| disease | Degenerative Joint Disease |
| alias | Chondromalacia Arthropathy, Primary Osteoarthritis, Degenerative Arthritis, Osteoarthrosis |
Osteoarthritis (osteoarthritis) and osteoarthrosis have recently also been described as chondromalacic arthrosis, degenerative arthritis, hypertrophic arthritis, or arthritis deformans, referring to idiopathic, chronic progressive diseases of synovial joints that occur in the elderly. Pathological features include focal degenerative changes in articular cartilage, subchondral bone sclerosis, marginal osteochondral osteophyte formation, and joint deformity. Clinical manifestations include recurrent joint pain, exudative synovitis, joint stiffness, and progressive limitation of movement. X-ray findings show narrowing of the joint space, thickening and sclerosis of subchondral bone, subchondral cysts, and marginal osteophytes. The degenerative process begins in the articular cartilage, with progressive changes starting from the superficial layer and extending to the full thickness of the cartilage. With biochemical alterations, the cartilage's ability to withstand pressure and tension decreases, leading to extensive fibrous tissue formation, deep fissures, fragmentation, and ultimately complete erosion of the cartilage, exposing the subchondral bone. Concurrent with early changes in the cartilage surface, vascular proliferation occurs in the subchondral bone, with vessels penetrating deep into the calcified layer and lesions. As the articular cartilage erodes, the subchondral lamellar bone and adjacent trabeculae thicken and coarsen.
bubble_chart Etiology
The cause of primary osteoarthritis is unclear, but related factors include:
1. Age: Degenerative changes in the human body begin at the age of 20, though they are not noticeable until middle age. By 55–65 years of age, approximately 85% of X-ray examinations reveal osteoarticular changes.
2. Gender: The disease affects men and women equally. Until the age of 54, the manifestations of the disease are similar in both sexes. After that, degenerative progression becomes more severe and widespread in women than in men.
3. Heredity: Epidemiological studies suggest that osteoarthritis is a joint manifestation of systemic changes caused by inherited metabolic abnormalities. Heberden’s nodes may be influenced by a single autosomal gene, exhibiting dominant inheritance in women and recessive inheritance in men. Penetrance varies with age, with the highest penetrance rate of 30% observed in elderly women. In elderly men, due to recessive inheritance, the penetrance rate is 3%. The exact genetic pattern remains unclear.
4. Obesity: The incidence of degenerative joint disease doubles in obese individuals, primarily affecting weight-bearing joints. Obese men with degenerative joint disease exhibit systemic changes more commonly seen in women.5. Disease extent: Degenerative manifestations vary among individuals and joints. Moreover, population studies have identified several patterns. Before the age of 54, joint involvement is similar in men and women. Women typically show more degenerative joint involvement, often with changes in the first carpometacarpal joint and distal interphalangeal joints. In men, hip joint involvement is more common.
Any synovial joint can be affected, but joints subjected to significant pressure exhibit the most severe degeneration. Weight-bearing and pressure-related sites include the lower spine, hip joints, and knee joints. Joints affected by strong, repetitive muscular forces include the first metacarpophalangeal joint, first carpometacarpal joint (trapeziometacarpal joint), and mid-cervical joints.
When osteoarthritis develops in a joint, it primarily affects non-pressure regions. Trueta’s examination of femoral heads from individuals aged 14 to 100 revealed cartilage degeneration, with 71% limited to non-pressure areas, only 3% occurring in pressure areas, and the remaining 26% affecting both pressure and non-pressure regions.
6. Inciting factors: The cause of primary osteoarthritis is unclear, while secondary osteoarthritis is determined by prior health conditions and diseases that alter articular cartilage. The following factors may accelerate the progression of pre-existing or subclinical degenerative processes:
(1) Inflammatory processes: For example, in rheumatic diseases, inflammation in periarticular and synovial tissues erodes and damages articular cartilage.
(2) Metabolic disorders: Conditions such as gouty urate deposition or ochronosis due to alkaptonuria alter the properties of articular cartilage, making it prone to damage. Hemochromatosis has a similar effect.
(3) Biomechanical factors: Cartilage is prone to fatigue (e.g., under repeated high stress). Thus, repetitive force application not only causes collagen fiber breakage but also depletes proteoglycans on the cartilage surface. Bone deformities can amplify such repetitive stress on cartilage.
Joint deformities (e.g., genu valgum or genu varum) create unbalanced load distribution, with excessive stress on one side, ultimately leading to cartilage destruction.
Abnormal forces acting on the body can cause internal joint disturbances. By using the hypothetical instantaneous center of force transmission in a joint, the direction and velocity of joint forces can be determined. Connecting any point on the joint surface to this instantaneous center of force transmission, with the line perpendicular to the acting surface, reveals differences between normal and abnormal joint conditions. In a normal joint, the velocity direction of the contact force on the joint surface is parallel to the joint surface. In patients with medial meniscus tears, an instantaneous center of force transmission is created. Due to joint twisting displacement during knee extension, the velocity direction of joint forces tends to transmit from the femur to the tibia. This substantial contact force leads to meniscus tears, subsequently resulting in degenerative joint disease.
The relative compression of the articular surfaces causes nutritional disturbances in the articular cartilage, leading to necrosis of chondrocytes. Subsequently, the depletion of matrix proteins (PG) and polysaccharides occurs, rendering the articular cartilage unable to withstand the pressure and shear forces of joint movement, resulting in degenerative changes.
In some experimental animals with prolonged flexion fixation of the knee, adhesions form between the articular cartilage and synovial membrane in areas where the joint surfaces do not contact. This may be due to cartilage nutritional disturbances, leading to degenerative changes in the cartilage beneath the adhesions.
(4) Hormonal effects: Articular cartilage changes are evident in acromegaly. Growth hormone (somatotrophin) stimulates chondrocytes, accelerating and enhancing their metabolic activity. As animals age, the deficiency of growth hormone becomes apparent, causing chondrocyte degeneration and reduced metabolic activity.
(5) Chemical injury: Systemic or local use of chemical agents can impair the viability and metabolic activity of chondrocytes.
