INTRODUCTION — In the past, osteoarthritis (OA) was considered to be simply a degenerative "wear and tear" process and therefore often misnamed as degenerative joint disease. However, the pathogenesis of OA is much more complex than just wear and tear and the term "osteoarthritis," where "-itis" is indicative of an inflammatory process, is indeed correct [1,2]. There are a variety of factors that play an important role in the pathogenesis of OA, including biomechanical factors, proinflammatory mediators, and proteases. By understanding the mechanisms driving joint tissue destruction in OA and identifying the key factors involved, new targets for therapy are emerging that will go beyond symptomatic relief to slowing or stopping the progression of OA .
This topic will review the pathogenesis of OA. The diagnosis, treatment, and other issues related to OA are discussed separately. (See "Investigational approaches to the management of osteoarthritis" and "Clinical manifestations and diagnosis of osteoarthritis" and "Overview of the management of osteoarthritis" and "Management of knee osteoarthritis" and "Management of moderate to severe knee osteoarthritis" and "Management of hip osteoarthritis" and "Management of hand osteoarthritis" and "Overview of surgical therapy of knee and hip osteoarthritis".)
ROLE OF INFLAMMATION — Classically, inflammatory arthritis was defined in part based on cellular inflammation represented by increased numbers of leukocytes in the affected joint tissues and synovial fluid. Classic cellular inflammation is not prominent in osteoarthritis (OA), where the number of leukocytes in the joint fluid is normally low, and rarely exceeds 1000 to 2000 cells per milliliter. This is in contrast to forms of inflammatory arthritis, such as rheumatoid arthritis (RA), where the number of synovial fluid leukocytes will commonly exceed 2000 and will be accompanied by a more extensive synovial infiltrate of leukocytes with synovial fibroblast proliferation resulting in pannus formation. Synovial inflammation is also present in OA and in some individuals can be indistinguishable from RA. An important difference is that macrophages are the predominate leukocyte found in OA synovium, while in RA there are more T cells and B cells . At the molecular level, OA is characterized by the presence of a host of proinflammatory mediators, including cytokines and chemokines, that are part of an innate immune response to joint injury .
As will be further discussed below, proinflammatory factors appear to be driving the production of the proteolytic enzymes responsible for the degradation of the extracellular matrix that results in joint tissue destruction. Although destruction and loss of the articular cartilage is a central component of OA, all joint tissues are affected in some way, indicating that OA is a disease of the joint as an organ . Mechanical factors certainly play a key role in OA and there is some debate in the field as to the extent to which OA is mediated by abnormal joint mechanics. However, the balance of evidence suggests that rather than simply causing joint tissue damage by wear and tear, excessive or abnormal joint loading stimulates joint tissue cells to produce proinflammatory factors and proteases that mediate joint tissue destruction. (See 'Inflammatory mediators' below and 'Proteases' below.)
OVERVIEW OF PATHOLOGY — Osteoarthritis (OA) is one of the most common causes of chronic disability in adults due to pain and altered joint function that result from characteristic pathologic changes in the joint tissues and their processing in a biopsychosocial context (figure 1). The pathologic findings described below are present to varying degrees in all people with OA, suggesting a common response of the joint to a variety of insults that results in "failed repair" and subsequent OA.
The order in which particular joint tissues are affected may depend on the initiating factors. With the exception of posttraumatic OA that starts with an acute injury to a key joint tissue component, such as a ligament tear, it is often difficult to know exactly which joint tissues are affected first. Plain radiographs underestimate the joint tissue involvement in OA since they only visualize a component of the condition including cartilage loss that results in joint space narrowing and bony changes that result in subchondral sclerosis, cysts, and osteophyte formation. Once these changes are apparent on radiographs, the condition has significantly advanced. Magnetic resonance imaging (MRI) studies can detect early disease and have provided evidence of matrix changes in cartilage, synovitis, bone marrow lesions, and degenerative changes in soft-tissue structures beyond the cartilage including ligaments and the knee menisci [5,6]. As OA progresses, it eventually affects the entire joint, resulting in failure of the component parts. However, OA does not progress at a similar rate in all individuals and not everyone with early disease will develop more severe OA. Predicting which patients will advance to the end stages of the disease remains a challenge.
