Molecular stress-inducing compounds increase osteoclast formation in a heat shock factor 1 protein-dependent manner

Ryan Chau Chia Chai, Michelle Maria Kouspou, Benjamin James Lang, Chau Hoang Nguyen, Amanda Gabrielle van der Kraan, Jessica Louise Vieusseux, Reece Chih Chian Lim, Matthew T Gillespie, Ivor J Bnejamin, Julian Michael Warner Quinn, John Timothy Price

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8 Citations (Scopus)

Abstract

Many anti-cancer therapeutic agents cause bone loss that increase the risk of fractures that severely reduce quality of life. In drug development it is thus critical to identify and understand such effects. Anti-cancer 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, while 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 over-expression of Hsf1 enhanced 17-AAG effects upon osteoclast formation. Consistent with these findings, protein levels of the essential osteoclast transcription factor MITF 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 through 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.
Original languageEnglish
Pages (from-to)13602 - 13614
Number of pages13
JournalThe Journal of Biological Chemistry
Volume289
Issue number19
DOIs
Publication statusPublished - 2014

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