Intra-articular injection of corticosteroids significantly reduces synthetic activity, lasting from several hours to a week or longer. Systemic use of corticosteroids at immunosuppressive doses similarly leads to reduced anabolism and loss of PG (proteoglycans). Histological changes are termed focal chondromalacia or early osteoarthritis.
Alkaline drugs (such as nitrogen mustard or thiotepa) injected intra-articularly can injure articular cartilage.
(6) Repeated intra-articular hemorrhage: In patients with coagulation factor deficiencies, repeated intra-articular bleeding can cause severe damage to the articular cartilage and subchondral bone structure. Iron pigments in the cartilage matrix may alter its physicochemical properties, or chondrocytes phagocytosing large amounts of iron pigments in the cytoplasm may trigger lysosomal release of degradative enzymes. This results in decreased PG concentration and reduced synthetic activity of chondrocytes.
A single or occasional intra-articular hemorrhage may not cause serious problems.
(7) Age-related changes: Some researchers believe that fibrosis of the articular cartilage surface is age-related, occurring in specific asymptomatic areas (e.g., the inferomedial femoral head fovea in the hip or the medial articular surface of the patella), sometimes leading to osteoarthritis.
Age-related changes in articular cartilage: In normal individuals, articular cartilage undergoes changes with age. Age-related changes observed in immature cartilage also occur during skeletal maturation and adult aging. Importantly, these changes differ from those associated with disease processes, particularly osteoarthritis.
① Cellular changes: Immature epiphyseal cartilage has a higher cell-to-matrix ratio than adult cartilage. Mitotic activity is prominent in two zones. Cell division contributes to the gradual enlargement of epiphyseal cartilage. Proliferation of cells at the base of the epiphyseal cartilage is a sign of endochondral ossification, forming small ossification centers in the epiphyseal plate. As animals age, typically within months after birth, mitotic activity decreases, and chondrocyte composition progressively declines until the age of 2, after which the overall cellular structure remains unchanged in adults. Notably, the number of surface chondrocytes does not change with age. A reduction in surface layer cells and an increase in middle layer cells in intact articular cartilage are early signs of osteoarthritis.
②Collagen Aging is associated with an increase in the number of mature collagen fibers. The diameter of the entire fiber zone increases, often showing fragmentation, and adjacent degenerating cell clusters frequently contain a calcification center. At birth, the collagen fiber zone lacks organized arrangement, except for superficial fibers running tangentially. This pattern persists throughout normal aging, except for the deepest fibers near the bone, which exhibit a vertical orientation. Superficial fibers are often not arranged in bundles but remain perpendicular to the joint surface. In elderly individuals, the fibrous tissue layer is replaced by stored amorphous debris.
③ Synthesis of proteins and glycosaminoglycans (GAGs) The synthesis rate remains absolutely fixed to maintain a balance between degradation and synthesis. The half-life of proteoglycans in adult rabbit articular cartilage is short, with most having a half-life of about 8 days. Other components, such as collagen, have a much slower half-life. Under pathological conditions, the fixed ratio of synthesis changes, and in certain states of osteoarthritis and after injury, synthetic activity increases significantly.
④ Chemical composition Chondroitin-6-sulfate is the fundamental component of glycosaminoglycans (GAGs), accounting for approximately 45–75% of the total composition. In immature cartilage, glycosaminoglycans (GAGs) consist mainly of chondroitin-4-sulfate and small amounts of keratan sulfate. As animals age, the concentration of chondroitin-4-sulfate decreases in adults, accounting for less than 5% of the total GAGs. Additionally, the amount of keratan sulfate increases with age, reaching up to 50% in adult animals. Normally, higher levels of chondroitin-4-sulfate are found only in immature cartilage. During compensatory responses to injury or disease (e.g., osteoarthritis), chondrocytes regain their chondroblastic function, synthesizing large amounts of chondroitin-4-sulfate, leading to an increase in this type of GAG.
After observations in animals, similar measurements in mature human articular cartilage showed little change. With aging, there are no significant alterations in the water content, collagen, total hexosamine, chondroitin sulfate, total nitrogen, sulfur, or bone ash content of articular cartilage.
In human aging, it remains unclear whether changes in collagen fiber morphology or the aging process itself affects the generation and transformation properties of articular cartilage collagen fibers. Moreover, the role of articular collagen cross-linking in cartilage aging is not well understood.
⑤ Physical changes With aging, the permeability of articular cartilage decreases, reaching its maximum between the ages of 10 and 40. Furthermore, this change in permeability is more pronounced in the superficial layers of articular cartilage than in the deeper layers.
The elasticity of normal articular cartilage does not change with age. When articular cartilage is loaded, instantaneous deformation occurs, followed by a creep state (slow deformation). Upon unloading, the cartilage gradually recovers its original thickness over time. If the load is removed quickly, approximately 90% of the instantaneous deformation is recovered. In contrast, fibrocartilage undergoes much greater deformation under load, recovers slowly, and often incompletely.
Articular tensile stiffness refers to the secondary compressive effect produced by forces parallel to the joint surface. The role of tensile forces in aging joint surfaces requires further study. In osteoarthritis, when lesions are primarily in the superficial layer of articular cartilage, joint stiffness and weakness are not prominent, but as the lesions deepen, joint stiffness increases.
⑥ Nutrition of articular cartilage Only during the embryonic stage and for a short period afterward do blood vessels extend from the metaphysis of the bone to all parts of the articular cartilage and directly enter the epiphysis from the periphery. In immature articular cartilage, the epiphyseal plate has not yet closed, so nutrition is obtained through diffusion from metaphyseal blood vessels beneath the epiphyseal plate and synovial fluid secreted by the joint. After articular cartilage matures, marked by the formation of a calcified zone and closure of the epiphyseal plate, almost all nutrition is obtained through diffusion from synovial fluid. Under pathological conditions, such as osteoarthritis or complete cartilage defects, a compensatory response occurs where metaphyseal blood vessels penetrate the subchondral epiphyseal plate and re-enter the deep calcified zone of the cartilage.
bubble_chart Pathological Changes
(1) Changes under the Light Microscope Normal articular cartilage is smooth, moist, and bluish-white. The synovial membrane is smooth and whitish, connecting to the edges of the articular cartilage. The physiological aging process begins after the age of 20 and progresses with age. Changes in chemical composition, histological manifestations, synthetic and degenerative activities, as well as pathological characteristics, have been introduced in the previous section and should be distinguished from the changes of osteoarthritis or osteoarthropathy.
