Biology Reference
In-Depth Information
In order for the cells to be responsive to PGE
2
levels, they must carry the
appropriate receptors. The prostaglandin receptors are EP1, 2, 3, and 4 coupled to
G
a
q, G
a
s, G
a
i, and G
a
s, respectively. The high level expression of the prostaglan-
din receptors EP2 and EP4 in precursor cells allows the cells to be responsive to
stimuli like PGE
2
and produce cAMP through adenylyl cyclase stimulation. Upon
differentiation, the prostaglandin receptors are downregulated, preventing the stim-
ulation or inhibition of the mature osteoclast by PGE
2
(Kobayashi et al.
2005b
;
Take et al.
2005
). If EP4 is reintroduced using an adenoviral transfection system,
osteoclastic function was drastically inhibited (Kobayashi et al.
2005b
). PGE
2
also
can directly inhibit bone resorbing function in mature OCs thru EP4 (Mano et al.
2000
) and an EP4 antagonist inhibited osteoclast formation (Ono et al.
1998
). EP1
and EP3 do not seem to play a major role in osteoclast formation because no
increase in osteoclast formation was observed with the administration of butaprost,
an EP1/3 agonist, while EP2-selective agonists slightly increase osteoclast forma-
tion (Ono et al.
1998
). The G
a
s-coupled prostaglandin receptors EP2 and EP4 seem
to have nonredundant roles in osteoclast formation as EP2 knockout mice exhibit
impaired osteoclast development, likely due to both a defect in the osteoblast and
having direct effects on PGE
2
-stimulated osteoclast function (Li et al.
2000
).
PDEs also play a role in controlling cAMP levels during differentiation of bone
marrow precursors to osteoclasts. Inhibition of PDE4 with rolipram indirectly
stimulates osteoclast formation through the ERK, p38, MAP kinase pathways by
leading to a change in COX2 expression in osteoblasts. Elevated COX2 expression
leads to an increase in PGE
2
, which in turn increased RANKL production by the
osteoblasts (Cho et al.
2004
; Park et al.
2007
; Takami et al.
2005
). PDE4 inhibi-
tion can also have effects directly on osteoclast formation from their precursors.
Yamagami and colleagues showed that when the PDE4 inhibitor XT-611 was added
to either a culture of bone marrow-derived osteoclastic precursors, or a coculture
with osteoblasts, osteoclast formation was blocked when given concomitantly with
PGE
2
. This effect seemed to be specific for PDE4 inhibition, as inhibition with
either a PDE3-selective inhibitor milrinone, or the cGMP-PDE inhibitor zaprinast,
had no effect on osteoclast differentiation in the presence of PGE
2
(Yamagami
et al.
2003
). In a similar study, it was found that both PDE3 and PDE4 inhibitors
had an effect on osteoclastic differentiation; however, these effects were largely on
the osteoblasts, not on the osteoclasts themselves (Noh et al.
2009
). PDE4 inhi-
bitors can also potentiate the effects of endogenous agonists such as calcitonin.
Calcitonin acts directly on osteoclasts to decrease osteoclastogenesis and this
process was found to be PKA dependent and rolipram potentiated these effects
(Miyamoto et al.
2006
).
PDE4 inhibitors as a therapeutic intervention for osteoporosis show some
promise based on animal models of osteopenia. Additionally, single-nucleotide
polymorphisms in the PDE4D gene have been shown to correlate with variations
in bone mineral density, possibly implicating PDE4D as a contributing genetic
factor in human osteoporosis (Reneland et al.
2005
). Both rolipram and pentoxifyl-
line were reported to increase bone density in normal mice after 5 weeks of
treatment (Kinoshita et al.
2000
). In rats, a PDE4 inhibitor decreased bone loss in
