Cyclic Nucleotides and Phosphodiesterases in Monocytic Differentiation - Phosphodiesterases as Drug Targets - page 380

(IL-10, TGF- b ), and tolerogenic factors (indoleamine 2,3-dioxygenase) (Novitskiy
et al. 2008 ). Consequently, these cells are impaired in their ability to induce T-cell
proliferation, by rendering the T cells anergic with indoleamine 2,3-dioxygenase,
and also exhibited a reduced capacity for IFN- g production. As expected, these
phenotypic changes result in drastic alterations in the capacity of these cells to
respond properly to abnormalities or inflammatory stimuli. For example, if these
adenosine-differentiated DCs were injected directly into a subcutaneous tumor in
mice, they actually promoted tumor growth through increased angiogenesis in the
tumor, rather than resolving the abnormality (Novitskiy et al. 2008 ).
The role of the A 2B receptor in cAMP-mediated regulation of pathological
conditions and cell differentiation has been historically difficult to study due to
its low affinity for adenosine and other selective agonists. A 2B receptors are
stimulated by micromolar concentrations of adenosine, rather than the normal
physiological submicromolar levels commonly observed and associated with the
A 1 ,A 2A , and A 3 receptors. However, this low affinity may carry physiological
importance as high concentrations of adenosine are often found at the site of
traumatic injury, ischemia, or inflammation (Hask´ et al. 2009 ). Overall, DC
differentiation and maturation is retarded in the presence of elevated cyclic
nucleotides, and this results in altered phenotypic characteristics affecting many
key DC functions.
4 Osteoclast Differentiation
Osteoclasts are a unique cell type involved in calcium homeostasis in the body.
They perform this function through the resorption of bone in response to either
direct or indirect hormonal regulation by parathyroid hormone, calcitonin, and
1,25-dihydroxyvitamin D 3 (Bar-Shavit 2007 ; Nakashima and Takayanagi 2009 ).
Osteoclasts work in harmony with their bone-building counterparts, osteoblasts, to
maintain the level of free calcium required for many bodily functions. Osteoblasts
regulate formation and differentiation of osteoclasts and so are major players in
homeostatic control of bone remodeling. cAMP and PDEs have profound effects
on osteoblastic function, namely the regulation of receptor activator of nuclear
factor-kappa B ligand (RANKL) production, but this will not be discussed in depth
in this chapter, as osteoblasts are derived from the mesenchymal lineage, not the
hematopoietic/monocytic lineage.
Osteoclasts are derived from the hematopoietic lineage with many steps along
their differentiation pathway, but require only two major cytokines to complete
their maturation. First, the hematopoietic stem cell can be started along the osteo-
clastic pathway by responding to cytokines such as M-CSF to become an osteoclast
precursor cell or CFU-M (see Fig. 1 ). These cells are monocyte-like and can be
differentiated to macrophages or dendritic cells at this stage, if they do not receive
additional signals guiding them toward an osteoclast. This major driving signal for