The early degenerative changes in the hyaline cartilage of a single joint surface are focal. Macroscopically, they appear dry, dull, yellowish, and lackluster, with a soft velvety feel on the fibrous surface. Microscopically, large lacunae are filled with about 20 chondrocytes (Weichselbaum's lacunae). This multicellular aggregation is termed "Chodron" or "Colne." Subsequently, the chondrocytes degenerate, appearing stellate or amorphous. With joint movement, pressure, and friction, the degenerated and exposed articular cartilage fragments become rough and patchy.
Normal cartilage matrix consists of tightly packed superficial collagen fiber bundles, a deep layer of randomly oriented fiber networks, and a bottom layer of vertically arranged fibers. Between the collagen fibers are glycoproteins (PG) and highly water-absorbent proteolytic products (PPS), among others. The refractive indices of collagen fibers and glycoproteins are the same, making the collagen fibers invisible. As degeneration progresses, glycoproteins (PG) are degraded and cleared, rendering the collagen fibers visible. The cartilage splits into numerous fissures. The vertical orientation of collagen fibers between deep fissures is the most distinctive feature of fibrillated osteoarticular cartilage. When cartilage is immersed in water, superficial collagen fiber bundles appear as fine, hair-like undulations, creating a velvety surface texture.
In some regions of the articular cartilage, regeneration and surface exfoliation occur. This suggests subsequent outcomes: complete disappearance of articular cartilage, exposure of subchondral bone to non-physiological forces, and fibrous fractures. Vascular cellular tissue fills the fissures, forming fibrocartilaginous tissue. This process resembles the repeated response of articular cartilage to complete defects caused by trauma or surgery.
Degenerative articular cartilage (especially in progressive degenerative joint disease) often shears off and enters the joint cavity, becoming a "joint mouse."
In the deep layers of articular cartilage, chondrocytes arrange in columns. Small vascular branches from the subchondral bone and marrow may extend into the calcified zone. The subchondral bone cortex thickens with new lamellar bone. This hypertrophy is a response to the loss of articular cartilage on the bone surface and increased vertical loading.
During remission (slowed disease progression), soft degenerative cartilage wears down, diminishes, is completely absorbed (by lysosomal enzymes), or expelled into the joint. The exposed subchondral bone then endures significant stress, triggering a strong osteogenic response due to increased vascularization. This change, driven by ongoing pressure and exacerbated by traction on the joint capsule, often extends to the joint margins, forming osteophytes that protrude into the joint capsule.
The synovial membrane proliferates, forming villi, and shows congestion and infiltration by mononuclear cells. Reactive inflammatory changes in the synovial membrane are less pronounced in non-weight-bearing or inactive joints. The synovial membrane may contain nests of chondrocytes due to tissue metaplasia or phagocytosis of cartilage fragments from the joint cavity. These chondrocyte nests may calcify, ossify, be completely absorbed, or form cartilaginous osteochondral bodies that extend into the joint.
At the stage of progress, the articular cartilage has completely worn away, and the subchondral bone cortex becomes hypertrophic and smooth, polished by continuous shear forces. As mentioned earlier, subchondral fractures occur, and the subchondral bone can no longer withstand vertical loads. Subchondral bone cysts may develop in areas of maximum stress. Within the synovial membrane, soft bone tumors and osteochondromas continuously form, either still attached by a pedicle or floating freely in the joint. After the "joint mouse" detaches from the articular attachment tissue, its blood supply is lost, leading to necrosis of the central bone nucleus. Meanwhile, the surface cartilage derives nutrients from the synovial fluid, allowing an additional layer of surviving cartilage to grow. The superficial layer of the cartilage may calcify at any time, followed by the formation of a new additional layer of cartilage. This process repeats itself. Consequently, a cross-section of such a "joint mouse" reveals alternating layers of calcified and non-calcified tissue, along with a central necrotic bone nucleus.
1. Vascular Changes There is dilation and proliferation of blood vessels in the subchondral region. In the early stages of osteoarthritis, the initial changes occur in the superficial layer of articular cartilage, showing blood vessels penetrating from the subchondral bone marrow through the calcified cartilage zone at the base. The structure of subchondral trabeculae becomes sparse and weakened due to congestion. Additionally, the loss of elasticity in articular cartilage prevents the dissipation of forces, increasing the stress on subchondral bone and leading to trabecular fractures. As trabeculae collapse and compress, new bone forms, and the fracture sites become denser. Partial bone tissue necrosis results in the formation of a dense bone segment as new bone appears alongside compressed bone tissue.
Increased vascularity indicates a reactive response to new bone formation, leading to osteophyte formation in non-weight-bearing areas and dense new bone in weight-bearing regions.
2. Cysts Bone cysts are radiolucent areas confined to the upper part of weight-bearing bone segments, typically located within the cortical bone deep to the dense articular surface. Cysts may contain loose, myxoid, dense, or fibrocartilaginous fibrous tissue. Numerous thin-walled venous anastomotic venules occupy the cystic bone structure and connect with slender, small stirred pulses. No blood vessels are visible within the cysts.
The cyst walls are formed by coarse trabeculae. When pressure is relieved (e.g., through surgery), the cysts undergo revascularization and osteogenesis, leading to their disappearance.
3. Microscopic Findings in Various Stages of Osteoarthritis There are three stages:
(1) Early Stage: Irregularity of the articular surface and fibrous tissue formation, with small fissures not extending beyond the superficial layer; Grade I hypercellularity of chondrocytes; slight reduction in mucopolysaccharides, not extending beyond the transitional zone or middle layer.
(2) Grade I Progressive Stage: Worsening damage to the articular surface, with small fissures extending throughout the middle layer of articular cartilage, occasionally involving the calcified layer; mucopolysaccharide reduction in the middle layer; increased chondrocyte clusters or cell division.
