CSF-1 Induces fos Gene Transcription and Activates the Transcription Factor Elk-1 in Mature Osteoclasts

Abstract

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.

M-CSF Potently Augments RANKL-Induced Resorption Activation in Mature Human Osteoclasts

“…Yao et al [35] have previously shown that M-CSF treatment of mature mouse OCs results in increased c-fos expression and transcriptional activation [35]. The key role of c-fos in OC differentiation is well established [36], [37].…”

The Transcription Factor T-box 3 Regulates Colony-stimulating Factor 1-dependent Jun Dimerization Protein 2 Expression and Plays an Important Role in Osteoclastogenesis

“…Whether the genetic absence of JDP2 also results in impaired function of mature osteoclasts requires further investigation, but we found that JDP2 expression was high in mature osteoclasts. Because we have reported that CSF1 subserves a variety of important functions in mature osteoclasts (7,15,46), it is possible that one function of this cytokine is to maintain expression of JDP2 in mature osteoclasts.…”

“…The regulation of these factors by RANKL has been studied, but whether CSF1 regulates the expression of transcription factors important for osteoclast differentiation is unclear, although we have previously reported that CSF1 transcriptionally increases c-Fos expression in mature osteoclasts (7). Jun dimerization protein 2 (JDP2), a member of the AP-1 transcription factor family, was first identified as a binding partner of c-Jun in a yeast twohybrid screen (8).…”

Correlation between the Expression of c-Fos and Osteoclasts in Induced Periapical Lesions in Rats

“…Osteoclasts are specialized cells derived from the monocyte/macrophage hematopoietic lineage that degrade the bone matrix (12,13). Numerous studies have demonstrated the roles of c-Fos in induction of osteoclastogenesis by targeting the transcription of Fos family and NFATc1 genes in RANKL signaling (8,14).…”