Osteoarthritis

Osteoarthritis

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

Factors responsible

• Ageing• Genetics• Hormones• Mechanics

Pathologic lesions

• Primary lesion appears to occur in cartilage• Leads to inflammation in synovium• Changes in subchondral bone, ligaments,

capsule, synovial membrane and periarticular muscles

Normal Cartilage

• Avascular, alymphatic and aneural tissue• Smooth and resilient• Allows shearing and compressive forces to

be dissipated uniformly across the joint

Structure of Normal Cartilage

• 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


Function of Normal Cartilage

• 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

Function of Normal Cartilage

• 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

OA cartilage

• 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

Degenerative cartilage

Mechanisms responsible for degradation

• 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

Mechanisms responsible for degradation

• 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

Synovial changes

Cytokines in OA

• 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

Proinflammatory cytokines

• 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

TNF-α

• 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

IL-1

• 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

TNF-α and IL-1

• 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

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

IL-8

• Chemotactic for PMNs• Enhances release of TNF-α, IL-1 and IL-6

Leukemic inhibitory factor (LIF)

• 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

Antiinflammatory cytokines

• 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

IL-4

• 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

IL-1Ra

• 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, IL-13

• IL-10 decreases TNF-α by increasing TNFsR• IL-13 inhibits many cytokines, increases

production of IL-1Ra and blocks IL-1 production

Osteoarthritis and Joint Replacement

• Once bone – bone articulation develops, joint replacement (Arthroplasty) is only viable option.

• Most common in Knees and Hips.• Very serious surgeries. Often takes months /

years to get back to full strength (if ever)

Knee Arthroplasty aka Total Knee Replacement (TKR)

Possible Side Effects of Knee Arthroplasty

• blood clots in the leg • blood clots in the lung • urinary infections or difficulty urinating • difference in leg length • stiffness • loosening of prosthesis• infection in knee

• 90% + report increased ROM following surgery• 25% report loosening of prosthesis @ 10 years–Caused by osteolysis; inflammatory

response: reabsorption of bone• Lots of isometric exercises and walking

Knee Arthroplasty

Possible Side Effects of Hip Arthroplasty

• blood clots in the leg • blood clots in the lung (1-2% Occurrence)• urinary infections or difficulty urinating • difference in leg length • stiffness • dislocation of hip • infection in hip

• Dislocation Prevention (2-3% Occurrence)– using 2-3 pillows between your legs while sleeping

and not crossing your legs – not bending forward 90 degrees

• Exercise– Lots of isometric exercises will be prescribed to

strengthen muscles surrounding joint– Lots of walking, cycling, swimming, etc.• Avoid high impact exercises and follow guidelines

listed above regarding prevention of dislocation.

Hip Arthroplasty

• 90 – 95% success rate @ 10 years post op.• Average lifespan 12 – 15 years– Less if active (IE Younger person)

• Very effective at providing complete pain relief– Often have to keep person from “over doing it”

Hip Arthroplasty

Usually Occurs @ the “Surgical Neck” of Femur

Often results in disruption of blood flow….Avascular Necrosis *

*

Hip Fractures

• Usually requires surgery– THR–ORIF (Open Reduction, Internal Fixation)• Uses plates, rods, & screws to fixate femoral

fracture• Post operative Exercise– Isometrics, ROM exercises– SLOWLY progress to weight bearing exercises

as directed by Physician

Treatment of Hip Fracture

• One year post mortality is as high as 40% (leading cause of “traumatic death” in elderly)

• Very small percentage regain previous mobility• 20% require nursing home care following

fracture• Often results in accumulation / increase in

incidence of other health problem– CAD, diabetes, stroke, pneumonia,etc…

Hip Fractures

Facts about Hip Fractures and Osteoporosis

• 44 million Americans suffer from osteoporosis and/or low BMD

• 80% are Women / 20% Men• Women can lose up to 20 percent of their bone

mass in the five to seven years following menopause, making them more susceptible to osteoporosis.

Risk of Hip Fracture and BMD

Facts about hip fractures and Osteoporosis

• Annual cost associated with osteoporotic fractures is $17 billion in 2001 ($47 million each day).

• One in two women and one in four men over age 50 will have an osteoporosis-related fracture in their lifetime. – 300,000 hip fractures; and approximately – 700,000 vertebral fractures, – 250,000 wrist fractures; and – 300,000 fractures at other sites.

• MOST ARE PREVENTABLE!!!