(3) Stage of Progress: Reduction in cartilage thickness; fissures extending to subchondral bone; significant mucopolysaccharide loss throughout the full thickness of articular cartilage; complete loss of articular cartilage in some areas of the articular surface, exposing dense subchondral cortical bone.
4. Histological Progressive Changes Osteoarthritis is a focal disease, with significant variations in histological, histochemical, biochemical, and metabolic changes across different regions of the same articular cartilage. Therefore, the following characteristics reflect the progressive developmental process of osteoarthritis.
The earliest histological changes in osteoarthritis are the disappearance of the superficial layer of articular cartilage, diffuse hypercellularity of chondrocytes, and Grade I reduction in metachromatic staining, indicating proteoglycan (PG) depletion. Blood vessels from the bone surface grow into and penetrate the cartilage. Vascular penetration throughout the cartilage is a hallmark feature of osteoarthritis and may contribute to osteophyte formation.
As osteoarthritis progresses, vertical clefts begin to appear on the cartilage surface. Initially, these clefts pass through the transitional layer, approaching densely packed tangential fiber bundles, which become deformed in the fiber bundle layer. As the disease worsens, the fissures deepen, extending to the calcified zone, resulting in fibrous formation and chondromalacia. Staining with metachromatic dyes (e.g., alcian blue) or orthochromatic dyes (e.g., safranine-O) shows progressively reduced color intensity in the matrix, indicating further loss of glycoproteins (PGs). At this stage of osteoarthritis, the most prominent feature of chondrocytes is their heightened metabolic activity. Chondrocyte numbers increase, forming clusters or clones, which are the most distinctive abnormalities in osteoarthropathy.
In the advanced stage of osteoarthritis, chondrocytes become eroded, eventually leading to the complete disappearance of focal lesion areas on the surface, exposing the underlying sclerotic and dense bone due to cartilage detachment. Subchondral bone cysts form, and the bone surface may be partially covered by newly formed cartilage repair zones, extending to marginal osteophytes.
(II) Ultrastructural Characteristics The following introduces electron microscopic studies, which will describe the pathological changes of osteoarthritis in each zone as early, intermediate, and late (third) stages.
1. Superficial Zone
(1) Matrix
① Early stage In certain regions of the articular surface, osteoarthritis still exhibits a thin, acellular layer of filamentous matrix covering the surface. This covering layer appears bright, possibly indicating the adsorption of macromolecules such as hyaluronic acid or proteoglycans (PG). The superficial collagen fibers exhibit a unique distribution pattern: collagen fiber bundles form small fiber bundles separated by gaps. In normal articular cartilage, collagen fiber bundles are closely packed and arranged at right angles, with small gaps and parallel to the articular surface.
② Intermediate stage (second stage) The articular surface loses its fine linear covering and develops numerous infoldings. Mature collagen fiber bundles align parallel to these infolded surfaces. As a result, individual collagen fibers and fiber bundles separate, exhibiting large areas of low electron density, likely reflecting a reduction in proteoglycans (PG).
③ Late stage The superficial layer of articular cartilage is covered by amorphous material and disrupted by deep fissures. Mature collagen fibers align parallel to the vertically oriented, fine filamentous articular surface. The inter-fiber spacing increases, and the electron density of the inter-fiber matrix decreases.
(2) Cells
① Early stage Some superficial chondrocytes remain viable, while others exhibit degenerative changes. The viable cells enlarge and elongate, with their long axes parallel to the articular surface. These cells contain abundant intracellular organelles, including prominent rough endoplasmic reticulum, clearly visible Golgi bodies, vacuoles, and a few mitochondria. The nuclei are irregular, often bilobed. The cytoplasm displays numerous branched projections. Mature collagen fibers are observed adjacent to the cell membrane. The cells exhibit fibroblast-like characteristics, with active metabolic activity suggesting collagen synthesis.
② Grade II stage of progress Chondrocyte clusters are frequently observed near cartilage fissures. These cell clusters, unlike the uniformly filamentous mucopolysaccharide-wrapped cell groups seen in deeper cartilage, are surrounded by fine collagen fibers. The nuclei and cytoplasmic organelles show no degenerative changes, with intact nuclei and cell membranes, prominent rough endoplasmic reticulum, Golgi bodies, and mitochondria. The organelles are well-developed.
③ Late stage Degenerative cells are generally observed in both the superficial and deep layers of articular cartilage. A prominent feature is the perinuclear arrangement of abundant filaments, lysosomes, prominent rough endoplasmic reticulum, and sparse Golgi bodies. Degenerative cells are surrounded by numerous spherical fibers (nuclear spacing 12 nm, diameter 120 Å), with mature collagen fibers located near the cell membrane. The number of such cells increases with the progression of osteoarthritis and aging.
2. Middle Zone
(1) Matrix
① Early stage Collagen fibers measure 20–160 nm (200–1600 Å) in diameter, arranged irregularly with large inter-fiber spacing and reduced electron density in the inter-fiber gaps.
② Grade II stage of progress Collagen fibers align more perpendicular to the articular surface, differing from the normal random arrangement.
③ Late stage Collagen fibers perpendicular to the articular surface become more pronounced.
(2) Cells
①Early stage: The chondrocytes are surrounded by a ring of thin filamentous fibrils. The cells are round, with abundant cytoplasm containing numerous mitochondria, well-developed rough endoplasmic reticulum, Golgi apparatus, lipid droplets, and few lysosomes. The presence of centrioles suggests possible cell regeneration. A large number of chondrocytes with highly developed organelles were observed in patients of different ages with early to grade II progressive osteoarthritis.
② Grade II stage of progress: The chondrocyte nests in the middle cartilage layer generally consist of 1 to 20 cells. Individual chondrocytes are surrounded by a filamentous fibrous ring and a large number of degenerated chondrocytes. Compared to the middle layer of normal articular cartilage in individuals of the same age, the number of chondrocytes is often 2 to 3 times higher, and an increase in organelles is also observed.
③ Stage of progress: A significant increase in the number of degenerated chondrocytes at various stages is observed.