●Articular cartilage – Although commonly thought of as a "shock absorber," articular cartilage primarily serves to provide a smooth, low-friction surface that allows for the normal gliding motion of the joint. Most of the load on the joint is absorbed by other tissues, including periarticular muscles and subchondral bone and, in the knee, the meniscus. Hyaluronic acid is the substance in the synovial fluid that provides viscosity, but it requires the presence of a large mucinous protein called lubricin (also known as proteoglycan-4 or superficial zone protein) to provide a low-friction state and protect the joint surface, including the superficial zone chondrocytes, from shear stresses . The collagen fibers provide the tensile strength and form a network that restrains the very hydrophilic proteoglycans that provide resiliency.
The earliest pathologic changes in OA are commonly seen at the surface of the articular cartilage with fibrillation in focal regions that experience maximal loading. The cartilage initially swells as the collagen network loosens allowing the hydrophilic proteoglycans to attract water and expand. Chondrocytes, the only cell type present in cartilage, are normally quiescent. Chondrocytes are active cells maintaining cartilage through normal anabolic/catabolic activities. As OA develops, this activity dramatically accelerates: chondrocytes proliferate (to a modest degree) and form clusters, likely in response to loss of matrix. At least a portion of the cells undergo a phenotypic switch to a hypertrophic chondrocyte which is similar to the cells found in the hypertrophic zone of the growth plate that produce type X collagen and matrix metalloproteinase (MMP)-13. As OA progresses, extensive matrix degradation and loss occurs due to the continued production of proteases driven by proinflammatory cytokines and fragments of matrix proteins that feedback and stimulate chondrocytes in an autocrine and paracrine manner to produce more cytokines and proteases. Cartilage has limited capacity to repair, and once collagen is degraded and lost, it is not replaced to a measurable degree . As significant matrix damage occurs, chondrocyte death can be seen, resulting in areas of matrix devoid of cells.
●Bone – Thickening of the subchondral bone (bone sclerosis) occurs due to increased production of collagen that is improperly mineralized. Osteophytes (bony spurs) form at the joint margins, often at the insertion site of tendons or ligaments. The subchondral sclerosis and osteophytes seen in OA occur as part of a joint remodeling process intended to stabilize the joint in response to abnormal mechanical loads. In more advanced disease, bone cysts occur but bone erosions are not typically seen. An exception to the latter is erosive OA that most commonly noted in the distal joints of the hands (distal interphalangeals and proximal interphalangeals) and is associated with centrally located erosions that differ in location from the marginal erosions seen in rheumatoid arthritis (RA) and gout. Bone marrow lesions, evident on MRI, can be seen most commonly in areas with overlying cartilage loss and where mechanical loads are greatest. Pathologically, these focal lesions consist of microstructural damage to bone accompanied by localized necrosis and fibrosis . Sensory nerves in bone marrow lesions and subchondral bone are potential sources of pain in OA .
●Synovium – Most people with symptomatic OA will exhibit some degree of synovial inflammation (synovitis) and/or synovial hypertrophy during the course of OA [11,12]. Unlike RA and other forms of so-called inflammatory arthritis, synovitis is not thought to be the initiating factor in primary OA and, as noted above (see 'Role of inflammation' above), different immune cell types are present, with macrophages being predominant in OA . Synovitis contributes to pain and disease progression , including cartilage destruction, mediated by the production of proinflammatory factors and proteins referred to as damage-associated molecular patterns (DAMPs), including the alarmins [2,5]. Secondary OA can be seen in joints previously affected by inflammatory arthritis, although the pathology is somewhat different from that of primary OA due to the prior effects of a more striking inflammatory component that causes more extensive joint destruction including bone erosions.
