Blood, 15 April 2003, Vol. 101, No. 8, pp. 2903-2903
`Les cytokinès responsables' in osteosclerosis
and myelofibrosis
Myelofibrosis with myeloid metaplasia (MMM) is a clonal stem
cell disease that is associated with distinct bone marrow histologic changes that include myelofibrosis, osteosclerosis, and angiogenesis. Chagraoui and colleagues have recently demonstrated, using a
combination of blood cell transplantation and gene knockout
experiments, the essential role of blood cell-derived transforming
growth factor beta 1 (TGF-
1) in the development of myelofibrosis in
thrombopoietin (TPO)-induced MMM-like disease in mice (Blood.
2002;100:3495-3503). In the current issue (page 2973), the same
group of investigators, using a similar experimental design, address
the mechanism of osteosclerosis in the aforementioned animal model of
MMM. The protein of focus this time was osteoprotegerin (OPG), a known inhibitor of bone resorption.
Osteoclast differentiation and activation is facilitated by the
receptor-ligand interaction between RANK (receptor activator of
NF-
B) and RANK ligand (RANKL). OPG, secreted by bone marrow stromal
cells and osteoblasts, is a decoy receptor of RANKL and thus interferes
with RANK-RANKL binding with the net result of impaired bone
resorption. The study mice in the current report included both
wild-type and mutant (OPG
//OPG/)
recipient-donor pairs in different combinations. The results suggest
that the presence of an intact OPG gene in bone marrow stroma, but not
in blood cells, was imperative for the development of TPO-induced
osteosclerosis in mice. Additional experiments suggested that stromal
OPG up-regulation may not be mediated by TGF-1.
The current study is one of a series of elegant experiments by
the above mentioned group from France concerning the pathogenesis of
MMM. The aforementioned set of findings are consistent with existing
circumstantial evidence that implicates TGF-1 and related cytokines,
derived from clonal megakaryocytes/monocytes, as having either a direct
or an indirect (via up-regulation of stromal OPG and possibly other
secreted molecules) influence on the bone marrow microenvironment in
MMM. The study raises additional questions including the identity and
source of the cytokine responsible for stromal OPG up-regulation and
other biologic effects of interference with the RANK-RANKL interaction
in MMM. Nevertheless, the availability of such information as well
as suitable animal models should allow the development of
pathogenesis-targeted therapeutic activities including pharmacologic
manipulation of the OPG-RANKL-RANK axis.
Ayalew Tefferi
Mayo
Clinic