3. Deep layer
⑴ Matrix: Under normal conditions, the arrangement of deep-layer collagen fibers only becomes perpendicular to the articular surface with aging. In young individuals, antagonism occurs, and the fibers are not arranged perpendicular to the articular surface. However, in osteoarthritis, unrelated to aging, collagen fibers are arranged perpendicular to the articular surface and separated from the matrix. This change is particularly seen in the normal articular cartilage of young individuals.
⑵ Cells: In early osteoarthritis, most chondrocytes exhibit early signs of degeneration: an increase in filamentous material within the chondrocytes, often located around the nucleus, and a reduction in organelles. By the Grade II stage of progress and the stage of progress, almost all chondrocytes are at various stages of degeneration, surrounded by an extracellular ring of mature collagen fibers, often with large diameters. The nuclei are dense, and the cytoplasm contains large coiled filaments, elongated and enlarged mitochondria, lysosome-like structures, and a small amount of rough endoplasmic reticulum.
Early osteoarthritis changes include: minor irregularities on the articular surface, the disappearance of a thin filamentous layer (the glossy layer), reduced electron density of the inter-fibrillar matrix, cellular changes, significant enlargement of superficial and middle-layer cells, an increase in the number of Golgi bodies, rough endoplasmic reticulum, and central granules. The change in cell number during degeneration is an increase in superficial and deep-layer cells. As osteoarthritis progresses, superficial layer folds deepen and extend inward. Collagen fibers align parallel to the superficial layer fissures and run perpendicular to the articular surface in the middle and deep layers. Surviving chondrocytes may exist singly or in clusters, exhibiting cellular hypertrophy across all cartilage layers, along with an increase in the number of intracellular organelles, which is associated with active intracellular synthetic activity. As osteoarthritis worsens, the number of degenerated chondrocytes increases, containing large amounts of intracellular filaments and lysosome-like structures. In progressive osteoarthritis, all cells show degeneration and some micro-scars.
(3) Biological characteristics of normal articular cartilage: To understand the biological changes in osteoarthritis articular cartilage, it is essential to first review the biological characteristics of normal articular cartilage. Below are key points summarized from relevant research.
1. Isolation: Articular cartilage is avascular and alymphatic, and except during the developmental phase of the epiphysis, it does not directly contact the vascular system. Nutrients must pass through two diffusion barriers to reach chondrocytes. In mature adults, all nutrients must first exit the synovial membrane vascular plexus, pass through the synovial membrane to reach the synovial fluid, and then diffuse through the dense matrix of hyaline cartilage to reach the chondrocytes. In immature animals, the basal layer of articular cartilage can receive some nutrients via diffusion from subchondral blood vessels.
The cartilage matrix allows free diffusion of nutrients, but the diffusion of macromolecular nutrients is concentration-dependent. The diffusion of polyionic glycosaminoglycans (GAGs) is strong, theoretically determined by pore sizes of 6.8 nm (68 Å). In normal articular cartilage, even low-molecular-weight proteins diffuse very slowly through the cartilage matrix.
2. Hypocellularity: The cell density of articular cartilage is very low. Despite the sparse cellular composition, chondrocyte activity is also limited. Fixed sections of chondrocytes appear small and pyknotic, with irregularly shaped nuclei. Chondrocytes are metabolically active cells, continuously synthesizing matrix components and participating in the catabolic processes of degeneration. Some matrix components exhibit rapid turnover.
3. Matrix Biochemistry The articular cartilage of a normal person is a highly hydrated tissue, with a water content as high as 80%. The remaining components are organic substances, consisting of macromolecular solids, with collagen fibers and proteoglycans (PG) each accounting for half. The collagen macromolecules in cartilage are composed of 3α-1 (II) chains (in contrast to the antagonistic bone and skin collagen, type I, which consists of 2α-1 chains and 1α-2 chains). Moreover, the α-1 (II) chain of type II collagen differs structurally from the α-1 (I) chain of type II collagen. The α-1 (I) chain of type I collagen has an increased number of hydroxylysine residues and enhanced glycosylation of hydroxylysine. There are also differences in intra- and intermolecular cross-links.
Proteoglycans (PGs) are composed of a series of high-molecular-weight compounds. These compounds are synthesized intracellularly and extracellularly through the aggregation of proteoglycan chains around a central hyaluronic acid core. The smallest sub-proteoglycan (PG) has a linear protein backbone approximately 200 nm (2000 Å) long, linked to polydimeric sugars (GAGs) of 50 nm or longer. At least three distinct proteoglycans (PGs) have been identified in articular cartilage: chondroitin 6-sulfate, chondroitin 4-sulfate, and keratan sulfate.
Normally, as animals age, the concentration of chondroitin 4-sulfate decreases by less than 5% compared to the total glycosaminoglycan (GAG) content in adults. Scanning of immature cartilage shows that the amount of keratan sulfate increases with aging, potentially rising to 50% of the GAG content in adult cartilage tissue. Chondroitin 6-sulfate is the predominant glycosaminoglycan (GAG), accounting for approximately 45–75% of the cartilage tissue composition.
4. Metabolic Activity The metabolic activity of normal chondrocytes is highly active. Under metabolic (EM, metabolism) conditions, chondrocytes in the middle layer of articular cartilage exhibit a rough-surfaced endoplasmic reticulum forming an extensive network, dilated cisternae, organelles, and Golgi bodies, indicating the synthesis of various matrix components. Radioisotopic studies reveal synthetic activity, with proteoglycan sugars (PGS) and collagen components assembling intracellularly before rapidly entering the extracellular matrix. This process ensures continuous renewal of the extracellular matrix. The half-life of proteoglycans is 8 days, while collagen turnover takes even longer. The renewal of proteoglycans may involve lysosomal enzymes and extralysosomal enzyme systems.
5. DNA Synthesis Under normal conditions, chondrocyte regeneration can be demonstrated by the uptake of tritiated thymidine, but only in immature articular cartilage. Chondrocyte regeneration occurs in two layers: the superficial layer, possibly associated with epiphyseal cartilage growth during active skeletal growth, and the basal layer near the proliferative zone of the epiphyseal ossification center. With aging, mitotic activity first decreases in the superficial layer and eventually ceases in the mature stage. No mitotic forms are observed in normal adult articular cartilage. Under certain conditions (e.g., cartilage tears or osteoarthritis), chondrocytes may resume DNA synthesis and cell division activity.
