Harnessing Cell–Biomaterial Interactions for Osteochondral Tissue Regeneration - Tissue Engineering: Cell-Surface Interactions for Tissue Culture - page 73

matrix is the largest portion of cartilage (more than 5 lm from the surface of
chondrocytes) and is responsible for the zonal architecture of cartilage [ 9 , 12 ]. This
area contains the most type II collagen and the lowest amount of aggrecan [ 12 ].
4 Chondrocyte-ECM Interactions
Cell-cell and cell-matrix interactions play a key role in the differentiation of
MSCs into chondrocytes during limb development. Initially, before condensation
occurs, MSCs produce type I and type II collagen, hyaluronan, fibronectin, and
tenascin C. These ECM components hinder the movement of the MSCs. However
during condensation, the progenitor cells produce enzymes that breakdown local
ECM components [ 24 , 25 ]. The lower ECM density allows the cells to directly
interact with each other via cell adhesion molecules, such as neural cadherin and
neural cell adhesion molecule [ 26 , 27 ]. Whereas neural cadherin and neural cell
adhesion molecule need to be expressed during condensation, their expression
must be lowered during the process of differentiation in order for chondrogenesis
to successfully occur [ 12 , 28 ]. During chondrogenesis, interactions of cells with
the ECM once again become crucial for proper cartilage formation. One important
ECM component that is not modulated during both the condensation and the
chondrogenesis process is type II collagen [ 12 ]. The expression of the transcription
factor SOX9 by the cells allows the continual synthesis of type II collagen and is
considered a major constituent in chondrogenesis, as the absence of SOX9 gene
expression has been shown to result in lack of cartilage development [ 29 , 30 ].
Additionally, L-SOX5 and SOX6 have been linked with SOX9 to further promote
chondrogenesis and can upregulate cartilage matrix production of type II collagen
and aggrecan [ 31 , 32 ].
Mature chondrocytes are able to maintain healthy cartilage as they balance the
degradation and synthesis of ECM components. The signals that chondrocytes
receive from the surrounding environment help to define what is necessary to
maintain the tissue. Chondrocytes interact with the ECM via receptors that are
classified as non-integrin and integrin. Two common non-integrin receptors are
annexin V/anchorin CII and CD44. Type II collagen binds to chondrocytes via the
annexin V/anchorin CII receptor [ 33 ]. CD44 is a cell-surface glycoprotein that has
a high affinity for hyaluronan in cartilage [ 34 ]. Integrins themselves are glyco-
proteins that function as heterodimeric transmembrane receptors with a and b
subunits. Different types of a and b subunits can noncovalently associate to form
receptors with a high affinity for various ligands. b 1 integrins with a 1 , a 2 , a 3 ,ora 5
have been found to influence chondrocyte attachment to type II collagen [ 2 ].
Chondrocytes interact with type VI collagen by a 1 b 1 integrin and NG2/human
melanoma proteoglycan receptors [ 35 , 36 ]. The a 3 b 1 and a 5 b 1 integrins can
mediate the binding of fibronectin [ 37 ].