Expression of RANK is dependent upon differentiation into the macrophage/osteoclast lineage: induction by 1α,25-dihydroxyvitamin D3 and TPA in a human myelomonocytic cell line, HL60
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Abstract
Receptor activator of nuclear factor (RANK) is a member of the tumor necrosis factor
receptor superfamily indispensable for osteoclast differentiation. However, little
is known about the regulatory mechanism of RANK expression. In the present study,
RANK expression during macrophage/osteoclast differentiation was investigated using
a human myelomonocytic cell line, HL60, capable of differentiating into mature osteoclasts
under appropriate conditions. RANK mRNA expression was barely detectable in growing
HL60 cells. We found that treatment with 1alpha,25-dihydroxyvitamin D(3) and TPA resulted
in an apparent induction of RANK mRNA and protein in association with differentiation
into the macrophage/osteoclast lineage. Induction of RANK was time and dose dependent
and lineage specific. Moreover, RANK induction was blocked by an RNA polymerase II
inhibitor, suggesting an involvement of a transcriptional mechanism. The induced RANK
was functional as it was able to bind RANK ligand and activate NF-kappaB. In the induced
HL60 cells expressing both c-Fms and RANK, RANK mRNA expression was further enhanced
by RANKL, but not by macrophage colony-stimulating factor. These results suggest a
positive feedback regulation of RANK expression by its own intracellular signaling.
The in vitro system described here may be a useful model to elucidate the regulatory
mechanism of RANK expression and its role in human osteoclastogenesis.