## 2 Anatomy of Articular Cartilage
### Chondrocytes  
Chondrocytes can be characterised as highly specialised and metabolically active cells. They are the resident cell type in articular cartilage [2]. Their share of the total articular cartilage volume is approximately 2% [52]. Chondrocytes produce enzymes that regulate extracellular matrix synthesis and growth factors [53]. When deposited in the ECM, they form articular cartilage [54]. The classic markers of the chondrocyte phenotype are the main components of the ECM, which include collagen II (COL2) and aggrecan (ACAN) [55]. In healthy articular cartilage, the chondrocyte population represents resting and differentiated cells whose function is to maintain a dynamic relationship between the anabolism and catabolism of the ECM [56; 57]. Mature chondrocytes are stored in lacunae in isogenic groups of a few cells in the territorial matrix in the vitreous cartilage in a specific physico-chemical environment [57]. They arise by mitotic division from a single mother cell [2]. The shape of the chondrocytes can be characterised as round or oval. The cytoplasm of chondrocytes has a small, spherical nucleus and contains the Golgi apparatus, mitochondria and lipid droplets [58]. Chondrocytes are formed from bone marrow mesenchymal stem cells (BMSCs) [53]. Aggregated BMSCs have the ability to differentiate into chondropgenitor cells and then become chondrocytes. The resulting chondrocytes go through differentiation processes so that they develop into hypertrophic chondrocytes. When the cartilage matrix is partially calcified, chondrocytes are gradually replaced by osteoblasts after apoptosis and endochondral ossification [53]. Apoptosis and chondrocyte hypertrophy are natural processes of endochondral ossification, but contribute to the more rapid development of osteoarthritis (OA) if cartilage is damaged [59]. The growth, metabolism, or differentiation of chondrocytes is an extremely complex process. Cytokines and cellular signals interact to maintain cartilage homeostasis and regulate chondrocyte function [60; 61; 62]. Therefore, an important aspect is to understand the impact of the interaction of regulatory factors and cellular signals on the growth and development of chondrocytes. An important influence in the differentiation of bone marrow mesenchymal stem cells into chondrocytes is the SRY-box 9 (Sox9) protein, which acts as a transcription factor [61]. It can be combined with ACAN and COL2, which affect the activation of its own gene expression and induction of chondrocyte proliferation, as well as ECM synthesis [63; 64]. Glutamine plays an important role in controlling the expression of chondrogenic genes, protecting the survival of chondrocytes and their proliferation and ECM synthesis [53]. However, this is associated with the stimulation of glutamine metabolism by Sox9 [65]. In order to maintain the chondrocyte phenotype, the Sox9 protein found in significant amounts in chondrogenic and cartilage progenitor cells is essential [66]. The role of Sox9 is also to inhibit the differentiation of chondrocytes into pro- hypertrophic chondrocytes, not participating in the final stage of further differentiation of hypertrophic chondrocytes [67]. For full expression of the chondrocyte phenotype, cooperation between high expression of the alpha-1 type collagen gene (COL2A1) and high expression of Sox9 is required [57]. The function of the COL2A1 gene is to encode the cartilage-specific molecule COL2 [66]. Another important transcription factor mediating chondrocyte maturation is run-related transcription factor 2 (Runx2). In proliferating chondrocytes, low expression of Runx2 is observed, which increases in terminally differentiated and hypertrophic chondrocytes [68; 69]. The function of Runx2 is to regulate collagen X expression in hypertrophic chondrocytes [70]. The use of Runx2 to regulate chondrocyte differentiation and apoptosis is made possible by its effect on chondrocytes [71].