Lecture 13 - Osteoarthritis Flashcards
Who does osteoarthritis primarily affect?
The elderly
Who gets arthritis?
What is the prevalence?
- 1 in 10 people
- The elderly
- Animals
- Kids: juvenile idiopathic arthritis
Which is more prevalent; Rheumatoid or osteoarthritis?
Osteoarthritis
What is the main feature of osteoarthritis?
Destruction of articular cartilage
Compare osteo and rheumatoid arthritis:
• Synovial inflammation
• Bone
• Cartilage
Rheumatoid has much inflammation, while osteo- has very little
Rheu.: bone thins, osteo: bone thickens, + spurs
Cartilage: destroyed in both
Describe the cartilage in a joint.
What are the functions?
Articular cartilage, very smooth surface at the articulation of the bones
• shock absorption
• lubrication
What is articular cartilage made up of?
What does it lack?
- 90% water
- collagen
- ECM components: aggrecans etc.
• chondrocytes
Lacks:
• blood supply
NB almost acellular
Describe collagen organisation in articular cartilage, through to the bone
- Superior: tight parallel arrangement
- Middle: mesh
- Deep: loose, perpendicular to superior layer
- Calcified cartilage (transition zone)
- Sub-chondral bone
Describe the presence of cells in articular cartilage
- Very few cells, and they are exclusively chondrocytes
* very sparse, not touching each other
Describe the structure of collagen
Three alpha helices → triple helix
Gly-X-Y repeating subunits
What are the two broad categories of collagen?
- Fibrillar
* Amorphous
Which types of collagen are fibrillar?
I, II & III
Where is fibrillar collagen found?
What is its function in these tissues?
Type I & III: • Tendons • Bone • Ligament • Skin
Type II:
• articular cartilage
(almost exclusively)
Provides tensile strength
Outline the biosynthesis of collagen
- Translation of RNA, fed into Golgi
- Signal peptide removed
- Hydroxylation (to form hydroxy-proline etc.)
- Glycosylation
- The three chains align
- Winding of chains to form the triple helix (from C to N terminus)
- Exocytosis through secretory pathway
- N and C-termini are cleaved by ADAMTS
→ COLLAGEN MOLECULES - Lateral association of collagen molecules, covalent cross linking
→ COLLAGEN FIBRILS - Aggregation of fibrils
→ COLLAGEN FIBRES
What is the function of ADAMTS?
Enzymes that cleave the N and C termini of collagen triple helices
What are the phases of collagen?
- Procollagen
- Collagen molecules
- Collagen fibrils
- Collagen fibres
Which other type of collagen associates with Type II collagen?
Describe this association?
Type IX collagen
• fibrils associate with the type II fibres
What are the features of proteoglycans?
- Protein core
* Glucosaminoglycan chains
What is an important proteoglycan?
Aggrecan
Describe the formation of glycosaminoglycan subunits
e.g.
Glucose + oxygen group
→ glucuronic acid
What are some common substrates for glycosaminoglycans?
What are the two groups?
Hexuronic acid: • GlcUA • IdUA Hexosamine: • GlcNAc • GalNAc
What do you get when you combine a Hexuronic acid and Hexosamine?
A disaccharide
How do you get a glycosaminoglycan?
Chain of repeating disaccharides
What sort of groups are commonly found on glycosaminoglycans?
Why?
Sulfate groups
Sulfate groups are critical for the function of proteoglycans as shock absorbers
Describe the presence of sulfate groups on glycosaminoglycans?
Highly variable and heterogeneous
Which glycosaminoglycans are found on aggrecan?
- Chondroitin sulfate
- Keratan sulphate
- Hyaluronan
Describe the structure of aggrecan
- 100 GAG chains
- which are attached to a protein core
- G1: binds aggrecan to hyluronan, immobilises aggrecan
- G2 domain (?)
- G3 domain: ligand binding
- Interglobular domain (IGD)
What is the charge of aggrecan?
How does this arise?
Negatively charged
The sulfate groups on the disaccharides have a negative charge.
Thus, there are countless disaccharides per monomer.
How is the negative charge of aggrecan handled?
Cations attracted
→ H20 drawn in
What is hyaluronan?
- Central core, binding the G1 regions of many aggrecans
* this stabilises the aggrecans
What are the functions of the three G domains in aggrecan?
G1: attachment to HA
G2: ?
G3: ligand binding
What is IGD?
What are the features of it?
- Interglobular domain
* susceptible to proteinases
What is the business end of the aggrecan molecule?
The end, where all the GAGs are (i.e. where the negative charges are)
What happens if enzymes cleave at the IGD?
The ‘business end’ of the molecule is lost from the G1 domain
Describe the changes to aggrecan aggregates over time
Over the course of one’s life, the aggregates become smaller, with fewer aggrecan monomers
Describe the result of type II collagen and aggrecan working together
Collagen: shape & tensile strength
Aggrecan: swelling pressure
Together they confer resistance of compressive forces
What is the effect of papain?
Cleavage of IGD
Collagen remains intact
→ Degradation of aggrecan
Which enzymes are aggrecanases?
ADAMTS-4
ADAMTS-5
What is important about ADAMTS-5?
It is the aggrecanase that destroys aggrecan in athritis
Describe the structure of a synovial joint
- Fibrous capsule
- Synovium (thin membrane that secretes synovial fluid)
- Synovial fluid
- Articular cartilage
How long can subclinical osteoarthritis last?
Up to 10 years
What features are seen in the joint in mild OA?
- Osteophytes
- Thinning and tearing of the cartilage
- Midly inflamed synovium
- Thickened capsule
What features are seen in the joint in severe OA?
- Joint space narrowing
- Extensive cartilage erosion
- Inflamed synovium
- Osteophytes
- Bone angulation
What are the aetiologies of OA?
- Normal load on abnormal joints
2. Abnormal load on normal joints
What are some risk factors for osteoarthritis?
What are the two categories of risk factors?
Non-modifiable:
• Old age
• Genetics
• Gender
Potentially modifiable: • Joint injury • Joint overload (body mass) • Muscle weakness • Joint mal-alignment • Heavy load carrying
Describe the pathogenesis of osteoarthritis
- Risk factors for OA
- Biochemical pathways
• i.e. activation of ADAMTS-5 - Cleavage of aggrecan at IGM
- Destruction of articular cartilage
Describe the effect of being overweight on OA
Overweight people: doubled risk
Obese people: quadrupled risk
Which molecules are involved in the biochemical pathways leading to OA?
- Cytokines
- Adipokines
- Proteinases
Describe the risk factor of injury and joint trauma
Injury to joint WILL lead to OA
• there is no evidence that surgery prevents the onset of OA
Describe the risk factor of mal-alignment
Varus (bow legs)
• high risk of knee OA
Valgus (knock knees)
• lower risk of OA than vargus
What happens when we wear high heel shoes?
- Shifts the body’s centre of gravity
* predisposes to OA
What are the treatments for OA?
What are the categories?
Symptom modifiers
• Analgesics, NSAIDs
• Glucosamine
• HA injections
In the future:
Disease modifiers
• Anti-IL-1
• Gene therapy
What are DMOADs?
Disease modifying OA drugs
- hope for these types of drugs in the future
- don’t have any at the moment
- difficult, because there aren’t any bio-markers
What are the first line therapies for OA?
- Exercise
- Weight loss
- Information
What type of molecule is hyaluronan?
A glycosaminoglycan
