Page 84 - Williams Hematology ( PDFDrive )

60 Part II: The Organization of the Lymphohematopoietic Tissues Chapter 5: Structure of the Marrow and the Hematopoietic Microenvironment 61

do not react with antibodies to CD3, CD15, CD20, CD34, CD45, CD68, Osteoclasts also can be derived from pro-B cells, as shown by Pax-5
or CD117. Enriched CD56+, CD45−, CD34− endosteal cells grown knockout mice, which have increased osteoclasts and severe osteope-
151
177
in the presence of cytokines (insulin growth factor I, basic fibroblast nia. When osteoclast activity or number are reduced or eliminated
growth factor [bFGF], SCF, IL-3, granulocyte-macrophage colony-stim- in mice through null mutations or homologous recombination, the
ulating factor [GM-CSF]) do not give rise to hematopoietic cells, which marrow cavities fail to form resulting in osteopetrosis. Based on stud-
151
suggests they are not totipotent MSCs. In the next sections, the two ies of osteopetrotic mice, proteins required for osteoclast differentiation
major types of cells responsible for endosteal activity, osteoblasts and include the macrophage transcription factor PU.1; the secreted and sur-
osteoclasts, are considered in terms of their potential roles in maintain- face displayed cytokine M-CSF of stromal cells and its receptor c-FMS
ing the hematopoietic niche. on osteoclasts; the transcription factor c-FOS; the cytokine RANKL;
its osteoclast receptor RANK, the signaling transducer tumor necrosis
Osteoblasts factor-α (TNF-α) receptor-associated factor 6 (TRAF 6); the down-
Osteoblasts have three major functions: formation of new bone by reg- stream transcription factor nuclear factor (NF)-κB, and nuclear factor
ulating the secretion of the bone matrix proteins, regulation of bone of activated T cells (NFAT). 175,178,179 Other osteopetrotic mice strains
resorption via osteoclast activity, and regulation of the hematopoietic have deficiency of proteins required for the bone resorption function of
environment mainly by secretion of cytokines. Bone-forming osteoblast osteoclasts. These proteins include the β component of the α β integrin
v 3
3
progenitor cells, like stromal precursors, reside in the CD34−, STRO- (vitronectin receptor) required for binding of the osteoclast sealing zone
1+ nonadherent marrow cell population. 152,153 The differentiation of to bone; c-Src signaling protein; the proton transporting H+ adenosine
mesenchymal cells into either osteoblasts or adipocytes is related to the triphosphatase (ATPase) and chloride channel protein required for
154
relative activities of Runx2 and PPARγ, respectively. With aging, the HCl secretion; and the secreted osteoclast proteins cathepsin K, matrix
sensitivity to PPARγ appears to increase, contributing to the increase metalloproteinases, and TRAP that digest the bone matrix. 174,175,179
155
154
in adipose tissue in the marrow found with older age. BMP2, Osteoblast/stromal cells regulate differentiation of osteoclasts
156
157
bFGF, hepatocyte growth factor (HGF), parathyroid hormone through intimate cell–cell contacts. They are found in direct apposition
12
and endothelin-1 promote osteoblast growth, whereas the cytokine to osteoclasts with coated pit formation, suggesting accumulation of
158
TGF-β and the transcription factor osterix promote differentia- receptor–ligand complexes in endocytic vesicles. 180,181 The recruitment
159
160
tion. Osteoblasts increase early hematopoietic progenitor survival in of the osteoblasts and osteoclasts appears to be through capillaries
182
long-term cultures and secrete hematopoietic growth factors such as associated with the remodeling compartment. A major regulatory
M-CSF, G-CSF, GM-CSF, IL-1, and IL-6. 161,162 Osteoblasts also produce mechanism by which osteoblasts and osteoclasts interact is the RANK/
various cytokines such as hematopoietic cell-cycle inhibitory factors RANKL/osteoprotegerin (OPG) system of signaling. Osteoclast dif-
182
163
12
TGF-β, osteopontin, and CXCL12, as well as cell-cycle stimula- ferentiation and maturation require the signaling cascade from RANK
164
tory factor Dickkopf-1, all of which contribute to stem cell regulation on the cell surface through TRAF 6, NF-κB, and NFAT. Osteoblasts
165
180
