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
lineage1,
2,
3. 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 transformation4,
5,
6. 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 domains4,
7) 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.