●Soft tissues – In addition to the cartilage, soft-tissue components of the joint, including ligaments, the joint capsule, and, in the knee, the menisci, are commonly affected by OA. These tissues exhibit disruption of their extracellular matrix and loss of cells. Thickening of the joint capsule along with osteophytes contribute to the enlargement observed in OA joints. In older adults with established OA, it is quite common to find tears in ligaments and the meniscus, which, without a history of prior joint injury, are most likely degenerative in nature . In addition to the effects of meniscal tears on joint mechanics, studies have shown that torn menisci can be a source of inflammatory mediators in the joint . Periarticular muscles and nerves are also affected by OA resulting in weakness and pain .
MULTIPLE PATHWAYS TO OSTEOARTHRITIS — The pathologic changes in osteoarthritis (OA) joints described above are commonly present, particularly in advanced stages of the disease, no matter the inciting factor (see 'Overview of pathology' above). However, the pathway from initiating factors to disease can vary. This has led some in the field to think of OA as a spectrum of conditions representing different OA phenotypes rather than a single disease. We discuss several factors below that are thought to play a role in the pathogenesis of OA.
Risk factors — Multiple risk factors have been linked to the pathogenesis of OA. Risk factors for OA include age, joint injury, obesity, genetics, anatomical factors including joint shape and alignment, and sex .
●Aging – Because OA is most clearly a condition associated with aging, a separate section below will review the aging changes that promote the development of OA. (See 'Aging' below.)
●Joint injury – OA that develops after injury to a joint is commonly called posttraumatic OA. The pathologic changes are often evident within 10 years after injury, with the time of onset influenced in part by the age of the individual at the time of injury . OA can develop after injuries that result in ligament and/or meniscal tears, or after injuries such as fractures that involve the joint . Tears incite acute inflammation with joint swelling that is particularly severe when a major ligament, such as the anterior cruciate ligament (ACL), is torn. Studies have shown a host of inflammatory mediators, including tumor necrosis factor (TNF)-alpha (elevated sixfold) and interleukin (IL) 6 (elevated 1000-fold), are present shortly after injury ; however, levels of specific inflammatory mediators have not predicted the future development of OA . The risk of developing OA after an ACL tear is the same whether the ligament is repaired or not . This suggests that either the mechanics of the joint are not completely restored after ACL reconstruction or that the acute inflammation that occurs with the tear puts the OA process in motion and it is not stopped by reconstruction of the ligament. The latter is supported by studies demonstrating that markers of collagen and proteoglycan degradation are present acutely after injury and sustained over time .
●Obesity – Body weight is a risk factor for OA not only in weightbearing joints including the knee and hip, but also in the hand [24,25]. Excess weight will certainly produce increased load on the joint, but there is growing evidence for a metabolic contribution to OA. This would explain the association of obesity with hand OA and why not all overweight and obese individuals develop knee or hip OA . Macrophages within adipose tissue are a source of proinflammatory cytokines, including IL-6 and TNF-alpha, and adipocytes produce adipokines such as leptin. The cytokines associated with obesity may promote a low-grade, systemic, proinflammatory state that could contribute to the development of OA, while leptin has been proposed to have direct effects on joint tissues that promote the development of OA . Metabolic OA related to obesity may also involve altered lipid metabolism and increased activity of peroxisome proliferator-activated receptor (PPAR)-delta .
