CSF-1 induces fos gene transcription and activates the transcription factor Elk-1 in mature osteoclasts.
Mice with targeted deletion of the fos gene fail to develop mature osteoclasts, reflecting an absolute requirement for the c-Fos proto-oncogene in osteoclast precursors. C-Fos is also expressed in mature osteoclasts; however, the regulation of fos in these cells has not been studied. By using cultured murine osteoclast-like cells (OCLs) we found that treatment with colony-stimulation factor 1 (CSF-1) induced a 3.9-fold increase in c-Fos rnRNA at 30 minutes and a 2.6-fold increase at 60 minutes. With use of mature osteoclasts isolated from transgenic mice expressing the bacterial Lac-Z gene under the control of the murine fos promoter, we were able to directly demonstrate transcriptional activation of fos by CSF-1 in these cells. Transcriptional activation was 2.6-fold greater at 5 minutes and 2.8-fold greater at 15 minutes in CSF-1-treated cells than in vehicle-treated cells. CSF-1 induced nuclear protein binding to the fos serum response element that was significantly attenuated by antibodies to the transcription factor Elk-1 but not by Sap-1a. Treatment of mature osteoclasts with CSF-1 for 2 hours resulted in a significant increase in the levels of nuclear c-Fos protein. These data demonstrate that CSF-1 upregulates c-fos expression in mature osteoclasts at least in part via transcriptional activation of fos. CSF-1 induced binding of Elk-1 to the fos gene serum response element appears to be part of the molecular mechanism by which this occurs.
Yao
G-Q
GQ
Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520-8020, USA. gang-qing.yao@yale.edu
Itokawa
T
T
Paliwal
I
I
Insogna
K
K
D000818:Animals; D000831:Animals, Newborn; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D016762:Genes, fos; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects; D050807:ets-Domain Protein Elk-1
D004268:DNA-Binding Proteins; C494113:Elk1 protein, mouse; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D016173:Macrophage Colony-Stimulating Factor