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Who gets arthritis?

- old people
- animals
- juveniles


What is the prevalence of arthritis?

- osteoarthritis: 1 in 10
- rheumatoid arthritis: 1 in 100
- gout: 1 in 100
- ankylosing spondylitis: 1 in 200
- juvenile idiopathic arthritis: 1 in 250
- SLE: 1 in 1000
- Scleroderma: 1 in 10,000

3.85 million Australians with arthritis (18.5%)
$23.7 billion and rising (Access Economics)
>74,000 knee and hip replacements


What is osteoarthritis?

a disease of joints associated with
- destruction of articular cartilage
- changes in the underlying subchondral bone
- only a small inflammatory component
- currently no effective treatments


What's the difference between OA and RA?

OA vs RA
- synovial inflammation: + vs ++++
- bone thickening vs bone thins
- bone spurs/osteophytes vs bony erosions
- both have cartilage destruction


What is articular cartilage? What does it do? What is it made up of?

- lines each end of the articulating bones
- soft, silky move tissue that lines the ends of bones
- shock absorber to dissipate load and compression during movement and weight-bearing
- 80% water

most of next 10% =
- type II collagen
- aggrecan

some other:
- other proteins
- very few cells:only chondrocytes
- no vascular supply
this leads to very poor ability to self repair


How is the collagen arranged in cartilage?

from top to bottom
- superficial zone: all cartilage fibres are aligned parallel with the surface
- mid zone: criss cross
- deep: perpendicular to surface
- calcified cartilage
- bone
- thought to be a structure that maximises functionality in the tissue


What is chondrocyte morphology?

- very sparse


What are some other proteins?

- lubricin: key lubricant in superficial zone
- type 9 collagen
- type 10 collagen


What are collagens?

- form fibres, fibrils, lattices, networks
- most abundant protein in mammals
- three polypeptide alpha-chains wound into a triple helix
- gly-X-Y amino acid
- Y is often hydroxyproline
- need glycine in the middle axis because it's the smallest
- proline has twister structures that add stability to the twist


What are fibrillar collagens?

- half total body proteins by weight
- types I, II, III
- tendons
- bone
- skin
- blood vessels
- tensile strength and elasticity


What is the type II collagen gene structure?

- 52 exons
- most gly-x-y coding exons are 54bp coding for 18 amino acids
- globular domains present at the N- and C-terminus - these get chopped off


How is type II collagen biosynthesised?

1. synthesis and entry of chain into lumen of rough ER
2. cleavage of the signal peptide
3. hydroxylation of selected proline and lysine residues
4. addition of N-linked oligosaccharide in the C-terminal propeptide domain
5. addition of galactose to hydroxylysine residues
6. chain alignment and formation of disulphide bonds between the C-propeptides
7. formation of triple-helical procollagen from C- to N-terminus - zipper
8. in golgi, completion of O-linked oligosaccharide chains by adding glucose
9. transport vesicle
10. secretion
11. removal of N- and C-terminal propeptides by ADAMTS proteinases
12. Lateral association of collagen molecules followed by covalent cross-linking, first step catalysed by lysyl oxidase
13. aggregation of fibrils to form fibre


What are proteoglycans?

- proteo = protein; glycan = sugar
- protein bearing one or more glycosaminoglycan chains
- not a close family of proteins; no unifying features except for the presence of glycosaminoglycan
- the extent of glycosaminoglycan substitution may vary


What are glycosaminoglycan dissacharides?

- oxidised glucose making hexuronic acid
- sometimes epimerase (i.e. make into different isomer) --> iduronic acid
- galactose is an isomer of galactose
- add an amine to either to form hexosamines
- GlcNAc or GalNAc

- hexuronic acid + hexosamine = disaccharide
- chain of repeating disaccharides = glycosaminoglycan


What are sulphated glycosaminoglycans?

- repeating disaccharide units, covalently attached to a core protein
- each disaccharide can be mono-, di-, tri-, or tetra-sulphated, or unsulphated
- sulphation patterns are heterogenous and dynamic
- sulphate groups on aggrecan are critical for its function as a shock absorber
- the disaccharide units comprise alternating hexuronate and hexosamine residues


What are the glycosaminoglycans on aggrecan?

- chondroitin sulphate: 3 sulphates on one, one sulphate on the next
- keratan sulphate: 2, 1
- hyaluronan: unsulphated, made at the cell membrane and put out into ECM, too boring to make to antibodies against


What is aggrecan?

- has a core protein with three globular domains
- on the long extended chains in between are all the extended GAG chains attached to it
- 100 GAG chains x 30-40 disaccharides x 2-3 SO4 groups x 2 negative charges
= 12,000 - 24,000 negative charges per aggrecan monomer
= ~ 1,000,000 negative charges per aggrecan aggregate
- this attracts a lot of cations which draws water
- G2 - G3 is the functional part
- the water is very important for creating the compressive resistance


What does the G1 domain of aggrecan do?

