pathophysiology+of+osteoarthritis

Osteoarthritis is an idiopathic disease Characterized by degeneration of

articular cartilage Leads to fibrillation, fissures, gross

ulceration and finally disappearance of the full thickness of articular cartilage

Most common MSK disorder worldwide Enormous social and economic

consequences Multifactorial disorder

Ageing Genetics Hormones Mechanics

Primary lesion appears to occur in cartilage

Leads to inflammation in synovium Changes in subchondral bone,

ligaments, capsule, synovial membrane and periarticular muscles

Avascular, alymphatic and aneural tissue

Smooth and resilient Allows shearing and compressive forces

to be dissipated uniformly across the joint

Chondrocytes are responsible for metabolism of ECM

They are embedded in ECM and do not touch one another, unlike in other tissues in the body

Chondrocytes depend on diffusion for nutrients and therefore the thickness of cartilage is limited

Extracellular matrix is a highly hydrated combination of proteoglycans and non-collagenous proteins immobilized within a type II collagen network that is anchored to bone

Divided into four morphologically distinct zones:

Superficial: flattened chondrocytes high collagen-to-proteoglycan ratio and high

water content. Collagen fibrils form thin sheet parallel to

articular surface giving the superficial zone an extremely high tensile stiffness

Restricts loss of interstitial fluid, encouraging pressurization of fluid

Transitional zone: Small spherical chondrocytes Higher proteoglycan and lower water

content than superficial zone Collagen fibrils bend to form arcades

Radial Zone: Occupies 90% of the column of articular

cartilage Proteoglycan content highest in upper radial

zone Collagen oriented perpendicular to

subchondral bone providing anchorage to underlying calcified matrix

Chondrocytes are largest and most synthetically active in this zone

Calcified zone: Articular cartilage is attached to the

subchondral bone via a thin layer of calcified cartilage

During injury and OA, the mineralization front advances causing cartilage to thin

Critically dependent on composition of ECM

Type II (IX&XI) provide 3D fibrous network which immobilizes PG and limits the extent of their hydration

When cartilage compresses H2O and solutes are expressed until repulsive forces from PGs balance load applied

On removing load, PGs rehydrate restoring shape of cartilage

Loading and unloading important for the exchange of proteins in ECM and thus to chondrocytes

Chondrocytes continually replace matrix macromolecules lost during normal turnover

Chondrocytes secrete degradative proteinases which are responsible for matrix turnover

These include: collagenases (MMP-1), gelatinases (MMP-2), stromolysin (MMP-3), aggrecanases

Normal cartilage metabolism is a highly regulated balance between synthesis and degradation of the various matrix components

The equilibrium between anabolism and catabolism is weighted in favor of degradation

Disruption of the integrity of the collagen network as occurs early in OA allows hyperhydration and reduces stiffness of cartilage

Catabolism of cartilage results in release of breakdown products into synovial fluid which then initiates an inflammatory response by synoviocytes

These antigenic breakdown products include: chondrointon sulfate, keratan sulfate, PG fragments, type II collagen peptides and chondrocyte membranes

Activated synovial macrophages then recruit PMNs establishing a synovitis

They also release cytokines, proteinases and oxygen free radicals (superoxide and nitric oxide) into adjacent and synovial fluid

These mediators act on chondrocytes and synoviocytes modifying synthesis of PGs, collagen, and hyaluronan as well as promoting release of catabolic mediators

It is believed that cytokines and growth factors play an important role in the pathophysiology of OA

Proinflammatory cytokines are believed to play a pivotal role in the initiation and development of the disease process

Antiinflammatory cytokines are found in increased levels in OA synovial fluid

TNF-α and IL-1 appear to be the major cytokines involved in OA

Other cytokines involved in OA are: IL-6, IL-8, leukemic inhibitory factor (LIF), IL-11, IL-17

Formed as propeptide, converted to active form by TACE

Binds to TNF-α receptor (TNF-R) on cell membranes

TACE also cleaves receptor to form soluble receptor (TNF-sR)

At low concentrations TNF-sR seems to stabilize TNF-α but at high concentrations it inhibits activity by competitive binding

Formed as inactive precursor, IL-1β is active form

Binds to IL-1 receptor (IL-1R), this receptor is increased in OA chondrocytes

This receptor may be shed from membrane to form IL-1sR enabling it to compete with membrane associated receptors

Induce joint articular cells to produce other cytokines such as IL-8, IL-6

They stimulate proteases They stimulate PGE2 production Blocking IL-1 production decreases IL-6

and IL-8 but not TNF-α Blocking TNF-α using antibodies

decreased production of IL-1, GM-CSF and IL-6

Increases number of inflammatory cells in synovial tissue

Stimulates proliferation of chondrocytes

Induces amplification of IL-1 and thereby increases MMP production and inhibits proteoglycan production

Chemotactic for PMNs Enhances release of TNF-α, IL-1 and IL-

6

Enhances IL-1 And IL-8 expression in chondrocytes and TNF-α and IL-1 in synoviocytes

Regulates the metabolism of connective tissue, induces expression of collagenase and stromolysin

Stimulates cartilage proteoglycan and NO production

3 are spontaneously made in synovium and cartilage and increased in OA

IL-4, IL-10, IL-13 Likely the body’s attempt to reduce the

damage being produced by proinflammatory cytokines, these two processes are not balanced in OA

Decreases IL-1 Decreases TNF-α Decreases MMPs Increases IL-Ra (competitive inhibitor of

IL-1R) Increases TIMP (tissue inhibitor of

metalloproteinases) Inhibits PGE2 release

Competitive inhibitor of IL-1R, not a binding protein of IL-1 and it does not stimulate target cells

Blocks PGE2 synthesis Decreases collagenase production Decreases cartilage matrix production

IL-10 decreases TNF-α by increasing TNFsR

IL-13 inhibits many cytokines, increases production of IL-1Ra and blocks IL-1 production

Neutralization of IL-1 and/or TNF-α upregulation of MMP gene expression

IL-1Ra suppressed MMP-3 transcription in a rabbit model

Upregulation of antiinflammatory cytokines

Primary etiology of OA remains undetermined

Believed that cartilage integrity is maintained by a balance obtained from cytokine driven-driven anabolic and catabolic processes

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