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

Osteoclasts are bone-resorbing cells derived from haematopoietic precursors of the monocyte-macrophage lineage. Mice lacking Fos (encoding c-Fos) deve lop osteopetrosis due to an early differentiation block in the osteoclast l ineage(1-3), c-Fos is a component of the dimeric transcription factor activ ator 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 b y Fos/1), c-Fos contains transactivation domains required for oncogenesis a nd cellular transformation(4-6). The mechanism by which c-Fos exerts its sp ecific function in osteoclast differentiation is not understood. Here we sh ow by retroviral-gene transfer that all four Fos proteins, hut not the Jun proteins, rescue the differentiation block in vitro. Structure-function ana lysis demonstrated that the major carboxy-terminal transactivation domains of c-Fos and FosB are dispensable and that Fra-1 (which lacks transactivati on domains(4,7)) has the highest rescue activity. Moreover, a transgene exp ressing Fra-1 rescues the osteopetrosis of c-fos-mutant mice in vivo. The o steoclast differentiation factor Rankl (also known as TRANCE, CUE and OPGL; refs 8-11) induces transcription of Fos/1 in a c-fos-dependent manner, the reby establishing a link between Rank signalling and the expression of Ap-1 proteins in osteoclast differentiation.