Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation

Abstract

Osteoclasts are bone-resorbing cells derived from haematopoietic precursors of the monocyte-macrophage lineage. Mice lacking Fos (encoding c-Fos) develop osteopetrosis due to an early differentiation block in the osteoclast lineage. c-Fos is a component of the dimeric transcription factor activator protein-1 (Ap-1), which is composed mainly of Fos (c-Fos, FosB, Fra-1 and Fra-2) and Jun proteins (c-Jun, JunB and JunD). Unlike Fra-1 (encoded by Fosl1), c-Fos contains transactivation domains required for oncogenesis and cellular transformation. The mechanism by which c-Fos exerts its specific function in osteoclast differentiation is not understood. Here we show by retroviral-gene transfer that all four Fos proteins, but not the Jun proteins, rescue the differentiation block in vitro. Structure-function analysis demonstrated that the major carboxy-terminal transactivation domains of c-Fos and FosB are dispensable and that Fra-1 (which lacks transactivation domains) has the highest rescue activity. Moreover, a transgene expressing Fra-1 rescues the osteopetrosis of c-Fos-mutant mice in vivo. The osteoclast differentiation factor Rankl (also known as TRANCE, ODF and OPGL; refs 8-11) induces transcription of Fosl1 in a c-Fos-dependent manner, thereby establishing a link between Rank signalling and the expression of Ap-1 proteins in osteoclast differentiation.

Molecular Understanding of Osteoclast Differentiation and Physiology

“…Activation of NFATc1 as well as c-Fos by RANKL signaling requires expression of NF-κB p50 and p52, indicating that c-Fos and NFATc1 are downstream of NF-κB [45,47,50]. In addition, NFATc1 seems to be activated by osteoblasts through a Ca 2+ oscillation-independent signal pathway during osteoclastogenesis and this clearly differs from that seen during RANKL/M-CSF-induced osteoclastogenesis [57].…”

“…The lack of Fos (encoding c-Fos) causes a lineage shift between osteoclasts and macrophages that results in increased numbers of bone marrow macrophages [44]. Fosl1 (encoding Fra-1) appears to be a transcriptional target of c-Fos since a transgene expressing Fra-1, a member of Fos proteins (c-Fos, FosB, Fra-1, Fra-2), rescues c-Fos-mutant mice from osteopetrosis in vivo [45]. Moreover, the rescue is both gene-dosage dependent and bone-development-specific [46].…”

Role of the Fos family members, c-Fos, Fra-1 and Fra-2, in the regulation of cell motility

“…Since the effects of Fra-1 and Fra-2 on cell motility differ in different cell lines, it is possible that these proteins dimerize with different transcription factors binding to various enhancers of target genes. The importance of the interaction of Fra-1 with the Jun proteins is confirmed by the fact that a transgene expressing Fra-1 rescues osteoclast differentiation which otherwise is compromised in vivo in mice lacking c-Fos (Matsuo et al, 2000).…”

AP-1 mediated retinal photoreceptor apoptosis is independent of N-terminal phosphorylation of c-Jun

“…53 In contrast to c-Fos, however, Fra-1 does not have a known transactivation domain. 54 Our results suggest that not AP-1 mediated activation but rather AP-1 dependent repression of target genes might be of importance during light-induced photoreceptor apoptosis. Future experiments are designed to test this hypothesis.>…”