Pathophysiology of Osteoarthritis

Nurul Paramita Department of Physiology, Faculty of Medicine, Universitas Indonesia Jakarta, September 2013

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

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

What is Osteoarthritis ?
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 cartilage

Leads to fibrillation, fissures, gross ulceration and finally disappearance of the full thickness of articular Most common musculoskeleteal disorder worldwide

Enormous social and economic consequences

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

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

Pathophysiology OA
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

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

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

Hypothetical model of cartilage and subchondral bone interaction in OA

A: healthy chondrocytes suffering from a pathological strain B: Persisting strain C: Progressive phase of OA

H. Weinans , M. Siebelt , R. Agricola, S.M. Botter, T.M. Piscaer, J.H. Waarsing, Bone 51 (2012) 190196

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;29:178894

Risk Factors
Systemic Factors
Age
Gender Genetic &hereditary

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

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

Disease of mechanics

What causes OA?

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

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

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

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

Pathophysiology of OA
Inflammation in OA is mostly a consequence of pathomechanics
Joint injury, abnormal shaped joint, and/or excess load with consequent pathomechanics Inflammatory Cytokine Release (cartilage, synovium, other)

Joint damage

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

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

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

 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

Inflammation theory
Many soluble mediators (cytokines or prostaglandins) can increase the

production of MMP by chondrocytes led to the first step of inflammation theory inflammatory mediators

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

OA is a much more complex disease with inflammatory mediators released by

cartilage, bone and synovium

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

Inflammation theory
Synovitis
(local inflammation) Innate immunity

Low-grade systemic inflammation

Aging and inflammation

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

Synovitis (local inflammation in OA)

Cartilage degradation

Metalloproteinase synthesis Synovial angiogenesis

Cartilage fragment fall into the joint and contact the synovium

Mediators activate chodrocytes present in the superficial layer of cartilage

Considered foreign bodies, synovial cells react by producing inflammatory mediators

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

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

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)

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

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