title: Molecular stress-inducing compounds increase osteoclast formation in a heat shock factor 1 protein-dependent manner.
abstract: Many anticancer therapeutic agents cause bone loss, which increases the risk of fractures that severely reduce quality of life. Thus, in drug development, it is critical to identify and understand such effects. Anticancer therapeutic and HSP90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) causes bone loss by increasing osteoclast formation, but the mechanism underlying this is not understood. 17-AAG activates heat shock factor 1 (Hsf1), the master transcriptional regulator of heat shock/cell stress responses, which may be involved in this negative action of 17-AAG upon bone. Using mouse bone marrow and RAW264.7 osteoclast differentiation models we found that HSP90 inhibitors that induced a heat shock response also enhanced osteoclast formation, whereas HSP90 inhibitors that did not (including coumermycin A1 and novobiocin) did not affect osteoclast formation. Pharmacological inhibition or shRNAmir knockdown of Hsf1 in RAW264.7 cells as well as the use of Hsf1 null mouse bone marrow cells demonstrated that 17-AAG-enhanced osteoclast formation was Hsf1-dependent. Moreover, ectopic overexpression of Hsf1 enhanced 17-AAG effects upon osteoclast formation. Consistent with these findings, protein levels of the essential osteoclast transcription factor microphthalmia-associated transcription factor were increased by 17-AAG in an Hsf1-dependent manner. In addition to HSP90 inhibitors, we also identified that other agents that induced cellular stress, such as ethanol, doxorubicin, and methotrexate, also directly increased osteoclast formation, potentially in an Hsf1-dependent manner. These results, therefore, indicate that cellular stress can enhance osteoclast differentiation via Hsf1-dependent mechanisms and may significantly contribute to pathological and therapeutic related bone loss.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Chai
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Kouspou
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Lang
authors.forename: Chau H
authors.initials: CH
authors.lastname: Nguyen
authors.forename: A Gabrielle J
authors.initials: AG
authors.lastname: van der Kraan
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Vieusseux
authors.forename: Reece C
authors.initials: RC
authors.lastname: Lim
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Gillespie
authors.forename: Ivor J
authors.initials: IJ
authors.lastname: Benjamin
authors.forename: Julian M W
authors.initials: JM
authors.lastname: Quinn
authors.forename: John T
authors.initials: JT
authors.lastname: Price
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000009:adverse effects / Q000494:pharmacology*; D001862:Bone Resorption / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D047029:Lactams, Macrocyclic / Q000009:adverse effects / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D013312:Stress, Physiological / Q000187:drug effects* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D047029:Lactams, Macrocyclic; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D014157:Transcription Factors; C112765:tanespimycin
keywords: Bone; Cell Stress; Chemotherapy; HSF1; HSP90; HSP90 Inhibitors; Heat Shock Protein; Osteoclast; Stress Response