The nineteenth century humanist, poet, essayist, and journalist Walter Whitman observed the way a joint of a finger is more complex than the most intricate machinery. Most orthopedic surgeons will concur with this observation. Artificial joints of today can partially fulfill requirements of the joints for a determined duration.

Joint cartilage is a highly specialized connective tissue tolerating broad range of motion between long bones. It generates a very low frictional surface and presents lubrication properties for millions of cycles through decades. This macroscopically shiny, light blue or opal tissue at young ages has distinctive structural features. Its thickness, cellular volume, extracellular matrix, and mechanical properties may vary between species, at different joints of the same kind and at different locations of the same joint [10]. The thickness of human knee joint cartilage is less than 10 mm. Six to eight times body weight is absorbed by this structure in a jogging human. Such an intensive load is very well distributed and absorbed in such a thin and small surface area. Macroscopically, the surface of joint cartilage is smooth and durable to deformation. Microscopically, this multilayered structure contains (a) one type of cells named chondrocyte, (b) is mostly of extracellular matrix, and (c) lacks blood and lymph vessels and nerve endings (Fig. 22.2) [11]. Chondrocytes are nourished from synovial fluid. They almost always metabolize through the anaerobic pathway and therefore have limited regeneration capacity. Their primary function is to maintain or restore the extracellular matrix. Chondrocyte function deteriorates with aging leading to cartilage degeneration. Thickness of the cartilage decreases and its molecular biologic structure weakens. The weakened microscopic molecular structure leads to abnormal fluid homeostasis depriving mechanical functions. Oriented fibers of joint cartilage act such as a natural sponge. Synovial fluid flows out of the sponge rapidly at initial loading. Micro- and nanopores of the sponge lock over each other when compressive loading continues and increases. A certain amount of synovial fluid is entrapped in the pores of the spongelike structure of the cartilage even under excessive loads allowing it to properly function. Synovial fluid may not be attained in joint cartilage when this fiber structure of the extracellular matrix is disrupted, and chondrocytes are primarily responsible for regulating this homeostasis. The number and function of chondrocytes decrease with age leading to osteoarthritis (OA). Joint cartilage and subchondral bone degenerate in OA. Pain, limitation of joint motion, and deformity are its clinical findings. Fifty percent of practitioner visits of 65+-year-old patients are due to OA [12].

Ratio of chondrocyte to extracellular matrix is 1.65 % and 2.6 % at the superficial and middle–deep zones, respectively [13]. The superficial zone is also named as the fibrous or tangential zone. Superficial zone chondrocytes are fibroblast-like flattened cells aligned in the plane of the articular surface. Middle and deep zone chondrocytes function in their lacunae. Molecular mechanism of how chondrocytes control cartilage repair and/or regeneration is less known [14–16]. Regeneration and repair alter with age [17]. Proteolysis, glycation, and calcification are frequent features of aging. Cell density decreases. Abnormal secretory profiles and anabolic responses lead to biomechanical dysfunction and tissue destruction [17].

Eighty percent of wet weight of articular cartilage is of the synovial fluid. Synovial fluid and extracellular matrix determine the phenotype and endurance of joint cartilage. Synovial fluid containment capacity of joint cartilage is dependent on the macromolecule named aggrecan and the electrolyte containment of the synovial fluid. Collagen, proteoglycan, and glycoproteins establish 60 %, 25 %, and 15 % of the dry weight of joint cartilage, respectively. Collagen fibers are aligned longitudinally and are intense under the joint surface at the superficial zone. Resistance to tensional forces is generated by these fibers. In the middle and deep zones, collagen fibers keep chondrocytes in their lacunae. Proteoglycans and glycoproteins determine the synovial fluid containment of the cartilage. Type IX and XI collagens cross-link type II collagen and are responsible of cartilage integrity. Ninety to 95 % of joint cartilage structure is of type II collagen. Half-life of collagen is calculated as 3 months. Type VI collagen is mostly located around chondrocytes. Type X collagen is largely located near calcified and hypertrophic cartilage zones. Type X collagen is assumed to function at the calcification process of joint cartilage (Fig. 22.3).

