title: Protein kinase C inhibitor, GF109203X attenuates osteoclastogenesis, bone resorption and RANKL-induced NF-κB and NFAT activity.
abstract: Osteolytic bone diseases are characterized by excessive osteoclast formation and activation. Protein kinase C (PKC)-dependent pathways regulate cell growth, differentiation and apoptosis in many cellular systems, and have been implicated in cancer development and osteoclast formation. A number of PKC inhibitors with anti-cancer properties have been developed, but whether they might also influence osteolysis (a common complication of bone invading cancers) is unclear. We studied the effects of the PKC inhibitor compound, GF109203X on osteoclast formation and activity, processes driven by receptor activator of NFκB ligand (RANKL). We found that GF109203X strongly and dose dependently suppresses osteoclastogenesis and osteoclast activity in RANKL-treated primary mouse bone marrow cells. Consistent with this GF109203X reduced expression of key osteoclastic genes, including cathepsin K, calcitonin receptor, tartrate resistant acid phosphatase (TRAP) and the proton pump subunit V-ATPase-d2 in RANKL-treated primary mouse bone marrow cells. Expression of these proteins is dependent upon RANKL-induced NF-κB and NFAT transcription factor actions; both were reduced in osteoclast progenitor populations by GF109203X treatment, notably NFATc1 levels. Furthermore, we showed that GF109203X inhibits RANKL-induced calcium oscillation. Together, this study shows GF109203X may block osteoclast functions, suggesting that pharmacological blockade of PKC-dependent pathways has therapeutic potential in osteolytic diseases.
authors.affiliation: Department of Orthopaedic Surgery, Research Centre for Regenerative Medicine, The First Affiliated Hospital of Guangxi Medical University, Guangxi, China; School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, Western Australia, Australia.
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.forename: Jianwen
authors.initials: J
authors.lastname: Cheng
authors.forename: Shek Man
authors.initials: SM
authors.lastname: Chim
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Julian M W
authors.initials: JM
authors.lastname: Quinn
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tickner
authors.forename: Jinmin
authors.initials: J
authors.lastname: Zhao
authors.forename: Jiake
authors.initials: J
authors.lastname: Xu
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D007211:Indoles / Q000494:pharmacology*; D008301:Maleimides / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D053245:RANK Ligand / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007211:Indoles; D008301:Maleimides; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D047428:Protein Kinase Inhibitors; D053245:RANK Ligand; D011493:Protein Kinase C; C070515:bisindolylmaleimide I