●Genetics – Heredity forms of OA due to certain rare mutations in collagen types II, IX, or XI, which are structural collagens found in articular cartilage, result in premature OA that can begin as early as adolescence, resulting in a severe destructive form of arthritis that affects multiple joints [28,29]. Because the vitreous of the eye also contains these collagen types, some patients also have eye disease. These mutations are causes of Stickler syndrome which affects 1 in 7500 to 9000 newborns (see "Syndromes with craniofacial abnormalities", section on 'Stickler and Marshall syndromes'). Less severe forms of OA also have a genetic component which, from twin studies, has been estimated to explain approximately 40 percent of the risk for OA . At least 100 risk loci have been discovered by genome wide-association studies with perhaps the most consistent association being found for polymorphisms in the gene that codes for growth and differentiation factor (GDF)-5, which is a bone morphogenetic family member that plays a role in joint development [30,31]. Mutations in GDF-5 are thought to predispose to OA due to altered joint shape. Genetic studies (other than the rare collagen mutations mentioned above) have found that individual genes provide a very slight increase in the risk for OA (odds ratios in the 1.2-1.4 range), suggesting that either multiple genes are needed for a more substantial OA risk or that environmental factors and/or epigenetics are important. (See 'Other pathways' below.)
●Anatomic factors – Joint shape, particularly of the hip, can influence the development of OA. Congenital acetabular dysplasia is associated with premature hip OA that often requires joint replacement. An important anatomic factor related to knee OA is lower-extremity alignment. Individuals who have a varus alignment (bow-legged) are at increased risk of medial tibial-femoral OA, while those with a valgus alignment (knocked-knee) are at risk for lateral tibial-femoral OA . The relationship of anatomic factors to OA is best explained by altered joint mechanics as the initiating cause for OA. Altered mechanics that place excessive and abnormal loads on joint tissue cells activate mechanotransduction pathways that result in increased production of inflammatory mediators and proteolytic enzymes .
●Sex – OA of the hands and knees is more common in women than men, while hip OA is equally prevalent . The strong association of OA with age could explain why OA is more common in the postmenopausal years, although there is some evidence that loss of estrogen could be a contributing factor [34,35].
Aging — OA is clearly related to aging, with both the incidence and prevalence of OA increasing with age . However, it is also clear that aging of joint tissues and the development of OA are distinct processes. Rather than being one and the same, aging changes most likely make the joint more susceptible to the development of OA and promote progression. The aging changes within the joint that contribute to OA can be divided into aging of the extracellular matrix and cellular aging. Matrix changes include thinning of the articular cartilage with age, reduced hydration, and an accumulation of proteins containing advanced glycation end-products (AGEs) . AGEs cause increased crosslinking of collagen, resulting in altered biomechanical properties characterized by increased "brittleness" . AGEs are best known for their role in diabetes, where their production is facilitated by chronic elevations in glucose (eg, hemoglobin A1c, which is glycosylated hemoglobin). In cartilage, AGEs can form and accumulate independent of blood glucose levels. The most likely explanation is the very long half-life of matrix proteins in cartilage, particularly type II collagen, which has a half-life calculated at over 100 years . The low turnover rate in cartilage  allows for a very slow accumulation of AGEs that are not removed as they would be in tissues that have a higher turnover of their matrix such as bone.
Another age-related matrix change seen in cartilage, as well as the meniscus, is abnormal calcification referred to as "chondrocalcinosis." Chondrocalcinosis is most commonly results from the accumulation of calcium pyrophosphate dihydrate (CPP) crystals, although basic calcium phosphate and hydroxyapatite crystals may also play a role . Chondrocalcinosis is associated with episodes of acute crystal-induced mono- or oligoarticular arthritis or pseudogout that is most commonly due to CPPD crystals. It is thought, although still debated, that chondrocalcinosis could contribute to the development of OA . Chondrocalcinosis is often seen in joints which also have radiographic evidence of OA; abnormal calcification could alter the mechanical properties of joint tissues, and crystal-induced inflammation that results from activation of the innate immune system in joint tissues could contribute to OA by stimulating production of proinflammatory mediators.
There are a host of cellular changes that can link aging and OA. These include mitochondrial dysfunction related to oxidative stress and mitochondrial DNA damage; reduced responsiveness to anabolic growth factor stimulation including insulin-like growth factor (IGF) 1 and transforming growth factor (TGF) beta; cell senescence that results in the senescence-associated secretory phenotype (SASP); and a reduction in the process called autophagy, which is a protective mechanism responsible for the degradation and removal of damaged cellular constituents . These cellular changes contribute to an imbalance between anabolic activity mediated by growth factors that is necessary to produce and repair damaged matrix and catabolic activity mediated by proinflammatory mediators and proteases that promote joint tissue destruction. (See 'Inflammatory mediators' below and 'Proteases' below.)
