Biomedical Engineering Reference
In-Depth Information
three cell types of the osteoclast lineage (with one being a state variable) plus
the osteocyte (one state variable) are considered in this chapter.
As can be seen from Figure  7.1, osteoblastic lineage derives from a
large pool of mesenchymal stem cells capable of differentiating into vari-
ous cells such as osteoblastic cells and adipocytes [30]. Pivonka et  al. [3]
denoted this pool of cells as OBU in their model. Once these cells commit
to the osteoblast lineage they are generally denoted as “responding” or
“preosteoblasts.”
The overexpression of opposite phenotypes of OPG as well as RANKL
deletion (osteopetrosis), and OPG deficiency or RANKL overexpression
(osteoporosis) have led to the hypothesis that OPG and RANKL could be the
mediators for the stimulatory or inhibitory effects of a variety of systemic
hormones, growth factors, and cytokines on osteoclastogenesis [19]. This
has recently been referred to as “the convergence hypothesis” in that the
activities of the resorptive and antiresorptive agents “converge” at the level
of these two mediators, whose final ratio controls the degree of osteoclast
differentiation, activation, and apoptosis [31].
In addition to the RANK-RANKL-OPG signaling pathway discussed,
the following two pathways are also important in bone remodeling analy-
sis. One is the TGF -β/ nodal / activin and BMP / GDF signaling pathway. TGF-β
superfamily members are classified into the TFG-β/nodal/activin group
and BMP/GDF group. TFG-β/nodal/activin signals are transduced through
type I and type II receptors for each member to R-SMAD proteins, such as
SMAD2 and SMAD3, while BMP/GDF signals are transduced through type I
and type II receptors for each member to R-SMAD proteins, such as SMAD1,
SMAD5, and SMAD8. Phosphorylated R-SMADs associated with SMAD4 are
then translocated to the nucleus to activate transcription of target genes [32].
BMP/GDF family genes within the human genome have been extensively
studied (http://www.gene.ucl.ac.uk, accessed March 2011); however, tran-
scriptional regulation of BMP/GDF family members by the canonical Wnt
signaling pathway remains unclear.
Another is the Wnt /β- catenin signaling and Wnt antagonists. Wnts constitute
a family of proteins important in cell differentiation, particularly play-
ing a critical role in OB cell differentiation and bone formation. When
Wnt receptor binding interactions are absent, β-catenin is phosphorylated
by glycogen-synthase kinase-3β (GSK-3β), leading to the degradation of
β-catenin in the proteasome. Upon binding of Wnt to frizzled receptors and
to the low-density lipoprotein receptor-related protein (LRP) coreceptors-5
and -6, the activity of GSK-3β is inhibited, leading to the stabilization of
β-catenin and its translocation to the nucleus. There, it associates with T-cell
factor (TCF) 4 or lymphoid enhancer binding factor (LEF) 1 to regulate gene
transcription [33].
Sclerostin (SOST), produced by bone cells, has recently emerged as an
important modulator of anabolic signaling pathways in bone, particularly
PTH stimulation and mechanical loading. By virtue of its relatively exclusive
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