6. Metabolism of Osteoarthritic Cartilage In human osteoarthritis, the synthetic activity of articular cartilage is significantly heightened. The increased ratio of sulfate (SO4) incorporation in osteoarthritic chondrocytes indicates an elevated synthesis rate of proteoglycans (PGs). The glycosaminoglycan (GAG) and protein synthesis rates in human osteoarthritis are twice those of normal articular cartilage, with the proteoglycan (PG) synthesis rate proportional to the severity of osteoarthritis. As the condition worsens, one affected aspect is proteoglycan (PG) synthesis. Measuring PG synthesis via SO4 incorporation, a significant decline suggests that the chondrocytes' physiological response capacity has been exceeded, indicating failure in chondrocyte regenerative function.
Using 3H-thymidine (3H-thymidine) as the active substance, the measurement of DNA synthesis can reveal the proliferation rate of cells. The speed of DNA synthesis correlates with the severity of osteoarthritis. In grade I or grade II osteoarthritis, the increased rate of DNA synthesis reflects the doubling division of cells, and histologically, cell clusters or cell masses can be observed. When osteoarthritis fully progresses to the stage of progress, the incorporation of 3H-thymidine rapidly decreases, indicating the cessation of cellular repair activity. Therefore, in cases of extremely severe osteoarthritis, the repair process is lost.
7. Biochemical Changes In osteoarthritis, the proteoglycan (PG) content of cartilage decreases, and the extent of reduction is proportional to the severity of osteoarthritis. This depletion is demonstrated by the decrease in constant charge density and changes in staining intensity with basic dyes. Although the total glycosaminoglycan (GAG) content of articular cartilage decreases, the effects vary among different macromolecular glycosaminoglycans: compared to normal levels, keratan sulfate decreases relatively, while chondroitin 4-sulfate increases.
When measured by hydroxyproline, the collagen component remains undetectable. However, changes occur in the morphology, chemical structure, and synthesis rate of collagen. Osteoarthritic chondrocytes synthesize not only type II collagen (α1II)3 chains but also significant amounts of type I collagen (α1I2α2). Consequently, the collagen fibers produced by osteoarthritic articular cartilage more closely resemble those of skin and bone collagen fibers than those of normal articular cartilage. Osteoarthritic collagen fibers are larger in diameter and more irregularly distributed, especially in the superficial layers of cartilage.
Normal articular cartilage contains about 72–78% water. In contrast, osteoarthritic articular cartilage exhibits a significant increase in water content. Although the hydrophilic proteoglycan (hydroxyproline-containing proteoglycan) decreases in osteoarthritic cartilage, it retains water sufficiently and exhibits a stronger affinity for water than normal articular cartilage. The cause of this phenomenon remains unclear. When 4M guanidinium hydrochloride is used to extract some proteoglycans from articular cartilage, the increased water-binding capacity can be reproduced.
8. Enzymes in Osteoarthritic Cartilage Enzymatic degradation is a major factor in the development of osteoarthritis. Theoretically, both hyaluronidase and protease can degrade proteoglycans. An acid cathepsin present in the lysosomes of chondrocytes has a strong hydrolytic effect on the protein core of macromolecular proteoglycans (PPS-proteinpolysaccharides). Since cathepsin is most active at acidic pH, its hydrolytic action under neutral conditions in normal tissue may be more relevant. When acid phosphatase levels are significantly elevated, it reflects a marked increase in lysosomal activity (acid phosphatase is a marker for lysosomes).
Initially, the protein core is cleaved. Finally, currently unidentified enzymes, such as polysaccharidases, sulfatases, and hexosaminidases, degrade glycosaminoglycans (GAGs).
Chloroquine is a potent inhibitor of cathepsin D. Cortisone and salicylates do not have this effect. Producing antibodies against cathepsin D can prevent cartilage autolysis.
9.osteoarthritis The physical changes in articular cartilage—measurements of creep, elastic modulus (coefficient), and stiffness in viscoelastic materials show close correlation with glycosaminoglycan (GAG) content and slight correlation with collagen content. Cartilage that appears normal but has begun to degenerate does not harden (rather softens) as the condition worsens. Although osteoarthritis changes may exhibit focal distribution, signs of stiffness are generally not prominent when degeneration extends to another area. Changes in creep modulus precede cartilage fibrillation. Since creep modulus correlates with glycosaminoglycan (GAG) concentration, alterations in creep modulus represent pathological changes occurring after GAG depletion.
10. Cartilage fatigue and mechanical abnormalities in the joints can lead to secondary osteoarthritis. For example, meniscectomy increases contact pressure on the side where the meniscus was removed, thereby raising the likelihood of osteoarthritis changes in that part of the joint. Hip joint incongruity, whether congenital or acquired, reduces the contact area of the joint and thus increases the chance of osteoarthritis.
Non-loaded cartilage consists of a hydrostatic proteoglycan (PG) gel embedded within a pre-tensioned collagen network. The pressure is approximately 354.64 kPa (3½ atmospheres). Therefore, the compressive capacity of articular cartilage is proportional to the amount of proteoglycan (PG) in the cartilage matrix, while its tensile properties are proportional to the collagen structure (and also to the amount of collagen).
The tensile properties of articular cartilage vary from the superficial to the deep layers, and this difference is related to the collagen structural composition of the cartilage. In the superficial layer of articular cartilage, the tension is tangential.
The tensile strength and stiffness of articular cartilage change with age. As age increases, the tensile strength and stiffness of articular cartilage decrease.
Throughout a person's life, articular cartilage undergoes cyclic loading, with its surface under normal compression. This cyclic loading can lead to cartilage fatigue injury. Fatigue refers to mechanical damage occurring in the loaded articular cartilage after repeated applications of the same magnitude of load, whereas a single application of the same load does not cause fatigue changes. The decreased resistance to fatigue in articular cartilage with aging reflects a tendency toward fatigue. Repeated compressive loading on the articular cartilage surface causes fragmentation, resulting in manifestations similar to fibrosis.
