**4. Extracellular matrix and cell signaling**

stabilize the matrix framework and bind the chondrocytes to the macromolecules of the network. The matrix protects the cells from injury due to normal use of the joint, determines the types and concentrations of molecules that reach the cells and helps to maintain the

The ECM surrounding the chondrocytes has been divided into zones depending on their distance from the cell. The pericellular matrix is localized immediately around the cell, the territorial matrix is next to pericellular matrix and the most distance is the interterritorial matrix. Each matrix zone is characterized by different types of collagens as shown in figure 1.

**Figure 1.** The organization of normal articular cartilage. The organization of chondrocytes is divided in superficial, middle or transitional, deep or radial and calcified cartilage zones with a boundary or tidemark between the first three zones and the calcified zone. The extracellular matrix is divided depending the distance from the chondrocytes. The pericellular zone is the matrix surrounding immediately the chondrocytes. The territorial zone is the next to pericellu‐ lar zone and the interterritorial zone is the most distant. Every zone has specific characteristics related with the shape

The pericellular matrix is a region surrounding chondrocytes in the articular cartilage where diverse molecules as growth factors have interaction with the receptors expressed on the membrane cell of chondrocyte. This region is rich in proteoglycans as aggrecan, hyaluronan and decorin. Type II, VI and IX are collagen most concentrated in the pericellular network of thin fibrils as fibronectin. Type VI collagen forms part of the matrix immediately surrounding

of the chondrocyte as well the activity and the expression of different molecules by the cell.

**Pericellular zone:**

Collagen type II Collagen type XI

Membrane receptors as integrins

**Territorial zone:** Procollagen type II Matrilins 1 and 3 Biglycan Decorin Collagen type VI

**Interterritorial zone:** Collagen type II Collagen type XI Collagen type IX Proteoglycans Heparan

sulfate Fibromodulin Decorin Matrilin 3 Asporin COMP

chondrocyte phenotype [29, 30].

368 Regenerative Medicine and Tissue Engineering

**Normal cartilage cartilage** 

Superficial zone

> Middle Zone

Deep Zone

Tidemark Calcified cartilage Zone (Bone)

Chondrocytes respond to the mechanical and biochemical changes in ECM through signaling events by various cell surface growth factor receptors and adhesion molecules. ECM proteins can determine the cell behavior, polarity, migration, differentiation, proliferation and survival by communicating with the intracellular cytoskeleton and transmission of growth factor signals. Integrins and proteoglycans are the major ECM adhesion receptors, which cooperate in signaling events, determining the signaling events, and thus the cell function [36].

Integrins are heterodimeric transmembrane receptors formed of eighteen α subunits and eight β subunits and they are non-covalently assembled into 24 combinations. The integrin dimers bind to different ECM molecules with overlapping binding affinities determining expression patterns and the downstream signaling events in the cell. Integrins respond specifically to the molecular composition and physical properties of the ECM and inte‐ grate both mechanical and chemical signals through direct association with the cytoskele‐ ton. Integrins recognize and bind to the Arg-Gly-Asp (RGD) motif that they are attachment sites for integrin mediated cell adhesion. It has been demonstrated that high density of RGD motifs allows a precise spatial distribution pattern of integrins for specific cellular response among ligand molecules [36, 37].

Integrins can activate several signaling pathways independently and frequently they act synergistically with other growth factor receptors as insulin receptor, type 1 insulin-like growth factor receptor, VEGF receptor, TGF-b receptor, platelet-derived growth factor-b (PDGF-b) receptor and epidermal growth factor (EGF) receptor [37,38].

#### **4.1. Role of proteoglycans in signal regulation**

The heparan sulfate proteoglycans (HSPGs) contribute to the organization of the matrix by binding to the many core matrix molecules via HS chains as laminin, fibronectin and collagen. The chondroitin sulphate proteoglycans (CSPGs) as aggrecan, versican, brevican and the small, leucine-rich proteoglycans such as decorin and biglycan also bind to and regulate a number of growth factors, such as members of the TGF family. The hyaluronic acid is a glycosamino‐ glycan synthesized on the cell surface and is responsible for the gel-like consistency of cartilage by its hydroscopic properties [36, 39].

#### **4.2. Remodelation and degradation of ECM**

During normal or pathologic physiology of the cartilage, the ECM must be remodeling and degraded to allow the chondrocytes for processing and deposition of new matrix by specific proteases. There are two well-known families of proteases that are involved in the biology of the ECM, the matrix metalloproteinase (MMP) and the desintegrins and metalloproteinases with thrombospondin motif (ADAMTS) families. The MMP-13 is involved in the cleavage of fibromodulin and type IX collagen and is present and active in the pathological process of cartilage as OA and rheumatoid arthritis. The aggrecanases family's ADAMTS-4 and ADAMTS-5 play an important role in cartilage damage during early OA which cleavage the glycosaminoglycans chains that are the key contributors to the maintenance of the charge density, the osmotic environment and water retain important characteristics of the mechanical properties of the cartilage [40, 41].
