pathophysiology of osteoarthritis

Pathophysiology of OsteoarthritisNurul ParamitaDepartment of Physiology, Faculty of Medicine, Universitas IndonesiaJakarta, September 2013

• Formerly referred to as osteoarthrosis and degenerative joint disease

• The most common form of arthritis

• Prior to 1986: no standard definition of OA existed; most discribed OA as a disorder of unknown etiology that primarily affects the articular cartilage and subchondral bone in contrast to rheumatoid arthritis, a disorder that primarily affects the synovial membrane

• 1986, the Subcommittee on Osteoarthritis of the American College of Rheumatology Diagnostic and Therapeutic Criteria Committee : A heterogeneous group of conditions that lead to joint symptoms and signs which are associated with the defective integrity of articular cartilage, in addition to related changes in the underlying bone at the joint margins

What is Osteoarthritis ?

Kenneth D. Brandt, Michael Doherty, L. Stefan Lohmander, editors. In: Osteoarthritis, 2nd ed. Oxford University Press, 2003.

• A group of overlapping distinct diseases, which may have different etiologies but with similar biologic, morphologic, and clinical outcomes

• Not only affect the articular cartilage, but involve the entire joint, including the subchondral bone, ligaments, capsule, synovial membrane, and periarticular muscles

• Defined as a focal lesion of the articular cartilage, combined with a hypertrophic reaction (sclerosis) in the subchondral bone and new bone formation (osteophytes) at the joint margins

• Leads to fibrillation, fissures, gross ulceration and finally disappearance of the full thickness of articular cartilage

• Most common musculoskeleteal disorder worldwide

• Enormous social and economic consequences


What is Osteoarthritis ?

Pathophysiology OA

• Not a degenerative disease

• A dynamic process

• A potential repair process in response to joint insult and cartilage destruction

• A variety of insults may trigger the need to repair. Once the process is initiated, all the tissues in the joint are involved in what may be considered an adaptive response

• The overall picture of OA resembles a failure in attempt at repair


• The initiating process : originates in the bone or in the cartilage?

• The heterogeneous character of the OA further complicates this discussion

• It is accepted that OA may occur as a consequence of multiple causes: • blunt joint trauma

• biomechanical overloading

• inborn or acquired joint incongruency

• genetic defects in matrix components or assembly

• imbalance of synovial homeostasis

• Probably, the osteoarthritic lesion may reflect a common endpoint

Pathophysiology OA


Hypothetical model of cartilage and subchondral bone interaction in OA

A: healthy chondrocytes suffering from a pathological strainB: Persisting strainC: Progressive phase of OA

H. Weinans , M. Siebelt , R. Agricola, S.M. Botter, T.M. Piscaer, J.H. Waarsing, Bone 51 (2012) 190–196

Rat knee joint showing the cartilage and subchondral bone of a normal (healthy) control (A) and of a rat that underwent a running protocol of 5 kilometers per week for a period of 6 weeks (B). A striking difference in GAG staining in cartilage and clear hypertrophy of chondrocytes in the deep cartilage zone

Siebelt M, et al. Quantifying osteoarthritic cartilage changes accurately using in vivo microCT arthrography in three etiologically distinct rat models. J Orthop Res 2011;29:1788–94

Risk Factors

Systemic Factors

Age

Gender

Genetic &hereditary

Estrogen defficiency

Nutritional factors (vitamin C & vitamin D)

Local Factors

Intrinsic Congenital & developmental deformities

Major joint injury

Malalignment

Extrinsic Obesity

Muscle weakness

Repeated use of joint (occupational & athletic activities)


OA are the result of an interplay between causes

A major injury (one cause) when combined with older age at the time of injury is more

likely to produce OA than a major injury alone

D.T. Felson / Osteoarthritis and Cartilage 21 (2013) 10-15

What causes

OA?

“Disease of mechanics”

Inflammation

OA as a disease of mechanics

• The hypothesis is that OA is caused by increased forces across a local area of a joint either from

(1) abnormal anatomy (congenital or acquired) leading to increased focal stress with the overall load across the joint being normal; or

(2) excess overall load either acutely or chronically such as might occur with an injury during sports or with obesity chronically; or

(3) a combination of anatomy and excess load

• Mechanical forces play a role in almost all OA but they do not necessarily act by themselves in causing disease


Abnormal mechanics causes OA

• The widespread use of surgically induced injuries that cause OA in animal models is among the best examples that abnormal mechanics causes OA.