Inflammatory mediators — Inflammatory mediators may play a role in the pathogenesis of OA as potential drivers of joint tissue destruction. The list of proinflammatory mediators found in the synovial fluid and tissues affected by OA continues to grow. Early studies focused on the role of the cytokine IL-1 which was initially named "catabolin" due to its ability to stimulate cartilage catabolic activity resulting in matrix degradation. The role of IL-1 in OA has been questioned because the levels found in OA joints (in the pg/mL range) are much lower than the levels required to cause cartilage degradation (ng/mL range). In addition, clinical trials of IL-1 inhibition in knee OA  and in erosive hand OA  failed to demonstrate significant structural or symptom benefits. Other cytokines are present in OA synovial fluid at much greater levels than IL-1 or TNF-alpha, including IL-6, macrophage chemotactic protein (MCP) 1, interferon-induced protein (IP) 10, and monokine induced by interferon (MIG) . Data from genetically modified mice have shown inconsistent protection from surgically induced OA in IL-1beta knockouts while IL-6 knockouts were protected from injury-induced OA but not age-associated OA, which was worse than the controls . However, secondary analysis of a cardiovascular trial of the anti-IL-1 antibody canakinumab in individuals with elevation of the inflammatory marker C-reactive protein noted a significantly lower risk for hip or knee replacement after a median follow-up of 3.7 years, suggesting that IL-1 inhibition for hip and knee OA still deserves further investigation . (See "Investigational approaches to the management of osteoarthritis", section on 'Interleukin 1beta inhibitors'.)
A number of other cytokines as well as chemokines have been found in synovial fluid or noted to be produced by articular chondrocytes and/or meniscal cells, including IL-7, IL-8, IL-15, IL-17, IL-18, IL-36, oncostatin M (OSM), growth-related oncogene (GRO)-alpha, chemokine (C-C-motif) ligand 19 (CCL19), macrophage inflammatory protein (MIP)-1beta, and TGF-alpha [2,5,47]. Other inflammatory mediators include the alarmins (S100 proteins) and the damage-associated molecular patterns (DAMPs). These mediators promote synovitis by attracting macrophages into the joint and promote matrix degradation by stimulating the expression of various proteases (see 'Proteases' below). Surprisingly, some studies have also provided evidence for complement activation in OA joints. Inhibition of complement activation by gene deletion or pharmacologic modulation was found to protect mice from surgically induced OA .
Important questions arise from examining the extensive list of inflammatory mediators found in OA joints. Experts have questioned what causes joint tissues to produce proinflammatory factors, and which are the most important drivers of joint tissue destruction that could serve as targets for therapeutic intervention. There is growing evidence that OA is associated with activation of the innate immune response that can be initiated by tissue damage [2,49]. The mediators found in the OA joint are similar to those found in a chronic nonhealing wound. The articular cartilage does not exhibit an adequate repair response, perhaps because it is avascular, and so once sufficient matrix damage has occurred it is not reversible. Fragments of matrix proteins, including fibronectin, cartilage oligomeric protein (COMP), fibromodulin, proteoglycans, and collagen are released from the damage matrix. These matrix fragments stimulate the innate immune response and further promote the upregulation of degradative pathways through activation of toll-like receptors and integrins [2,5,50]. Many of the proinflammatory and catabolic pathways at work in the OA joint involve activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) family of transcriptional regulators .
