Pathophysiology

Function and Structure of Normal Articular Cartilage

Function of Articular Cartilage

The bones in a synovial joint are covered by a thin layer of cartilage called articular cartilage. Articular cartilage is softer than bone. The principal roles of articular cartilage are to:

• reduce friction at the joint
• act as a cushion to absorb the shock associated with joint use
• efficiently transmit weight loads to the underlying bone.

Articular cartilage, along with the synovial fluid in the joint, permits almost frictionless movement of joint bones at their points of contact. The frictional resistance of normal joints is estimated to be about one-tenth that of an ice skate on ice. Another principal role of the cartilage layer is to absorb the shock associated with joint use. The figure below shows that the articular cartilage also efficiently transmits weight loads to the underlying bone. When weight is loaded onto the joint, the cartilage layer compresses. Once the weight is removed, the cartilage rebounds to its original dimensions.

Joint Loading

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Structure of Articular Cartilage

Despite its high water content, the structure of the articular cartilage allows it to remain firm and resilient. The articular cartilage is firmly attached to its underlying subchondral bone by a subchondral plate. This allows the subchondral plate to act as a shock absorber, which protects the joint from applied stresses. A thin layer of calcified cartilage separates the noncalcified or articular cartilage from its bony subchondral bed. The interface between the calcified cartilage and articular cartilage is known as the tidemark. The articular cartilage, with the subchondral bone and the surrounding skeletal muscles, supports even distribution of weight loading across the entire joint structure. These layers are shown in the following figure.

Cross-section of Articular Cartilage

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Components of Articular Cartilage

Articular cartilage has a milky, glass-like appearance and is composed of:

• extracellular matrix (ECM) (98-99% of total volume)
• chondrocytes (1-2% of total volume).

Extracellular Matrix

The ECM is made up of water, collagen (mostly type II collagen fibrils), and proteoglycans. The ECM of the articular cartilage contains more than 70% water and over 90% of its dry weight consists of type II collagen and proteoglycans. Embedded in the ECM are the chondrocytes, the cells of the articular cartilage.

Proteoglycans

Proteoglycans are polysaccharide chain structures that have an overall negative charge due to their molecular structure. This gives them a high attraction for water. In the ECM of articular cartilage, large numbers of proteoglycans are arranged in aggregates that are tightly bound within a framework of arching collagen fibrils. The collagen fibrils form a tight network that restrains and anchors the water-loaded proteoglycans to keep them in place. This unique structure gives cartilage its properties of tensile strength and resilience. The tensile strength of the collagen resists deformation and maintains the basic structural framework. The proteoglycans, through strong, charged interactions with water, control the flow of solutes and the time-dependent deformation of the cartilage with weight bearing on the joint. This process is similar to that seen when compressing a water-loaded sponge.

The main proteoglycan in cartilage is called aggrecan (the aggregating large proteoglycan), which consists of a protein core to which chondroitin sulfate and keratan sulfate chains are attached. It provides articular cartilage its properties of compressive stiffness. The terminal end of aggrecan can link to hyaluronic acid. The nature and quantity of proteoglycans changes with use and disease.

Chondrocytes

Chondrocytes are widely disbursed throughout the cartilage, embedded in the ECM. Chondrocytes are the only cells of the articular cartilage. Because the articular cartilage lacks blood vessels, the chondrocytes must receive nutrients and eliminate waste through the process of diffusion. Nutrients and wastes diffuse through the synovial fluid within the joint capsule and through the surrounding blood vessels. Blood vessels are located in the synovial membrane and subchondral bone [Dequeker and Dieppe, 1998].

Chondrocytes are metabolically very active; however, they normally do not divide after adolescence. The integrity of the cartilage is dependent on the activity of the chondrocytes. Their function is to regulate both the synthesis and degradation of articular cartilage through the secretion of enzymes [Dequeker and Dieppe, 1998].

Breakdown and Repair of Articular Cartilage

In normal, adult articular cartilage, ECM is constantly being degraded and repaired. However, when compared with other connective tissues, turnover is slow and the capacity of repair is limited. These two processes of degradation and repair are normally kept in balance by the activity of the chondrocytes. As seen in the following figure, the chondrocytes are stimulated by and secrete a number of enzymes that help regulate the balance of synthesis and degradation of the ECM.