- Hyaluronan binding
- immobilisation
- can be up to 100 aggrecans on a single HA chain


What is the function of the G2 domain of aggrecan?

- function unknown


What is the function of the G3 domain of aggrecan?

- ligand binding in the matrix


What is the interglobular domain?

- between G1 and G2
- proteinase sensitive
- very dangerous to cut here with enzymes as it releases the functional end of the molecule
- this is what happens in arthritic diseases


How do aggrecan and collagen II work together?

- collagen is like the string bag holding the aggrecan 'water ballons' together
- creates a weight bearing structure
- aggrecan molecules occupy large, hydrodynamic domains that provide osmotic swelling pressure
- collagen molecules for fibrous networks that provide shape and tensile strength


What does functional cartilage need? In what experiment was this shown?

- a high concentration of intact aggrecan
- shown in experiment by Lewis Thomas, 1956

healthy rabbit
1. high [aggrecan]
2. water drawn into tissue
3. high swelling pressure
4. collagen network expanded and under tension
5. rigid ear

rabbit with intravenous papain
1. loss of aggrecan
2. no swelling pressure
3. collagen network no longer under tension
4. ears become loose and floppy


What are aggrecanases?

- enzymes that cut up aggrecan
- ADAMTS-4 and ADAMTS-5 were thought to contribute
- experiments on mice showed that ADAMTS-5 is the main enzyme involved in the degradation of cartilage through cutting aggrecan
- the same proteinases are involved in cartilage destruction in both inflammatory and non-inflammatory arthritis
- therefore trying to develop ADAMTS-5 inhibitors for therapeutic use


What is the anatomy of a normal knee?

- fibrous capsule on outside
- thin synovial membrane that secretes fluids to hydrate the joint
- cartilage
- bone
- ligament
- the outside of the joint is supported by extra articular structures such as muscle and tendons


What is the pathology of osteoarthritis?

- subclinical OA can exist for many years

mild OA
- mildly inflamed synovium
- thick stretched capsule
- rough, thinned cartilage
- osteophyte

severe OA
- thick bone with no covering cartilage
- inflamed synovium
- extensive cartilage erosion
- osteophyte (more extensive)
- bone angulation (deformity)

loss of cartilage envisaged as joint space narrowing on x-ray


What causes OA?

- normal load on an abnormal joint
- abnormal load on a normal joint

predispose to OA:
- age
- gender
- genetics

Joint biomechanics:
- injury
- overload
- instability

these lead to biomechanical pathways (cytokines, proteinases, adipokines) which contribute to the site and severity of OA

this leads to pain which leads to distress and disability


What are risk factors for OA?

- age
- gender
- genetics

potentially modifiable
- injury and joint trauma
- body mass and composition
- muscle weakness
- mechanical stress (recreation, occupation)
- deformity and malalignment (in a healthy individual load bearing goes in a straight line from him through knee to ankle)
- inflammatory disorders
- endocrine, metabolic, hormonal

- obesity, static load and minimal physical activity are associated with a high OA risk

- UK study found that being overweight doubles the risk while being obese quadruples

- also occupation:
-- heavy lifting (builder)
-- kneeling (kindergarten teacher)
-- professional ballet dancer

- currently no evidence that ACL or meniscal surgery prevents future development of OA
- more randomised clinical trials needed for different subgroups

- in a healthy individual load bearing goes in a straight line from him through knee to ankle
- in a varus alignment (bow-legs) load bearing goes inside the knee --> high risk of knee OA
- in valgus alignment (knock-knees) load bearing goes outside the knee, less destructive than varus for knees, but maybe more prone to osteoarthritis

mechanical stress
- barefoot - even distribution of weight
- heeled shoes = centre of gravity (and body weight) shifted to the ball of the foot
- weight adjustment to balance; strain on knee, foot, back


Are there any drug treatments for OA?

symptom modifiers
- analgesics, NSAID (non-steroidal anti-inflammatory drugs)
- glucosamine and chondroitin sulphate
- hyaluronic acid injections

for the future: disease modifying OA drugs (DMOADS)
- metalloproteinase inhibitors
- IL-1 inhibitors
- growth factors
- gene therapy
- althought it is pain that brings OA patients to the physician, it is structural damage that leads to disability and joint replacement


Why is joint space narrowing not a good means for testing the outcome for efficacy of DMOADS?

- jsn in insensitive
- takes years to develop
- may not even be meaningful
- mean rate of JSN is ~ 0.13 ± 0.15mm/yr


How can we manage OA?

- research findings and meta-analyses are improving the evidence level for non-pharmacological and non-surgical treatments in hip and knee OA
- information, exercise and weight loss are supported as first line treatments and as adjunct therapies prior to surgery
- randomised controlled trial investigating the efficacy of "unloading" shoes for the treatment of symptoms in people with knee OA
- specially designed midsole with medial side softer than normal and lateral side is harder. Also includes a lateral wedge