Proteoglycan structure is of several glycosaminoglycan chains attached to a central protein chain. Glycosaminoglycan chains are of repeating disaccharides that contain amino glucose. Each disaccharide unit contains a negatively charged carboxyl or sulfate ring. Hyaluronic acid, chondroitin sulfate, keratan sulfate, and dermatan sulfate are major glycosaminoglycans. Keratan sulfate to chondroitin sulfate ratio increases with age as chondroitin sulfate degrades between globular domains two and three [18]. The big molecules of the 100 mg/ml dense proteoglycan are named as aggrecan. Decorin, biglycan, and fibromodulin are smaller proteoglycans. Type IX collagen is named as a glycosylated protein due to its glycosaminoglycan content (Fig. 22.4).

Keratan and chondroitin sulfates construct aggrecan structure [19]. Aggrecans fill 90 % of joint cartilages’ interfibrillar space. Decorin, biglycan, and fibromodulin contain one, two, and several sulfate chains, respectively. These fill up the remaining interfibrillar space from the aggrecan. Aggrecan is attached to hyaluronic acid by non-covalent bindings. Aggrecan and hyaluronic acid are further attached to each other by connecting proteins. Aggrecan augments all proteoglycans, glycosaminoglycans, and collagen. Hyaluronan that expands from 100 to 10,000 nm establishes the central skeleton allowing about 300 aggrecan attachment (Fig. 22.4). Small proteoglycans that do not attach to other proteins maintain chondrocyte homeostasis. Fibromodulin and decorin stabilize type II collagen and biglycan attaches to type VI collagen. Small proteoglycans furthermore regulate repair by attaching to transforming growth factor (TGF)-β. They also control degeneration triggering enzymes. Proteoglycans and connecting proteins are synthesized from the endoplasmic reticulum, whereas hyaluronan is assumed to be synthesized from the cell membrane.

Core protein of the aggrecan contains a single genetic code. Its three-dimensional structure is of three globular proteins and two other extensions. This structure is different in other species. The aggrecan monomer connects to the central hyaluronic acid skeleton through its N terminal. G1, G2, and G3 globular connection points separate this core protein to E1 and E2 sections. Aggrecan terminates at the G3 globular connection that is also named as the C terminal. The E1 and E2 sections are about 21 nm and 260 nm, respectively. Most of keratan sulfate and all of chondroitin sulfate are attached to the core protein E2 section. Globular connection points are of folding immunoglobulins and disulfide double loop repeating chains. They present CD44 staining and are immunogenic [20]. The three-dimensional G1 domain that is at the N terminal, which connects aggrecan to the central hyaluronic acid skeleton, is a complex structure [21]. G1 domain is stable for heat and proteinases. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) may catabolize this naturally stable trimeric complex and cause degeneration [22, 23]. ADAMTS are potential therapeutic targets for OA. Syndecans that fix ADAMTS to the cell membrane disintegrate by the inflammatory molecule interleukin-1 and lead to cartilage breakdown at synovial inflammation [24]. The G3 globular connection that is of ten cysteine molecules is defined in only 10–50 % of joint cartilage samples. The function of G3 globular connection is not clearly defined. G3 globular connection is assumed to regulate matrix organization, synthesis, intracellular translocation, and glycosylation.

Carbohydrate distribution of cartilage proteoglycans varies between chondroitin sulfate, keratan sulfate, and O-linked and N-linked oligosaccharides. Dimensions, quantity, pathway of sulfatization, and electrical charges of these proteoglycans change with age. Non-collagenous proteins and glycoproteins are oligosaccharides and monosaccharides. Ancorin CII and cartilage oligomeric matrix protein (COMP) connects chondrocytes to the extracellular matrix. COMP is specific to joint cartilage and increases in serum and synovial fluid with degradation [25]. Load-bearing exercise increases serum COMP levels [26]. Functions of non-collagenous proteins fibronectin and tenascin are still searched.

Collagen fibers resist against tensional forces, whereas the tough and intense structure of proteoglycans allows them to electrostatically bind to glycosaminoglycans and increase strength toward compression [37]. Continuous production and degradation of proteoglycans, collagen, and other matrix molecules preserves mechanical properties of joint cartilage. Density and structure are controlled by molecular biological and cellular harmony under physical conditions.

Loads on the joint and motion may exacerbate complex metabolic activity. Proteoglycan synthesis increases to some extend with increased dynamic load. Static or impact loads however injure joint cartilage. Rupture of the anterior cruciate ligament deteriorates matrix metabolism and may cause osteoarthritis [38]. Physiological loads may lead to structural adaptation when skeletal muscles of the knee joint are trained. Structural adaptation due to mechanical stimulation is difficult to monitor in vivo. Indirect methods include measuring joint cartilage metabolites and growth factors of the serum or synovial joint.