Factors that Regulate Normal Articular Cartilage Homeostasis

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Interleukin-1 (IL-1), a cytokine produced by chondrocytes and other cells in the joint, plays an important role in cartilage degradation by stimulating the synthesis of degradative enzymes that inhibit the production of proteoglycans. Other cytokines that appear to act synergistically with IL-1 to promote matrix breakdown are tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). All of these cytokines are routinely found in inflamed joints.

Enzymes secreted by the chondrocytes are released into the ECM and degrade the matrix structure. Among the enzymes that have been identified as playing a major role in proteoglycan and collagen degradation are the matrix metalloproteinases (MMPs), such as collagenase, stromelysin, and gelatinase. Other proteinases include cysteine proteinases, cathepsin, and serine proteases, such as tissue plasminogen activator.

The above figure illustrates how, normally, the activation of these degradative enzymes is held in check by inhibitors, such as tissue inhibitor of metalloproteinase (TIMP) and plasminogen activator inhibitor-7 (PAI-7). These inhibitors work by forming complexes that inactivate the degradative enzymes. Chondrocytes are responsible for maintaining the balance between the degradative enzymes and their inhibitors.

In OA, an imbalance between the levels of these degradative enzymes such as MMPs, and their inhibitors, such as TIMP, has been proposed as a contributing factor.

As part of the cartilage degradation and synthesis process, polypeptides, such as insulin-like growth factor-1 (IGF-1) and transforming growth factor beta (TGF-beta), stimulate chondrocytes in the matrix to synthesize proteoglycans. IGF-1 and TGF-beta regulate matrix metabolism in normal cartilage and may play a role in matrix repair in patients with OA.

Development of OA

Pathogenesis

As shown in the figure below, OA is primarily a disorder of articular cartilage that appears to result from an imbalance between the destructive and reparative or synthetic processes of the articular cartilage. In addition to the degenerative processes, the pathology of OA also appears to include processes that represent real or attempted repair of the joint. Although the exact cause of OA remains elusive, it is believed to result from a complex interplay of genetic, environmental, metabolic, and biochemical factors.

Balance of Synthesis Repair and Degradation

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Initially, some "triggering factor" seems to activate the division and multiplication of the chondrocytes. Currently, it is thought that this activation may be related to excessive force being applied to the joint (i.e., repetitive impact loading) or to a fundamental defect in the articular cartilage or underlying subchondral bone. Whatever the cause, chondrocytes multiply and become very metabolically active. Groups of these cells may appear in "nests," termed brood clusters, within the cartilage matrix.

In the early stages of OA, the chondrocytes attempt to compensate for this imbalance by producing increased quantities of proteoglycans and collagen. This may lead to an initial thickening of the articular cartilage and enable the joint to maintain normal function for years; however, the quantity and quality of the proteoglycan and collagen produced are not normal. Some components of the matrix are overproduced and the quality of the proteoglycans resemble immature fetal forms. Eventually, the arrangement and size of collagen fibers are altered and the proteoglycans begin to break down faster than they can be synthesized. The decreased proteoglycan content and altered collagen structure of the matrix result in a deterioration of the cartilage's normal physiologic properties.

Early damage to the cartilage may consist of microfractures and fibrillations. As OA progresses, gross evidence of damage to articular cartilage becomes evident. The normally smooth surface of the cartilage becomes rough or eroded with cracks. The cartilage may also show signs of chondromalacia due to the increase in the ratio of water to proteoglycan in the cartilage matrix. Moreover, cartilage erosions (ulceration with exposure of underlying bone) can be seen in more severe OA. The figure below illustrates changes seen in OA cartilage. Views 1 and 2 are cross-sections of articular cartilage illustrating fibrillation and erosions. Cracking can be seen by looking down on the surface of articular cartilage (view 3).

Damage to Articular Cartilage in OA

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Other Joint Structures Affected

OA affects not only the articular cartilage, but also the underlying bone and adjacent joint structures. As the cartilage becomes eroded, fragments may break loose and float within the joint capsule. These loose pieces of cartilage can damage the synovial lining of the joint and interfere with proper joint function. Progressive damage to the cartilage results in narrowing of the space between the two bones (joint space) because areas of bone become denuded of cartilage, causing the loss of the shock-absorbing mechanism and allowing for the contact of bone on bone. The underlying subchondral bone may form a new articulating surface in the joint and become smooth and polished, like marble. This is called eburnation.