within the marrow microenvironment. Direct cell–cell communication and their progenitor cells display RANKL on their surfaces, and binding
has been shown in the marrow and in osteoblastic cell networks, of RANKL to the RANK on the osteoclasts and their progenitors pro-
166
indicating a potential regulatory role for anatomical gap junctions in motes differentiation and activation of the osteoclasts. Osteoblasts also
hematopoiesis. 167,168 The size of stem cell niches increases after secrete OPG, a decoy receptor for RANKL, which inactivates RANKL
osteoblastic expansion and Notch activation in transgenic models. 11,12 by binding to the active site of RANKL, thereby preventing its bind-
In another model, intramedullary hematopoiesis and stem cell num- ing to RANK. As a result, osteoclastic activity is decreased when OPG
183
bers are severely diminished following in vivo ablation of osteoblasts, concentrations are high and increased when they are low. Another
169
underscoring the importance of this cell type to the marrow hemato- signaling mechanism by which osteoclasts and osteoblasts reciprocally
poietic inductive microenvironment. The lymphoid niches for early regulate the differentiation and activities of each other is the ephrin-
lymphoid progenitors and differentiating B cells are located adjacent B2-EphB4 signaling system. Osteoclasts express ephrinB2 on their
184
to the endosteal surface. 92,93 Osteocytes, which are terminally differ- surfaces while the osteoblasts express EphB4, a member of the recep-
entiated osteoblasts trapped in the bony matrix, secrete cytokines into tor tyrosine kinase (RTK) family, which is the receptor for ephrinB2.
the marrow space that act in a negative feedback manner on new bone Binding of ephrinB2-EphB4 results in bidirectional signaling in which
formation. Specifically, the osteoblast and stromal cell surface protein osteoclast differentiation is decreased though suppression of the
receptor activator of nuclear factor-κB ligand (RANKL) activates osteo- c-FOS–NFATc1 activity, whereas osteoblast differentiation is increased
170
171
clasts, while the cytokine sclerostin suppresses osteoblast activity. by EphB4 signaling. 184
Disruption of the signaling mechanism of G-protein receptors in osteo- Osteoclasts produce HGF and express c-Met, the HGF receptor,
cytes leads to an expansion of myelopoiesis that is mediated by secreted implying a paracrine and autocrine regulatory pathway between them
myelopoietic cytokines, most likely G-CSF. 172 and adjoining osteoblasts. 157,185 Similarly, blocking expression of cad-
herin-6 interferes with heterotypic interactions between osteoclasts and
Osteoclasts stromal cells, impairing their ability to support osteoclast formation.
186
Mature osteoclasts are multinucleated giant cells derived from fusion of CD9, a tetraspanin transmembrane adhesion protein on stromal cells,
187
progenitor cells of the monocyte/macrophage lineage of the HSC. The influences myelopoiesis in long-term marrow cultures. Inhibition of
173
188
mature osteoclasts resorb and remodel bone, regulate osteoblast activ- stromal cell CD9-mediated signaling by a blocking antibody reduces
ity, and help control the HSC entry into and exit from the marrow. 174,175 osteoclast differentiation factor transcription, leading to reduced osteo-
The osteoclasts have motile and resorptive phases. They require the clastogenesis. Macrophage-stimulating protein, a HGF-like protein,
189
Wiskott-Aldrich syndrome protein during clustering and fusion of signals through the stem cell-derived tyrosine kinase, a member of
actin-based adhesion structures named podosomes. Podosomes are the HGF receptor family. It also stimulates osteoclast bone-resorb-
176
involved in the formation of specific structures termed sealing zones ing activity by enhanced cytoskeletal reorganization without affecting
in which actin rings surround an area of ruffled plasma membrane at proliferation of osteoclast precursors. 190,191 Osteoclast differentiation is
the face of the endosteal bone. Within these sealing zones, osteoclasts influenced by monocytes expressing ADAM-8 (CD156), a protein of the
secrete hydrochloric acid and digestive enzymes that resorb bone. disintegrin and metalloproteinase family, and eosinophil chemotactic
192
Kaushansky_chapter 05_p0051-0084.indd 60 9/19/15 12:10 AM