These facts indicate that osteoarthritis-related cartilage fatigue injury leads to fibrosis, thereby causing fatigue failure of the collagen fiber network in the cartilage. This explains why the incidence of osteoarthritis increases with age.
Although the amount of collagen in the cartilage matrix does not decrease with aging or the onset of osteoarthritis, the mechanical structural relationships of the collagen fiber network are compromised, likely due to breakage of the collagen fibers themselves or their cross-links. Once the articular cartilage surface fragments, the collagen fibers that normally retain proteoglycans (PG) may rupture, leading to their depletion solely due to this damage.
bubble_chart Clinical Manifestations
Although the aging process is a chronic and progressive change (as seen on X-ray examination), only 5% of people over 50 years old exhibit clinical symptoms of osteoarthritis. Pain in the joints is triggered by mechanical obstruction due to loose bodies, subchondral fractures, cartilage debris encapsulated by the synovial membrane, or other factors.
The onset is insidious. Typically, there is grade I persistent dull pain, which may be localized to one side of the joint or diffusely present around the joint. The pain worsens with joint movement and may lessen with rest. The pain becomes significantly more severe due to swelling of the synovial membrane caused by low barometric pressure. This is a well-known phenomenon (pain varying with weather changes). Stiffness occurs in the joints after rest and relaxation, particularly noticeable in the morning. Heat and salicylate preparations are most effective in alleviating joint pain and stiffness.
1. Clinical Findings: Non-inflammatory joints may exhibit palpable membranes and audible dry crepitus. In the progressive stage, marginal proliferation of the joint, thickening of the joint capsule, and enlargement of the joint are observed. Movement is restricted. Severe joint destruction leads to markedly limited movement, with joint deformity consistent with the extent of destruction. Complete loss of joint movement never occurs. When inflammation is present, increased synovial fluid may cause localized tenderness within the joint space. There is no muscular rigidity or atrophy. Heberden's nodes are a distinctive manifestation of osteochondral enlargement on the dorsal aspect of the distal interphalangeal joints. These nodes typically appear on multiple fingers, either spontaneously or following trauma, and are particularly common in postmenopausal women. The nodes are either painless or quickly accompanied by pain, swelling, and tenderness upon appearance. The masses may be soft, sometimes cystic, or exhibit sclerotic features. The enlarged masses are primarily cartilaginous and thus may not be detectable on X-ray. Systemic symptoms are generally absent. Age: middle-aged or elderly. Gender: Diffuse osteoarthritis is more common in women, with osteoarthropathy often developing postmenopause. In men, it is more frequently associated with weight-bearing joints. Predilection sites: distal interphalangeal joints, lumbar spine, knees, hips, lower cervical vertebrae, sacroiliac joints, and elbows. Patients often have an obesity-type body shape.
2. Laboratory Findings: Erythrocyte sedimentation rate, blood cell count, and hematopoiesis are normal; the heat agglutination test is positive. 10–30% of patients exhibit hypothyroidism in thyroid morphology. Synovial fluid analysis can differentiate degenerative joint disease from rheumatoid arthritis and infectious arthritis. During acute inflammatory reactions, when the joint accumulates a large amount of fluid, the joint fluid resembles normal synovial fluid—clear, transparent, slightly yellow, viscous, and without clot formation. The cell count is normal (60–3000), predominantly mononuclear. Glucose concentration matches blood levels, and protein content does not exceed 5.5g/100mL.
In contrast, the synovial fluid in rheumatoid arthritis is thin, turbid, and forms clots upon standing. The Ropes test is positive in rheumatoid arthritis but negative in osteoarthritis. The cell count is often elevated above 3000, primarily polymorphonuclear cells, with total synovial fluid protein frequently exceeding 8g, and globulin concentration often equal to or greater than albumin.
When osteoarthritis coexists with rheumatoid arthritis, the synovial fluid may exhibit features of both diseases. Thus, even if the synovial fluid shows typical characteristics of rheumatoid arthritis, osteoarthritis cannot be ruled out, meaning synovial fluid analysis alone can only confirm the primary disease cause. Additionally, if the synovial fluid exhibits osteoarthritis features, rheumatoid arthritis may be in a quiescent phase. If both conditions are suspected, repeated synovial fluid examinations are necessary.
3. X-ray Findings: Early-stage osteoarthritis appears normal on X-ray. Later, gradual narrowing of the joint space reflects thinning of the articular cartilage covering the cortex. In advanced stages, progressive osteoarthropathy leads to marked joint space narrowing, sharpening of joint margins, formation of osteophytes (bone spurs) at the edges, subchondral bone thickening and sclerosis, and bone cysts in areas of maximum subchondral pressure. A negative X-ray does not exclude osteoarthritis. Conversely, even with typical X-ray findings, primary osteoarthritis cannot be definitively confirmed. Degenerative changes often coexist with other conditions, such as gout, infectious arthritis, and rheumatoid arthritis, which warrant attention.
bubble_chart Treatment Measures
When osteoarthritis affects the entire body or a few joints, it is considered a benign condition. Most degenerative joint diseases involve multiple joints, gradually worsen, and are relatively non-disabling. Patients often seek medical attention due to generalized joint pain, stiffness, or acute pain in a single joint. Non-surgical therapy aims to halt disease progression, alleviate joint pain and stiffness, prevent joint deformity, and improve joint movement and stability.
In some cases of osteoarthritis, which progresses as a single-joint disease with severe functional impairment due to pain, limited mobility, joint deformity, or intra-articular derangement, surgical treatment becomes necessary.
### (I) Conservative Treatment The following outlines the principles of non-surgical treatment for single or multiple joints. For surgical treatment of individual joints, refer to orthopedic surgery.
1. **Rest** Reducing stress and shear forces on the affected joint allows synovial membrane inflammation to subside. This is mostly used when osteoarthritis symptoms are severe or degeneration is worsening. During acute episodes in a single joint, it is best to rest the affected joint in bed to relax the joint capsule and ligaments, thereby reducing pressure on the joint surfaces.
