Stem Cell-Based Tissue Engineering for Bone Repair - Tissue Engineering: Computer Modeling, Biofabrication and Cell Behavior - page 9

Cadherin junctions consist of a long N-terminal extracellular domain, a transmem-
brane domain, and a small intracellular C-terminal [ 18 ]. Many different tissues ex-
press multiple cadherins.
In bone, osteogenic cells during differentiation express a variety of cadherins.
R-cadherin/cadherin-4 is downregulated as differentiation progresses, while
cadherin-11 (also known as osteoblast-cadherin, or OB-Cad) is upregulated
[ 12 ]. N-cadherin is the most abundant cadherin, as it is present throughout
osteogenic differentiation [ 15 , 18 ].
In-vitro studies of bone have shown that cultured osteoblasts also express N-
cadherin and cadherin-11 [ 20 , 21 ]. Using various inhibitors of these cadherins, re-
searchers have shown that blocking cadherin expression in osteoblast lineage cells
impairs differentiation into osteoblasts [ 20 , 21 ], thereby demonstrating the neces-
sity for cadherins in full osteoblast phenotype development [ 12 ]. In addition to in-
vitro approaches, isolating the function of cadherins in bone requires in-vivo study.
Experiments involving genetic deletion of the N-cadherin gene in mice has been
shown to lead to an embryonic lethal product [ 12 , 21 ]. However, heterozygous N-
cad mutants were shown to have normal bone density with an osteoblast abnormal-
ity identified [ 12 ]. Homozygous cadherin-11 deficient animals have been shown to
develop a phenotype that appears normal at birth, but then progresses to defects
in the calcification of cranial sutures, and osteopenia (a condition where the bone
mineral density is low) in trabecular bone, both of which are pathologies linked to
a defect in the functionality of osteoblasts [ 12 , 21 ]. Extensive work on the role of
OB-Cad in bone has shown that this protein is not only responsible for osteoblast
differentiation and function, but also is involved in bone marrow cell lineage de-
termination and signaling [ 20 , 21 ]. Cadherins have also been shown to be involved
in osteogenic commitment of mesenchymal stem cells, primarily through β -catenin
signaling [ 12 ].
Cadherins have also been implicated to be important for mechanotransduction
[ 22 ]. In-vitro experiments involving plating surfaces with cadherin extracellular do-
mains caused spreading and clustering of cells, as well as organization of cadherins
into streaks on the surface [ 22 , 23 ]. Moreover, it was demonstrated that cells with
N-cadherin complexes exerted traction forces on the surface which they were on
[ 22 , 24 ]. Studies of the cadherin-mediated mechanotransduction in bone still need
to be investigated, however studies in more specialized systems have been exam-
ined. For example, the response of the villi on inner ear hair cells to sound waves is
mediated by a conformational change in cadherin structure that transmits the sound
wave force to stretch-activated channels [ 22 ]. These channels then open, allowing
conductance to occur.
Therefore, since these cell junctions are integral in both embryonic and mes-
enchymal stem cell differentiation, and seem to play a role in mechanotransduc-
tion, understanding how they are regulated and the impact of their presence on cell