Proteases — The destruction of joint tissues in OA is mediated by a variety of proteases including several matrix metalloproteinases (MMPs), cysteine proteinases including cathepsin K, and serine proteinases . Our understanding of the proteases involved in OA is concentrated on those that mediate degradation of cartilage extracellular matrix proteins. Aggrecan is the large proteoglycan that provides much of the resiliency of cartilage. It is degraded, starting in the early stages of OA, by members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family referred to as aggrecanases (ADAMTS-4 and -5). Type II collagen, the most abundant collagen in cartilage, is responsible for the tensile strength of cartilage and is degraded by collagenases, which, like aggrecanases, are MMPs. MMP-13 is thought to be the major collagenase responsible for cartilage degradation in OA . Once significant collagen degradation has occurred, it is felt that repair of the damaged matrix is not possible and progression of matrix loss is likely. Given the importance of aggrecanse-2 (ADAMTS-5) and MMP-13 in OA, development of specific inhibitors to these proteases has been of interest for use as potential disease-modifying therapy . Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors found in joint tissues and synovial fluid that may serve as an alternative to synthetic small molecule inhibitors.
MMPs are produced as pro-forms that require proteolytic cleavage to be activated. Serine proteases, including HtrA1 and activated protein C, can serve this role and therefore could also serve as therapeutic targets in OA. Cathepsin K is a cysteine proteinase that is expressed by osteoclasts that can degrade type I collagen in bone but also may degrade type II collagen in cartilage.
Other pathways — Several studies have provided evidence for a number of potential mediators of OA that are not considered proinflammatory mediators but appear to promote OA by either activating pathways that promote joint tissue destruction or inhibiting the ability of cells to repair damaged matrix.
●FGF signaling – The concept that OA might recapitulate developmental processes has facilitated an exploration of the role of bone morphogenetic proteins (BMPs), fibroblast growth factors (FGF), and the Wnts . FGFs can promote chondrocyte proliferation and stimulate either anabolic or catabolic processes depending on which specific FGF receptor is activated. FGF-18 is a potent cartilage anabolic factor that signals through FGF receptor-3 and is being investigated as a potential intraarticular therapy for OA .
●BMP and Wnt signaling – Besides regulating joint development, the connection of BMPs and Wnts to OA is suggested by the concept that OA involves interactions between the subchondral bone (where BMPs and Wnts are also active) and the overlying articular cartilage . BMP-2 and TGF-beta produced locally in the joint appear to be major mediators of osteophyte formation in OA [57,58]. Excessive activation of the Wnt-beta catenin-signaling pathway in cartilage promotes chondrocyte hypertrophy and expression of matrix-degrading enzymes, possibly through Wnt-induced signaling protein 1 [56,59]. The role of Wnt family members in mediating the cartilage-bone connection is less clear, with conflicting results from gene deletion and inhibitor studies depending on the animal model used and the family member targeted . However, there are mouse model data to suggest that TGF-beta activity in subchondral bone mesenchymal stem cells may play a role in promoting degradation of the overlying cartilage . More work is needed to determine how this may apply to human OA, but the findings demonstrate that in some cases OA may originate in the bone rather than the articular cartilage.
●Epigenetics – Another area of active investigation in the pathogenesis of OA is epigenetics. Epigenetic control of gene transcription includes an expanding lists of processes such as DNA methylation, histone modifications (acetylation and methylation), micro-RNAs, and long noncoding RNAs. Using samples of cartilage or bone from normal and OA joints, a number of studies have found significant differences in DNA methylation patterns and likewise a growing list of micro-RNAs and long noncoding RNAs that differ between normal cartilage and OA cartilage [54,61-63]. It is not yet clear which of the various epigenetic changes play a key role in the development of OA in humans.
●Sirtuins – The sirtuin (SIRT) family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases provides a mechanistic link for the regulation of gene expression in response to altered energy metabolism. SIRT1 was found to be a key factor in the promotion of longevity in response to dietary restriction . SIRT1 serves as a histone deacetylase and mice lacking SIRT1 in cartilage develop spontaneous OA . There are additional SIRTs, including SIRT6, found in cartilage that may also have an important function in maintaining cartilage homeostasis .