2. **Joint Movement** To prevent joint capsule contracture, perform full-range joint movements several times daily. However, vigorous movements that significantly compress joint surfaces must be avoided.
3. **Weight Avoidance** Use crutches or assistance to avoid weight-bearing on the affected joint.
4. **Use of Walking Aids** A cane on the opposite side of the affected joint can reduce vertical load on weight-bearing joints. In advanced osteoarthritis or bilateral joint involvement, bilateral canes, crutches, or assistance may be needed. Patients should be taught proper gait techniques.
5. **Traction During Acute Inflammation** For weight-bearing joints, traction can prevent joint surface adhesions and capsule contracture until acute inflammation subsides.
6. **Physical Therapy** After massage and functional exercises (active and passive movements), damp-heat therapy can be applied. Avoid forceful attempts to restore lost joint motion. For painful Heberden’s nodes, warm water or paraffin therapy may be helpful.
Although joint stress should be minimized, active exercises (isometric exercises) are better than passive exercises (isotonic exercises) for improving muscle strength.
7. **Maintaining Proper Mechanical Posture** Avoid unfavorable joint mechanics, use shoe inserts, and perform staged functional exercises for the entire joint.
8. **Orthopedic Appliances** Removable plaster splints ensure rest and daily physical therapy. For lumbar osteoarthritis, a simple plastic or textile corset may suffice. Braces are more effective for immobilization. Although not highly recommended, elastic bandages can limit excessive joint movement when necessary. A half-ring ischial seat brace reduces weight-bearing pressure on the lower limb, while a leather sleeve immobilizes the knee.
9. **Electrical Iontophoresis Therapy** Typically using mecholyl or histamine, though its efficacy is unreliable.
10. **X-ray Therapy** Its presumed effects include reducing inflammation and scar formation. Although some advocate its use, symptom relief is not long-lasting, and its therapeutic value is limited.
11. Corticosteroids Corticosteroid suspensions are sometimes used as solutions for intra-articular injections, which can relieve pain and swelling within hours to days and improve mobility. No systemic reactions have been observed. Steroids exert their effects through anti-inflammatory actions, with symptom relief durations varying from weeks to months. The injection schedule is set at fixed intervals, determined by the duration of therapeutic effects, aiming to keep the patient pain-free and able to continue treatment, although it does not halt disease progression.
Intra-articular corticosteroid injections have been shown to have detrimental effects on articular cartilage, inhibiting the synthetic activity of chondrocytes and causing a reduction in proteoglycan content within the cartilage matrix. This effect is reversible within two weeks, indicating the minimum interval required between joint injections.
Commonly used preparations include hydrocortisone, third-generation hydrocortisone butylacetate, triamcinolone (fluoroxyprednisolone), 6-methyl prednisolone, and dexamethasone.
12. A hot, dry climate is beneficial for recovery.
13. Graded functional exercise Muscle imbalances can lead to abnormally high stress concentrations on one side of the joint, significantly accelerating the degenerative process. A structured, graded exercise program should be implemented to improve and balance the muscular forces acting on the joint.
14. Pharmacotherapy Medications can relieve pain and reduce inflammation but do not halt the progression of the pathological process. Salicylates are the most effective drugs for pain relief and anti-inflammatory effects. Experimental evidence suggests that salicylates may inhibit cartilage degradation and reduce hexosamine and hydroxyproline levels, though this has not yet been confirmed.
⑴ Acetylsalicylic acid (aspirin) Aspirin serves as both an analgesic and an anti-inflammatory agent and is the preferred drug for osteoarthritis. A therapeutic dose must be achieved for efficacy. The initial dose is 640 mg, taken four times daily, with gradual increases until symptom relief is obtained. Elderly patients are more prone to toxic effects and gastrointestinal discomfort. If tinnitus or hearing impairment occurs, aspirin should be discontinued immediately. For gastrointestinal symptoms, buffered aspirin, enteric-coated tablets, salicyl-salicylic acid, magnesium salicylate, or choline salicylate may be used.
⑵ Acetophenetidin (phenacetin) If aspirin is not tolerated, phenacetin may be substituted. The usual dose is 300 mg four times daily, but long-term use is not recommended due to the risk of nephritis.
⑶ Acetaminophen Acetaminophen is both an analgesic and antipyretic with minimal toxicity and side effects, though it may potentiate oral anticoagulants. The adult dose is 325–650 mg three times daily; for children aged 7–12, 162–325 mg three times daily; and for children aged 3–6, 120 mg three times daily.
⑷ Propoxyphene hydrochloride (dextropropoxyphene, Darvon) For pain relief, propoxyphene hydrochloride 65 mg may be combined with ethoheptazine citrate (Zactane) 75 mg as needed or three times daily.
⑸ Pentazocine (Talwin) For severe pain, the oral dose is 50 mg. Common side effects include nausea, rash, and vertigo (light-headedness).
(6) Indomethacin (Indocin) - An analgesic and anti-inflammatory drug. Must be used with caution, especially in patients who react to aspirin. Total dose 75 to 150mg, divided into several doses, taken with food or antacids to reduce gastrointestinal discomfort, gastrointestinal bleeding, headache, vertigo, and other reactions.
(7) Phenylbutazone (phenylbutazone, butazolidin) Its derivative oxyphenylbutazone (Tandearil) has low toxicity. Possible toxic effects include: bone marrow suppression, upper gastrointestinal bleeding, edema (water retention), and dermatitis. If there is any justification for routine use, repeated blood cell counts must be performed.
(8) Liniment (liniment) The application of liniment to the affected area may produce "counterirritation" hyperemia and pain relief. Methyl salicylate is commonly used. Its effect is likely psychological.
(2) Surgical Treatment Surgical therapy is considered to relieve pain, improve joint function, correct deformities and malalignment, reduce vertical load and shear forces, eliminate intra-articular disease causes that erode joint surfaces, and when the disease is clearly progressive and meets surgical indications, artificial joint replacement may be performed to create a new joint. Arthrodesis is merely a method to relieve pain and stabilize joint function, and should only be used when other more conservative surgical options are impossible or have already failed.
