Cartilage Biology and Osteoarthritis Flashcards
What is osteoarthritis?
a disease of the whole joint which involves the loss of articular cartilage
- commonest form of arthritis and numbers are rising
What is arthroscopy?
arthroscopy is a type of keyhole surgery for checking or repairing your joints
(picture shows normal and chondral defects)
What is the structure of (normal) articular hyaline cartilage (microscopic)?
Superficial (flatter chondrocytes)
Transitional or intermediate
Deep or radial
Calcified
Bone
What is the ECM of healthy cartilage made of?
Proteoglycan (aggrecan)- exert swelling pressure, resists compression
type II collagen- high tensile strength
Water
What is a chondrocyte and what conditions does it exist in and how/ when does it divide? And what are its interactions with the matrix?
<5% tissue
Producer and degrader of the cartilage matrix
Highly metabolically active
Exists in relative hypoxia
Interactions with matrix: growth factors, mechanotransduction
No cell division after adolescence
What is the word for complete lack of oxygen?
Anoxia
What are the matrix molecules in cartilage?
Type II collagen and collagenases
Aggrecan and aggrecanases
What enzymes break down Type II collagen in cartilage?
Metalloproteinases (metalloproteinases are collagenases)
MMP-1, MMP-8, MMP-13
MMP-3
What is special about MMP-3?
It is a stromelysin
MMP3 is released from the synovial membrane under inflammatory conditions and may serve as biological markers for inflammatory osteoarthritis
Where in Type II collagen is it cleaved?
Clip at 3/4 point of collagen chain by collagenases
N—/-C
What is aggrecan made of?
Hyaluronan
Keratin sulfate chain
Chondroitin sulfate
What are G1, G2, G3 in aggrecan?
globulins
what breaks the chain between hyaluronan and keratin sulfate in aggrecan?
Matrix metalloproteinases
e.g., MMP-3
where the chain is broken…
DIPEN(341)~(342)FFGVGG.
What breaks the rest of the chain in aggrecan?
Aggrecanases (ADAMTS-4 & 5)
where the chain is broken…
NITEGE(373)~(374)ARGSV…
What are TIMPs?
Tissue inhibitors of metalloproteinases
(1-4)
They are naturally occuring
What are the types of anabolic or anti-catabolic factors articular cartilage in the joint?
Intrinsic and extrinsic
What are the intrinsic anabolic and anti-catabolic factors for articular cartilage in the joint?
TIMPs
Growth factors e.g. fibroblast growth factor (FGF-2), Insulin-like growth factor (IGF), Transforming growth factor (TGF)-β, activin A
What are the extrinsic anabolic and anti-catabolic factors for articular cartilage in the joint?
Hormones e.g. testosterone, estrogen
Some drugs e.g. FGF-18
Why does matrix loss occur?
Excessive degradation
Reduced anabolism/ repair
What does your cartilage need to maintain cartilage thickness and turnover?
mechanical load
without this there is cartilage atrophy
e.g., in stroke patients
Where does the load go thorugh?
tibiofemoral joint of your knee,
The load increases as you walk, jump, run and climb stairs compared to when your standing
How much does the load increase during various exercises? (walking, jumping, running, climbing stairs)
walking- 2-6x body weight
jumping- 7-9x body weight
running- 3-8x body weight
climbing stairs- 3-10x body weight
How much more pressure does your knee have to support if you gain 5kg while walking?
If you increase your weight by 5 kg, your knees support 15-30 kg more pressure on walking
Where is load always greater in your body?
Medial compartment of the knee
What are the processes occuring in the synovial joint during osteoarthritis?
Inflammation
Repair Modelling
Pain
What are the tissues and structures in/ around the synovial joint?
Ligament/ soft tissue
Articular cartilage
Synovium
Subchondral bone
What happens first in osteoarthritis, molecular changes or structural changes?
Molecular changes procede structural changes
molecular changes first
What happens to the matrix molecules during osteoarthritis?
Proteoglycan= fragmented by aggrecanases
Collagen= broken down by collagenases
Water- initial swelling of matrix, then lost
what is the pathology of early osteoarthritis?
Loss of PG (proteoglycans) in superficial zone of cartilage
Fibrillation
What is the pathology of osteoarthritis in established OA? (6)
Loss of integrity
Fissuring
Partial and full thickness loss;
osteophytes,
bone cysts,
synovial inflammation
What are osteophytes?
bony growths that form in your joints or in the spine
Does OA affect the whole cartilage and what does it lead to?
yes, it is a disease of the whole cartilage
which can lead to joint failure
Why is obesity a risk factor for OA development?
increased splenic load
What are the risk factors for OA? (7)
Age
Obesity
Mechanical factors such as 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
How many genetic variants are associated with OA risk and give an example?
e.g., TGF beta
100
What is a common OA in younger population (30s-40s)?
Post traumatic OA
What happens in post traumatic OA?
~50% of those with meniscal or anterior cruciate ligament tear will develop OA within 5-10 years
Individuals are generally young (30s- 40s)
An inflammatory response can be seen in the joint in response to joint trauma (e.g. MMP-3; IL-6 in synovial fluid)
What is evidence for mechanical factors in OA? (5)
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 malalignment and medial joint OA
Paralysed joints are usually protected from OA
What does meniscal destabilization result in?
progressive articular cartilage damage
What happened in this picture of 4 weeks post ligament transection, and what is the white thing?
Meniscus floated out
White is osteophyte
What is cartilage loss and what does it depend on?
active biological process and depends on aggrecanases (e.g., ADAMTS-5)
What leads to symptomatic OA?
Mechanical tissue injury ->
tissue damage/ inadequate repair ->
Symptomatic OA
How does prevalence change with age and sex?
Increases with age and more common in women
Do all OA progress?
No
Why is OA increasing?
Because of ageing population
How is OA diagnosed?
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; sometimes warmth/effusion
What is crepitus?
a popping, clicking or crackling sound in a joint
Are x-rays necessary for diagnosis of OA?
Not necessary to diagnose OA,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
What is subchondral sclerosis?
Subchondral sclerosis is a thickening of bone that happens in joints affected by osteoarthritis
Are blood tests used for diagnosing OA?
None in routine clinical use which diagnose OA
Often normal; sometime there 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
What is the most common site for OA?
The knee, symptomatic disease is more common in women
What is seen in hand arthritis?
Heberden’s Nodes (bony expansions)
What are the joints affected in hand OA?
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
When is hand arthritis often seen time period wise?
Often around menopause; symptoms may settle after 2-5 years
How do we manage OA lifestyle wise?
Exercise (e.g., joint exercise)
Weight management
What are surgical options for OA? (4)
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)
Unicompartmental 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
What are the current aims of current treatments for OA?
aim for self management, improve pain and inflammation, improve mechanical environment; ultimately joint replacement is an effective treatment
What are the aims for new treatments of OA?
treat pain and improve function
(SyMOAD- symptom modifying OA drug)
Slow/ prevent early disease (DMOAD- disease modifying OA drug)
there is a complex relationship between pain and structure in OA
optimise repair responses, or reduce matrix destruction
What are the unmet clinical needs in OA clinical trials?
What does OA affect and what type of disease is it?
affects the articular cartilage but is a disease of the whole joint
Why is OA not simply ‘wear and tear’?
it is a consequence of abnormal chondrocyte responses and subsequent matrix degradation
What does matrix catabolism result from?
From signalling downstream of mechanical injury
