5.1 - Cartilage Biology and Osteoarthritis

Question 1

What is osteoarthritis?

Answer 1

• disease of the whole joint which involves the loss of articular cartilage
• affects cartilage, soft tissue and bone
• can eventually lead to joint failure
• commonest form of arthritis, numbers rising

Question 2

What is the difference between normal articular cartilage and chondral defect?

Answer 2

• normal arthroscopy - you can see the two surfaces of the joints, articular cartilage
• articular cartilage is also known as hyaline cartilage
• smooth, moony white, deforms when probed but bounces back, resilient, tough, designed to take load
• chondral defect - raggedy edge (lose smooth, moony white), pink bone
• can give rise to pain and OA

Question 3

What does normal articular (hyaline) cartilage look like microscopically?

Answer 3

• toluidine blue stain - proteoglycans in ECM stained blue
• little spots = articular chondrocytes - the only cell in articular cartilage
• bottom = bone - calcified, tide mark
• bone –> deep/radial zone –> intermediate/transitional zone –> superficial zone
• deep zone: bone-like, chondrocytes are stacking, lot of proteoglycans
• intermediate zone: chondrocytes more widely spaced, more round
• superficial zone: flatter chondrocytes running parallel to articular cartilage surface

Question 4

What does healthy cartilage look like?

Answer 4

• proteoglycan (mainly aggrecan) - proteins and mucopolysaccharide chains - combination of protein and carbohydrate
• proteoglycan molecules are big
• they have negative charges = pull water into articular cartilage –> resilient and resists compression
• type II collagen fibrils - architecture and inherent tensile strength
• water molecules pulled in then held as collagen constraining the shape of the cartilage

Question 5

What is the chondrocyte?

Answer 5

• only cell in cartilage
• makes up <5% of the tissue
• produces and degrades the articular cartilage matrix arounds its ECM
• highly metabolically active
• exist in relative hypoxia - no blood vessels around
• interactions with ECM - growth factors, receive mechano-transduction signals from matrix
• no cell division after adolescence

Question 6

What is type II collagen and collagenases?

Answer 6

• type II collagen is the articular cartilage collagen
• metalloproteinase - MMP-1, MMP-8, MMP-13 are collagenases
• cleavage is 3/4 way along the collagen molecule
• other molecules can also act as collagenases e.g. cathepsin K

Question 7

What is aggrecan and aggrecanases?

Answer 7

• protein stems with three globular domains - G1, G2, G3
• side of backbone has mucopolysaccharide chains - chondroitin sulfate and keratin sulfate chains - highly -ve charged = pulls in water and holds it
• lots of these molecules join on to sugar backbone - hyaluronan chain
• two types of enzymes break down aggrecan at specific points:
• matrix metalloproteinases e.g. MMP-3 (a stromelysin)
• aggrecanases e.g. ADAMTS-4&5

Question 8

What are anabolic and anti-catabolic factors for articular cartilage in the joint?

Answer 8

• stop the breakdown of cartilage

Intrinsic:

• TIMPs (tissue inhibitor of metalloproteinases) 1-4
• growth factors e.g. fibroblast growth factor (FGF-2), insulin-like growth factor (IGF), transforming growth factor (TGF-B), activin A

Extrinsic:

• hormones e.g. testosterone, oestrogen
• some drugs e.g. FGF-18

Question 9

Why does matrix loss occur?

Answer 9

• excessive degradation - too much breakdown from these metalloproteinases
• reduced anabolism/repair

Question 10

How does mechanical load affect cartilage?

Answer 10

• cartilage/chondrocytes need mechanical load to maintain cartilage thickness and turnover - without this, there is cartilage atrophy e.g. in stroke patients
• compared to standing, the load going through the tibiofemoral joint of your knee increases:
• walking - 2-6x body weight
• jumping - 7-9x body weight
• running - 3-8x body weight
• climbing stairs - 3-10x body weight
• if you increase your weight by 5kg, your knees will support 15-30kg more pressure on walking
• load is always greater through the medial compartment of the knee

Question 11

What is the pathogenesis of osteoarthritis?

Answer 11

• many tissues are affected in the synovial joint in OA:
• articular cartilage
• subchondral bone
• ligament and soft tissue
• inflammation, repair and remodelling, pain pathways are important

Question 12

What are the molecular changes that precede structural changes in OA?

Answer 12

• excessive degradation
• proteoglycan is fragmented by aggrecanases
• collagen broken down by collagenases
• water - initial swelling of matrix, then lost

Question 13

What is the pathology of OA?

