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MITF and PU.1 recruit p38 MAPK and NFATc1 to target genes during osteoclast differentiation

Sudarshana M Sharma1, Agnieszka Bronisz, Rong Hu

  • 1Department of Molecular and Cellular Biochemistry and the Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.

The Journal of Biological Chemistry
|April 4, 2007
PubMed

Insights

Transcription factors MITF and PU.1 initiate gene expression during osteoclast differentiation by integrating CSF-1/RANKL signals. NFATc1 involvement later helps maintain this expression in mature cells.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Osteoclast differentiation is crucial for bone remodeling.
  • Signaling pathways involving CSF-1 and RANKL are key regulators.
  • The precise roles and timing of transcription factors like MITF, PU.1, and NFATc1 are not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms and timing of transcription factor involvement in CSF-1 and RANKL signaling during osteoclast differentiation.
  • To define the roles of MITF, PU.1, and NFATc1 in regulating target gene expression.

Main Methods:

  • Utilized bone marrow-derived precursors.
  • Investigated transcription factor complex assembly and gene promoter binding.
  • Analyzed MAPK phosphorylation and chromatin remodeling complex recruitment.
  • Employed genetic analysis in mouse models (Mitf and Pu.1).

Main Results:

  • CSF-1 alone promoted MITF-PU.1 complex assembly at target promoters without inducing expression.
  • Combined RANKL and CSF-1 increased MAPK-phosphorylated MITF, p38 MAPK, SWI/SNF complexes, and gene expression.
  • NFATc1 was recruited later in differentiation to maintain gene expression.
  • Genetic studies confirmed the essential roles of Mitf and Pu.1.

Conclusions:

  • MITF and PU.1 act as early nuclear effectors integrating CSF-1/RANKL signals to initiate osteoclast target gene expression.
  • NFATc1-containing complexes likely maintain target gene expression in terminally differentiated osteoclasts.

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