Biology Reference
In-Depth Information
a model of osteoporosis in rats (Miyamoto et al.
1997
) and increased bone density
in ovarectomized, neurectomized rats (Waki et al.
1999
).
One report regarding cGMP and osteoclastogenesis suggests that cGMP can
block the differentiation of osteoclasts, but only when present during the final
3 days of a 6-day differentiation process (Holliday et al.
1997
). As there has been
some debate as to the pathways used for intracellular signaling by nitric oxide, both
nitric oxide releasers such as sodium nitroprusside, used at low concentrations, and
the cGMP analogues 8-Br-cGMP and dibutryl-cGMP, were used to demonstrate
reduced osteoclast formation in the presence of elevated cGMP. Elevating cGMP
using an inhibitor of PDE5, zaprinast, also inhibited osteoclast formation when
administered through the final 3 days of differentiation, while decreasing cGMP
using nitric oxide synthase inhibitors increased osteoclast formation. It was con-
cluded that elevated cGMP inhibits osteoclast formation, but only when present
during the final stages of differentiation.
5 Murine Bone Marrow Differentiation
Bone marrow progenitors can be differentiated to macrophages in the presence of a
number of factors, such as M-CSF, GM-CSF, and PMA. It has long been observed
that agents that can elevate cAMP can inhibit macrophage formation from progeni-
tors. M-CSF can also induce proliferation of differentiated bone marrow macro-
phages, and PGE
2
negatively regulates this process (Kurland et al.
1977
,
1978a
,
b
).
Several agents that can increase cAMP, such as PGE
2
, 8-Br-cAMP, and IBMX, can
suppress the mitogenic actions of M-CSF, GM-CSF, and PMA through the inhibi-
tion of DNA synthesis. This effect of cAMP does not appear to affect the cells'
early response to colony-stimulating factors, but exerts its effect during the late G1
phase in the cell cycle (Vairo et al.
1990
). Inhibition by PGE
2
seems to be part of a
negative feedback loop controlling proliferation of monocytes and macrophages.
PGE
2
may feedback to control macrophage formation by inhibiting proliferation
and differentiation of immature monocytoid cells.
M-CSF-induced proliferation of mouse bone marrow macrophages is suppressed
by adenosine-mediated signaling through the G
a
s-coupled A
2B
receptors. The
downstream cAMP signaling mechanism involved a PKA-dependent induction of
a cyclin-dependent kinase inhibitor known as p27
kip-1
that leads to growth arrest at
the G1 phase of the cell cycle (Xaus et al.
1999
). This molecular mechanism could
potentially apply to the negative regulation of monocytic proliferation caused with
elevated cAMP, regardless of the source, but this has not been fully tested in all cell
systems. Using A
2B
knockout mice and pharmacological inhibition of adenosine
receptors several groups demonstrated that adenosine or ATP signaling through this
receptor inhibits TLR-dependent IL-12p70 and TNF-
a
production in bone marrow
derived DCs while enhancing IL-10 production (Addi Abduelhakem et al.
2008
;
Wilson et al.
2009
). These cells were also less effective at stimulating T-cell
proliferation, likely due to reduced MHC II and CD86 levels.
