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Articular cartilage functions as a wear-resistant, smooth, nearly frictionless, load-bearing surface. The composition and physiochemical properties of articular cartilage, the fundamental organization of the collagen network, and the molecular organization of collagen and proteoglycans all have profound effects on the intrinsic mechanical properties of the extracellular matrix.¹⁸ Cartilage is composed of a complex extracellular matrix of collagen and elastic fibers within a hydrated gel of glycosaminoglycans and proteoglycans. This extracellular matrix, which makes up 98% of the articular cartilage volume, is synthesized by the chondrocytes which comprise the other 2% of the cartilage tissue. It is well known that chondrocytes can synthesize the extracellular matrix such as proteoglycans, collagen, fibronectin, integrins, and other adhesive proteins which are needed to maintain the high tensile strength and low compressibility under load of the articular cartilage.^{19, 20} Type II collagen is the predominant collagen type in the extracellular matrix with proteoglycan (PRG) macromolecules dispersed throughout. They contain highly negatively charged carboxyl and sulfate groups (keratin and chondroitin sulfate) on the glycosaminoglycans, giving them a high affinity for water. (See Figure 4.)

The nature of the high density of negative charges imparts the physical properties to PRGs. Because of their attraction and binding of water, PRGs are viscous, making them ideal for lubricating fluid in joints. The charges repel each other, which gives them an open structure and is space-filling. These biochemical traits contribute to the mechanical properties of PRGs in articular cartilage, such as absorption and distribution of compressive weight, protecting structures in the joints from mechanical damage.²¹ The normal synthesis and breakdown of the PRGs and their component molecules, including glycosaminoglycans, is mediated by the indigenous chondrocytes. Glycosaminoglycans turn over several times as rapidly as the fibrillar collagen. If any part of this complex system is disrupted, the normal properties of articular cartilage are jeopardized, leading to joint degeneration. It is the extracellular matrix of articular cartilage that is the primary target of osteoarthritic cartilage degeneration and the accelerating effects of this breakdown by NSAIDs.

One of the earliest features of the development of osteoarthritis is degeneration of the articulating surfaces of the joint. This is characterized by fibrillation of the articular cartilage, in which the mesh of collagen fibers is disrupted. Degeneration of type II collagen is seen, as well as a decrease in the extracellular matrix.²² Loss of proteoglycan from the matrix is characteristic. The loss of aggrecan, the predominant PRG in articular cartilage imposes an increasing load on the collagen fibrils, causing further breakdown.²³ Early in the course of OA, the tissue mounts an attempt at repair. Chondrocytes proliferate and there is an increase in matrix synthesis.²⁴ However, if this repair process is disrupted for any reason including the use of NSAIDs, degradative enzymes overwhelm the synthetic capability and the repair fails. Particular compositional, molecular, and structural changes will continue to occur within the articular cartilage including decreased proteoglycan and increased water content, collagen fibril network disorganization, and proteoglycan separation, as long as the inciting issue (NSAID use) continues. (See Figure 5.) These changes alter the intrinsic mechanical properties of articular cartilage and produce swelling.²⁵ The articular cartilage, having lost some of its compressive ability under load, further degenerates. As the surface fibrillation progresses, the articular defects penetrate deeper into the cartilage until the cartilage is lost. The increased pressure on the subchondral bone causes it to thicken. Often bone cysts form deep to the eburnated areas. Eventually, bony nodules or osteophytes form at the periphery of the cartilage surface. All of these changes account not only for the pathology found on radiographs or histologically (findings under the microscope), but also for the joint pain, tenderness, loss of motion and stiffness of OA.²⁶ It is the relief of some of these clinical manifestations that accounts for the widespread use of NSAIDs not only in the United States, but around the world.