title: The Proteasome Inhibitor Carfilzomib Suppresses Parathyroid Hormone-induced Osteoclastogenesis through a RANKL-mediated Signaling Pathway.
abstract: Parathyroid hormone (PTH) induces osteoclast formation and activity by increasing the ratio of RANKL/OPG in osteoblasts. The proteasome inhibitor carfilzomib (CFZ) has been used as an effective therapy for multiple myeloma via the inhibition of pathologic bone destruction. However, the effect of combination of PTH and CFZ on osteoclastogenesis is unknown. We now report that CFZ inhibits PTH-induced RANKL expression and secretion without affecting PTH inhibition of OPG expression, and it does so by blocking HDAC4 proteasomal degradation in osteoblasts. Furthermore, we used different types of culture systems, including co-culture, indirect co-culture, and transactivation, to assess the effect of CFZ on PTH action to induce osteoclastogenesis. Our results demonstrated that CFZ blocks PTH-induced osteoclast formation and bone resorption by its additional effect to inhibit RANKL-mediated IκB degradation and NF-κB activation in osteoclasts. This study showed for the first time that CFZ targets both osteoblasts and osteoclasts to suppress PTH-induced osteoclast differentiation and bone resorption. These findings warrant further investigation of this novel combination in animal models of osteoporosis and in patients.
authors.affiliation: From the Center for Translational Medicine, Departments of Medicine and.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Yang
authors.affiliation: the Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania 15240, and Departments of Pathology and of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
authors.forename: Harry C
authors.initials: HC
authors.lastname: Blair
authors.affiliation: Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Irving M
authors.initials: IM
authors.lastname: Shapiro
authors.affiliation: From the Center for Translational Medicine, Departments of Medicine and bin.wang@jefferson.edu.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D010281:Parathyroid Hormone / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016328:NF-kappa B; D009842:Oligopeptides; D053244:Osteoprotegerin; D010281:Parathyroid Hormone; D061988:Proteasome Inhibitors; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505689:Tnfsf11 protein, mouse; C524865:carfilzomib
keywords: NF-kappa B (NF-KB); bone; osteoblast; osteoclast; rankl; receptor