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Blood, 1 November 2001, Vol. 98, No. 9, pp. 2707-2713
HEMATOPOIESIS
FLT3 ligand can substitute for macrophage colony-stimulating
factor in support of osteoclast differentiation and
function
Jeny Maree Lean,
Karen Fuller, and
Timothy John Chambers
From the Department of Cellular Pathology, St George's
Hospital Medical School, London, United Kingdom.
Although bone resorption and osteoclast numbers are reduced in
osteopetrotic (op/op) mice, osteoclasts are nevertheless present and
functional, despite the absence of macrophage colony-stimulating factor
(M-CSF). This suggests that alternative factors can partly compensate
for the crucial actions of M-CSF in osteoclast induction. It was found
that when nonadherent bone marrow cells were incubated in RANKL with
Flt3 ligand (FL) without exogenous M-CSF, tartrate-resistance acid
phosphatase (TRAP)-positive cells were formed, and bone resorption occurred. Without FL, only macrophagelike TRAP-negative cells were
present. Granulocyte-macrophage CSF, stem cell factor, interleukin-3, and vascular endothelial growth factor could not similarly replace the
need for M-CSF. TRAP-positive cell induction in FL was not due to
synergy with M-CSF produced by the bone marrow cells themselves because
FL also enabled their formation from the hemopoietic cells of op/op
mice, which lack any M-CSF. FL appeared to substitute for M-CSF by
supporting the differentiation of adherent cells that express mRNA for
RANK and responsiveness to RANKL. To determine whether FL can account
for the compensation for M-CSF deficiency that occurs in vivo, FL
signaling was blockaded in op/op mice by the injection of soluble
recombinant Flt3. It was found that the soluble receptor induced a
substantial decrease in osteoclast number, strongly suggesting that FL
is responsible for the partial compensation for M-CSF deficiency that
occurs in these mice.
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