with LY294002, a specific inhibitor of the Akt up-stream molecule PI 3-kinase, or an with adenoviral vector for a dominant-negative form of Akt prevented the stimulation of osteoclast survival by IL-1alpha. PD98059, a specific inhibitor of the ERK-activating kinase MEK1, also abolished the effects of IL-1alpha on ERK activation and osteoclast survival. IL-1alpha reduced the apoptosis of osteoclasts by reducing caspase 3 activity. The IL-1alpha-mediated suppression of apoptosis was abolished by the PI 3-kinase/Akt or MEK1/ERK pathway inhibitor. These findings implicate the PI 3-kinase/Akt and ERK signaling pathways in the promotion of osteoclast survival by IL-1alpha.
authors.affiliation: National Research Laboratory for Bone Metabolism, Research Center for Proteineous Materials, and School of Dentistry, Chosun University, Gwangju, Korea.
authors.forename: Zang Hee
authors.initials: ZH
authors.lastname: Lee
authors.forename: Shee Eun
authors.initials: SE
authors.lastname: Lee
authors.forename: Chang-Woo
authors.initials: CW
authors.lastname: Kim
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Si Wouk
authors.initials: SW
authors.lastname: Kim
authors.forename: KyuBum
authors.initials: K
authors.lastname: Kwack
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology
chemical_list: D002867:Chromones; D005419:Flavonoids; D007375:Interleukin-1; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one