In subchondral bone, osteoblasts begin to form new bone tissue, probably in response to chemical messengers produced by the chondrocytes. This leads to bone remodeling. Around the edges of the joint, bony and cartilaginous overgrowths or "spurs," called osteophytes may develop in nonweight-bearing areas of the joint. The figure below illustrates the formation of osteophytes, joint space narrowing, and eburnation of the subchondral bone in a distal interphalangeal (DIP) joint of the hand.

Osteophytes in an Arthritic Joint

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For each joint, the site of osteophyte formation is characteristic. Thus, osteophytes that form in the DIP joints produce a characteristic nodular appearance on the fingers, called Heberden's nodes. Similarly, a characteristic swelling of the proximal interphalangeal joints, called Bouchard's nodes, can be seen in many patients with OA. Often, these nodes are initially tender and red and may cause pain. Later in the course of the disease, they may be associated with joint instability and loss of function. Despite the loss of bone and cartilage in other areas of the joint, the presence of osteophytes tends to increase the size of osteoarthritic joints. The osteophytes frequently lead to gnarling or joint deformity.

Although new bone and cartilage tissue grow in areas where the articular cartilage has been completely worn away, the composition of this new tissue is not normal. Due to these compositional changes, the bone is stiffer and becomes subject to the formation of microscopic fractures. In areas where cartilage is absent, subchondral bone may appear thickened or sclerotic ("subchondral sclerosis"). In the subchondral bone, areas of focal pressure and the denuded cartilage result in necrosis of bone and bone marrow, leading to subarticular or subchondral bone cysts. An X-ray of a normal knee and an OA knee is shown below. There is a narrowing of the lateral compartment of the joint and sclerosis of adjacent bony margins. This unicompartmental joint space loss and reactive new bone formation help differentiate degenerative from inflammatory arthritis.

X-ray Comparison of (A) an OA Knee and (B) a Normal Knee

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Pathologic Changes in Other Tissues

Although OA is considered a noninflammatory form of arthritis, there are changes that occur within the joint that may be associated with inflammation. The inflammation, however, is much less than is seen with RA, which is considered an inflammatory arthritis. Inflammation appears to be related to the introduction of bone and cartilage breakdown products into the synovial fluid. These products are phagocytized by cells in the synovium, resulting in chronic, low-grade inflammation. Consequently, the synovial membrane becomes thickened. Inflammation of the synovial membrane may be absent in the earlier stages of OA; however, as the disease progresses, some degree of synovitis usually exists.

Once mild synovial inflammation is established, the synovium becomes a source of cartilage-degrading enzymes (e.g., MMPs) and cytokines, including IL-1, IL-6, and TNF-alpha. These substances diffuse through the synovial fluid and cause further degradation of articular cartilage. IL-1 and TNF-alpha stimulate the chondrocytes to produce more degrading enzymes, and the process continues in a vicious cycle (see figure below). Most studies on cytokines in OA have focused on IL-1, IL-6, and TNF-alpha because these are believed to be the main cytokines linked to the disease process.

Cytokine and Protease Production from Inflamed Synovium

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Possible Role of Nitric Oxide

Nitric oxide (NO) is an inorganic compound that is found at higher levels of osteoarthritic cartilage than in normal cartilage. A form of NO can be expressed after the activation of chondrocytes by cytokines (i.e., in association with inflammation). Once formed, NO may contribute to IL-1-induced degradation of cartilage, mainly by decreasing the synthesis of the ECM.

Role of Prostaglandins

Studies have shown that IL-1 derived from the osteoarthritic cartilage stimulates the production of prostaglandin E₂ (PGE₂). Once formed, PGE₂ increases the synthesis of stromelysin, a cartilage-degrading protein (MMP). PGE₂ also has important pro-inflammatory properties and contributes to vasodilation and pain in patients with OA.

References

Dequeker J, Dieppe PA, eds. Disorders of bone cartilage and connective tissue. In: Klippel JH, Dieppe PA, eds. Rheumatology. 2nd ed. London: Mosby, 1998.

American College of Rheumatology. Clinical Slide Collection on the Rheumatic Diseases. Atlanta: American College of Rheumatology, 1997.

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