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Pathogenesis of osteoarthritis

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Pathogenesis of osteoarthritis
Topic Outline

 SUMMARY
 INTRODUCTION
 ROLE OF INFLAMMATION
 OVERVIEW OF PATHOLOGY
 MULTIPLE PATHWAYS TO OSTEOARTHRITIS
o Risk factors
o Aging
o Inflammatory mediators
o Proteases
o Other pathways
 CLINICAL IMPLICATIONS
 SOCIETY GUIDELINE LINKS
 SUMMARY
 ACKNOWLEDGMENT
 REFERENCES
GRAPHICS

 FIGURES
o - Pathogenesis of osteoarthritis

RELATED TOPICS
 Clinical manifestations and diagnosis of osteoarthritis
 Investigational approaches to the management of osteoarthritis
 Management of hand osteoarthritis
 Management of knee osteoarthritis
 Overview of surgical therapy of knee and hip osteoarthritis
 Overview of the management of osteoarthritis
 Society guideline links: Osteoarthritis
 Syndromes with craniofacial abnormalities

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Pathogenesis of osteoarthritis
Author:
Richard F. Loeser, MD
Section Editor:
David Hunter, MD, PhD
Deputy Editor:
Monica Ramirez Curtis, MD, MPH

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Feb 2018. | This topic last updated: Feb 02,
2018.

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 [3].

This topic will review the pathogenesis of OA. The diagnosis, treatment, and other
issues related to OA are discussed separately. (See "Overview of surgical therapy
of knee and hip osteoarthritis" and "Investigational approaches to the management
of osteoarthritis" and "Clinical manifestations and diagnosis of osteoarthritis" and
"Management of knee osteoarthritis" and "Overview of the management of
osteoarthritis" and "Management of hand 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. Although synovial inflammation is also present in OA and in some
individuals can be indistinguishable from RA, the inflammatory component of OA is
best appreciated at the molecular level and 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 [2].

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 [4].
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 also
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 pathological 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.

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 [4,5]. As OA progresses, it eventually
affects the entire joint, resulting in failure of the component parts. However, OA
does not progress to 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 [6]. 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 [7]. 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. 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 [8].
●Synovium – Most people with symptomatic OA will exhibit some degree of
synovial inflammation (synovitis) and/or synovial hypertrophy during the
course of OA [9,10]. Unlike RA and other forms of so-called inflammatory
arthritis, synovitis is not thought to be the initiating factor in primary OA.
However, synovitis contributes to pain and disease progression [11],
including cartilage destruction, mediated by the production of
proinflammatory factors and proteins referred to as damage-associated
molecular patterns (DAMPs), including the alarmins [2,4]. 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 [12]. 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 [13]. Periarticular muscles and nerves are
also affected by OA resulting in weakness and pain [14].

MULTIPLE PATHWAYS TO OSTEOARTHRITIS — The pathological 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 or
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 gender [15].

●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 [16]. 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 [17]. The risk of
developing OA after an ACL tear is the same whether the ligament is
repaired or not [18]. 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 [19].
●Obesity – Body weight is a risk factor for OA not only in weightbearing joints
including the knee and hip, but also in the hand [20,21]. 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 [22]. 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 [22].
Metabolic OA related to obesity may also involve altered lipid metabolism
and increased activity of peroxisome proliferator-activated receptor (PPAR)-
delta [23].
●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 [24,25].
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 [26]. Several 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 [26]. 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 [27]. 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 [28].
●Gender – OA of the hands and knees is more common in women than men,
while hip OA is equally prevalent [21]. 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 [29,30].

Aging — OA is clearly related to aging, with both the incidence and prevalence of
OA increasing with age [31]. 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) [32]. AGEs cause increased crosslinking of collagen,
resulting in altered biomechanical properties characterized by increased
"brittleness" [33]. 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 [34]. The low turnover rate in cartilage [7] 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 [35]. 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 [36]. 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, and a
reduction in the process called autophagy which is a protective mechanism
responsible for the degradation and removal of damaged cellular constituents [32].
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). 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) [37]. 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 [38].

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, oncostatin M (OSM), growth-related
oncogene (GRO)-alpha, chemokine (C-C-motif) ligand 19 (CCL19), macrophage
inflammatory protein (MIP)-1beta, and TGF-alpha [2,4]. 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 [39].

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 [2,40]. 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 [2,4,41]. 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 [42].

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 [43]. 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 [43]. 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 [44].
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 [45]. 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 [3].
●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 [46]. BMP-2 and TGF-
beta produced locally in the joint appear to be major mediators of osteophyte
formation in OA [47,48]. 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 [46,49]. 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 [45]. 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 [50]. 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 [45,51-53]. 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 [54]. SIRT1 serves as a histone deacetylase and mice lacking
SIRT1 in cartilage develop spontaneous OA [51]. There are additional SIRTs,
including SIRT6, found in cartilage that may also have an important function
in maintaining cartilage homeostasis [55].

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. (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 [56].

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".)

SUMMARY

●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). Pathological 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 gender. (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 thought to
affect bone turnover. 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.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to

acknowledge Kenneth Kalunian, MD; Susan Ritter, MD; and Peter Tugwell, MD,
who contributed to an earlier version of this topic review.

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Topic 5498 Version 24.0

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