Biology Reference
In-Depth Information
explores the effects of PDE inhibition and increases in cGMP and cAMP on mono-
cytic differentiation into osteoclasts, dendritic cells, and macrophages.
Keywords Bone-marrow derived macrophage
Dendritic cell
Macrophage
Monocyte
Osteoclast
1
Introduction
Monocytes are circulating peripheral immune cells that can differentiate into a
number of cell types including macrophages, dendritic cells, and osteoclasts upon
exposure to various cytokines (see Fig.
1
). The phenotypes of these differentiated
cells are highly heterogeneous and their differentiation can be affected by the cyclic
nucleotides, 3
0
-5
0
-cyclic adenosine monophosphate (cAMP) and 3
0
-5
0
-cyclic gua-
nosine monophosphate (cGMP). The intracellular levels of cAMP and cGMP are
controlled through regulation of production by adenylyl and guanylyl cyclases and
through degradation by cyclic nucleotide phosphodiesterases (PDEs).
Eleven different families of PDEs have been identified, and these enzymes differ
in their cellular and tissue expression, substrate specificity, kinetics, modes of
regulation, and sensitivity to inhibitors (Bender and Beavo
2006a
). These PDEs
have emerged as well-validated drug targets especially with the success of the
PDE5 inhibitors Cialis, Viagra, and Levitra for the treatment of erectile dysfunction
and more recently for pulmonary hypertension. In addition, several other classes of
Fig. 1 Hematopoietic differentiation. Differentiation of multiple cell types from a common
progenitor cell can be accomplished through their exposure to the appropriate cytokines at various
stages of differentiation. Abbreviations:
HSC
Hematopoietic stem cell,
CFU
colony-forming unit,
RANKL
Receptor Activator for Nuclear Factor
k
B Ligand