• In humans there are many examples of major joint injuries or abnormally shaped joints produce high levels of focal stress across the joint causing OA• Removal or injury to meniscus• Tears of ACL• Varus or valgus malalignment of the knee accompany the onset of knee OA


Pathophysiology of OA

Joint injury, abnormal shaped joint, and/or

excess load with consequent

pathomechanics

Inflammatory Cytokine Release (cartilage, synovium, other)

Joint damage


• Inflammation in OA is mostly a consequence of pathomechanics

Facts to remember:

• Major risk factors for knee OA according to recent reviews include: older age, female gender, obesity, knee injury and occupational overuse

• Other than older age and female gender (which increase the vulnerability of structures within the knee to injury), all of the factors that have been identified, consistently represent types of mechanical overload


• The issue with respect to inflammation is not whether inflammation is present within osteoarthritic joints

• Rather the issue is how much and whether inflammation contributes to the joint damage experienced as a consequence of pathomechanics

• Many soluble mediators (cytokines or prostaglandins) can increase the production of MMP by chondrocytes led to the first step of “inflammation theory”

• Subchondral bone: not only a mechanical damper but also as a source of inflammatory mediators

• OA is a much more complex disease with inflammatory mediators released by cartilage, bone and synovium

Inflammation theory

F. Berenbaum, Osteoarthritis and Cartilage 21 (2013) 16-21

Inflammation theory

Synovitis (local inflammation) Innate immunity

Low-grade systemic inflammation Aging and inflammation


Synovitis (local inflammation in OA)

Cartilage degradation

Cartilage fragment fall into the joint and contact

the synovium

Considered foreign bodies, synovial cells react

by producing inflammatory mediators

Mediators activate chodrocytes present in the superficial layer of

cartilage

Metalloproteinase synthesis

Synovial angiogenesis


Innate immunity

• Innate immune system/non-spesific immune system: comprises the cells and mechanism that defend the host from infection by other organisms in a non specific manner

• Triggered by: binding of pathogen-associated molecular pattern (PAMPs) and danger-associated molecular pattern (DAMPs) on pattern-recognition receptors (PRRs)

• PRRs includes: TLRs, NODs, NALPs, etc

• PAMPs: bacterial and viral ligands and extracellular matrix molecules

• TLRs are increased in level in OA cartilage lesions (Kim HA,et al, 2006)

• TLR-2 and TLR-4 ligands have been found in OA synovial fluid (Scanzello CR et.al, 2008)


Low-grade systemic inflammation

• Additional data link the local production of inflammatory mediators to a more systemic pathway

• The risk of hand OA is increased two-fold in obese patients• Adipokines, leptin, adiponectin, resistin and visfatin have pro- and/or inti-inflammatory

properties in OA

• Metabolic syndrome (MetS) rather than obesity itself has the greatest impact on the initiation and severity of OA

• There is an independent association between carotid intima medial thickness with the prevalence of knee OA, and carotid plaque with distal interphalangeal OA• Oxidized lipids are the most likely triggering factors for cytokine production


Aging and inflammation

• Chondrocytes have a secretory senescence role , driven by oxidative stress

• Advanced glycation endproducts (AGEs), produced by a non-enzymatic process in aging tissues, weaken cartilage by modifying its mechanical properties.

• AGEs trigger chondrocytes activation by binding to specific receptors present in the surface of the chondroctes, called RAGE.

Direct link between mechanics and inflammation: mechanoreceptor signaling

• Any abnormal mechanical stress applied to a joint can be converted into activated intracellular signals in joint cells by mechanoreceptors present at the surface of joint cells (ion channels, integrin)

• These signals may eventually lead to the over-expression of inflammatory soluble mediators such as prostaglandins, chemokines and cytokines

Conclusion

• OA is not a degenerative disease, but a dynamic disease from repetitive insult-repair process

• OA are the result of an interplay between causes

• According to “mechanics” theory, OA is primarily caused by mechanical overload in certain joints

• There is increasing evidence that inflammation process plays a critical role in the symptoms and structural progression of OA; leading to ongoing researches to find a disease modifying OA drugs

pathophysiology of osteoarthritis

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