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Molecular stress-inducing compounds increase osteoclast formation in a heat shock factor 1 protein-dependent manner. J Biol Chem 2014 May 09;289(19):13602-14

Date

04/03/2014

Pubmed ID

24692538

Pubmed Central ID

PMC4036365

DOI

10.1074/jbc.M113.530626

Scopus ID

2-s2.0-84900416874   8 Citations

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.

Author List

Chai RC, Kouspou MM, Lang BJ, Nguyen CH, van der Kraan AG, Vieusseux JL, Lim RC, Gillespie MT, Benjamin IJ, Quinn JM, Price JT

Author

Ivor J. Benjamin MD Center Director, Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Benzoquinones
Bone Resorption
Cell Differentiation
Cell Line
DNA-Binding Proteins
HSP90 Heat-Shock Proteins
Heat Shock Transcription Factors
Lactams, Macrocyclic
Mice
Mice, Inbred BALB C
Mice, Knockout
Microphthalmia-Associated Transcription Factor
Osteoclasts
Stress, Physiological
Transcription Factors
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a