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HSP90 inhibitors enhance differentiation and MITF (microphthalmia transcription factor) activity in osteoclast

A Gabrielle J van der Kraan1, Ryan C C Chai, Preetinder P Singh

  • 1Prince Henry's Institute, Monash Medical Centre, Clayton, VIC 3168, Australia.

The Biochemical Journal
|February 6, 2013
PubMed

Insights

Heat-shock protein 90 (HSP90) inhibitors like 17-AAG promote osteoclast differentiation. This process involves microphthalmia-associated transcription factor (MITF) and is independent of NFATc1 signaling.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • Heat-shock protein 90 (HSP90) inhibitors, such as 17-allylamino-demethoxygeldanamycin (17-AAG), are known to influence cellular processes.
  • 17-AAG has been observed to increase osteoclast formation, potentially impacting cancer progression in bone.
  • The precise cellular mechanisms underlying 17-AAG's effect on osteoclasts remain unclear.

Purpose of the Study:

  • To elucidate the cellular mechanisms by which 17-AAG enhances osteoclast formation.
  • To investigate whether other HSP90 inhibitors share similar osteoclast-promoting properties.
  • To determine the specific signaling pathways involved in 17-AAG-mediated osteoclastogenesis.

Main Methods:

  • Dose-dependent assessment of HSP90 inhibitors (17-AAG, CCT018159, NVP-AUY922) on osteoclastogenesis in mouse bone marrow and RAW264.7 cell cultures stimulated with RANKL.
  • Evaluation of 17-AAG's effect on RANKL- and TNF-induced osteoclastogenesis and osteoclast survival.
  • Analysis of intracellular signaling pathways, including c-Fos, NFATc1, NF-κB, and MITF, in response to 17-AAG treatment.

Main Results:

  • 17-AAG, CCT018159, and NVP-AUY922 dose-dependently increased RANKL-stimulated osteoclastogenesis.
  • 17-AAG enhanced RANKL- and TNF-induced osteoclastogenesis but did not affect osteoclast survival, indicating a focus on differentiation.
  • 17-AAG treatment elevated microphthalmia-associated transcription factor (MITF) protein levels and MITF-dependent vATPase-d2 gene promoter activity, independent of NFATc1 signaling.

Conclusions:

  • HSP90 inhibitors enhance osteoclast differentiation through a mechanism involving increased MITF levels and activity.
  • This osteoclast differentiation enhancement by HSP90 inhibitors is independent of NFATc1 signaling.
  • The findings clarify the cellular actions of 17-AAG and suggest a novel pathway for modulating osteoclastogenesis relevant to bone microenvironment and cancer progression.

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