Answer 13

• early OA - loss of proteoglycans in superficial zone of articular cartilage
• there is then fibrillation of surface - loss of articular cartilage integrity, more loss of proteoglycan staining
• established OA - fissuring - loss of integrity going down into the cartilage rather than just superficial
• partial and full thickness loss, osteophytes (new bits of bone emanated that are generated as part of healing attempts), bone cysts, synovial inflammation

Question 14

What are the risk factors for OA development?

Answer 14

• age
• obesity - increased mechanical load, systemic inflammation
• mechanical factors e.g. joint injury, malalignment
• family history
• chondrodysplasias (e.g. defects in type II collagen) e.g. Stickler syndrome
• other medical conditions e.g. haemochromatosis
• secondary joint damage due to inflammatory arthropathies e.g. rheumatoid arthritis
• around 100 genetic variants associated with OA risk

Question 15

What is post-traumatic OA?

Answer 15

• OA following injury
• a model for understanding early mechanisms in OA
• 50% with meniscal or anterior cruciate ligament tear will develop OA within 5-10 years
• individuals are generally young (30s-40s)
• inflammatory response can be seen in the joint response to joint trauma (e.g. MMP-3, IL-6 in synovial fluid)

Question 16

What is the evidence for mechanical factors in OA?

Answer 16

• destabilising joint injuries increase risk of OA
• intra-articular fracture increases the risk of OA
• occupational examples of increased use - ‘Foundry workers’ elbow’; ‘Coal miners’ back’
• mal-aligned joints get OA e.g. varus malignment and medial joint OA
• paralysed joints are usually protected from OA

Question 17

What does meniscal destabilisation result in?

Answer 17

Progressive articular cartilage damage

Question 18

What kind of process is cartilage loss after injury?

Answer 18

• active biological process
• depends on an aggrecanase
• not just attrition/wear and tear, it is active

Question 19

What is a simple hypothesis for OA?

Answer 19

• normal joint, abnormal load OR abnormal joint, normal load –> mechanical tissue injury –> tissue damage/inadequate repair –> symptomatic OA

Question 20

How does incidence and prevalence of OA change?

Answer 20

• increases with age and is greater in women
• not all OA progresses - some improves/gets better

Question 21

How is OA diagnosed clinically?

Answer 21

• diagnosis is often clinical
• joint pain (typically on activity)
• stiffness typically <30 mins
• loss of function
• examination findings: crepitus, bony deformity and joint line tenderness, loss of normal range, warmth/effusion

Question 22

How is OA diagnosed through X-rays?

Answer 22

• X-rays - not necessary to diagnose but can be useful for staging and treatment planning
• can show diagnostic changes but these may be absent early in disease: osteophytes, joint space narrowing, subchondral sclerosis, bone cysts

Question 23

How is OA diagnosed through blood tests?

Answer 23

• none in routine clinical use which diagnose OA
• often normal but can be a low ‘inflammatory response’ e.g. slight increase in CRP
• tests for rheumatoid arthritis (where appropriate) are negative
• other blood tests may be relevant to exclude secondary causes e.g. iron, calcium, PTH, glucose

Question 24

What is knee osteoarthritis?

Answer 24

• knee is the most commonly affected site
• symptomatic disease more common in women
• women have a lifetime risk of 45% of knee OA

Question 25

What is hand osteoarthritis?

Answer 25

• hand OA very common - 26% women and 13% men aged 70
• joints - distal interphalangeal and proximal interphalangeal, followed by the base of the thumb
• base of thumb or multiple joint interphalangeal joint disease particularly affects hand function
• often around menopause - symptoms may settle after 2-5 years
• Heberden’s nodes are common - bumps in fingers

Question 26

How can OA be managed?

Answer 26

• exercise e.g. local muscle strengthening, general aerobic fitness
• weight management
• information and support
• some drugs can be used for pain relief
• manual therapy
• devices e.g. walking aids
• joint replacement

Question 27

What are surgical options for OA?

Answer 27

• total joint replacement / arthroplasty (hip or knee) is a highly effective treatment (best results when pain high, function poor, over 60, end stage radiographic disease)
• uni-compartmental replacement for the knee is possible
• trapeziectomy (removal of a thumb bone) is a good surgical treatment for base of thumb OA
• other surgical treatments such as arthroscopy are not evidence based

Question 28

What are new treatments for OA aiming for?

Answer 28

• symptom modification (SyMOAD - symptom modifying OA drug) - treat pain and improve function
• slow/prevent early disease (DMOAD - disease modifying OA drug)
• complex relationship between pain and structure in OA
• the right drug targets (efficacy and safety), the right population, the right outcome measures