CLINICAL IMPLICATIONS — Available treatments for osteoarthritis (OA) target pain, and none have been proven to alter the structural progression of the disease. As the understanding of the mechanisms underlying OA improves, treatments are being developed that target specific mediators thought to promote joint tissue destruction. Because OA results from a change in the balance of catabolic and anabolic activity in the joint, both anti-catabolic agents and pro-anabolic agents are being developed and tested. Discovery of new targets is being facilitated by identification of possible effector genes in large OA genome-wide analysis studies including four genes, TGFB1, GDF5, FGF18, and CTSK (cathepsin K), that have associated therapeutic agents in early-phase clinical trials . Studies demonstrating that removal of senescent cells in preclinical models of OA reduces OA severity have suggested that targeting cell senescence and the senescence-associated secretory phenotype (SASP) may be of therapeutic benefit in OA . (See "Investigational approaches to the management of osteoarthritis" and "Overview of the management of osteoarthritis".)
Until an agent that targets a specific mediator of OA is successfully shown to slow or stop structural progression, it will not be clear which mediators are key to the development and progression of OA. Given that joint tissues, including cartilage, are not capable of adequate intrinsic repair and that advanced disease involves the entire joint, resulting in significant alterations in joint mechanics, it is unlikely that treatment of advanced disease will be successful in reversing the OA process. Rather, targeting patients at earlier stages who are most likely to progress will be needed. Advances in imaging and biochemical biomarkers are bringing the field closer to identifying these patients .
Improvements in treating structural disease in OA will also require better phenotyping of patients based on the various pathways to OA . It is becoming evident that the pathways and mediators that promote the development of OA after joint injury (posttraumatic OA phenotype) are different from those associated with obesity (metabolic OA phenotype) and aging (age-related OA phenotype). In addition, in some individual factors in the bone may predominate (bone OA phenotype), or mechanical alterations (mechanical OA phenotype) or genetics (genetic OA phenotype) may be the driving forces.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteoarthritis".)
●Osteoarthritis (OA) was formerly considered to be simply a degenerative "wear and tear" process and therefore often misnamed as degenerative joint disease. However, the pathogenesis of OA is much more complex than just wear and tear and the term "osteoarthritis," where "-itis" is indicative of an inflammatory process, is correct. (See 'Introduction' above.)
●OA is one of the most common causes of chronic disability in adults due to pain and altered joint function that is associated with characteristic pathologic changes in the joint tissues (figure 1). Pathologic findings in articular cartilage, bone, synovium, and soft tissues are present to varying degrees in all people with OA, suggesting a common response of the joint to a variety of insults. (See 'Overview of pathology' above.)
●Multiple risk factors have been linked to the pathogenesis of OA, including age, joint injury, obesity, genetics, anatomical factors including joint shape and alignment, and sex. (See 'Risk factors' above and 'Aging' above.)
●Proinflammatory factors appear to be driving the production of the proteolytic enzymes responsible for the degradation of the extracellular matrix that results in joint tissue destruction. Although destruction and loss of the articular cartilage is a central component of OA, all joint tissues are affected in some way, indicating that OA is a disease of the whole joint as an organ. While mechanical factors play a key role in OA, excessive or abnormal joint loading also stimulates joint tissue cells to produce proinflammatory factors and proteases that mediate joint tissue destruction. (See 'Role of inflammation' above and 'Inflammatory mediators' above and 'Proteases' above.)
●There are a number of other potential mediators of OA that are not considered proinflammatory mediators but appear to promote OA by either activating pathways that promote joint tissue destruction or inhibiting the ability of cells to repair damaged matrix. (See 'Other pathways' above.)
●As the understanding of the mechanisms underlying OA improves, treatments are being developed that target specific mediators, including various growth factors and cytokines. Until an agent that targets a specific mediator of OA is successfully shown to slow or stop structural progression, it will not be clear which mediators are key to the development and progression of OA. (See 'Clinical implications' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Kenneth Kalunian, MD, and Susan Ritter, MD, who contributed to an earlier version of this topic review.
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