Pathogenesis of OA Flashcards
What is the purpose of articular cartilage? (3)
Smooth slippery surface, caps the ends of bones in synovial joints Reduces friction (low coefficient of friction) Helps absorb impacts - acts as a shock absorber to protect underlying bone
What type of cartilage is articular cartilage?
Hyaline cartilage
What is meant by the ‘tidemark’?
Deeper layer of hyaline cartilage merges with a calcified layer (tidemark) that attaches it to the sub-chondral bone.
What properties allow articular cartilage to absorb impacts? (2)
Elastic, resilient
What do the properties of articular cartilage depend on?
Composition of extracellular matrix, which depends on maintenance and synthesis by chondrocytes.
What are the layers of articular cartilage? (5)
Tangential/superficial layer - 10-20% Transitional/intermediate layer - 40-60% Radial/deep layer - 30% (TIDEMARK) Calcified cartilage Bone (subchondral, then cancellous)
What is the shape of the chondrocytes in the…
superficial zone?
transitional zone?
deep zone?
Flattish, small and in greater density
Rounder, larger and sparser
More rounded, stacked up as they have proliferated
What do chondrocytes do? (2)
Regulate both synthetic and catabolic processes
Establish a specialised microenvironment (they are responsible for ECM around them)
What % of the total volume of cartilage is made up of chondrocytes?
Less than 5%
Why do deep chondrocytes have prominent endoplasmic reticulum and Golgi apparatus?
Responsible for protein synthesis and sulphation of mucopolysaccharrides that form proteoglycan side chains.
Each chondrocyte sits in a…?
Lacuna (space)
Why do chondrocytes have a low number of mitochondria?
Low oxygen consumption
Cell division of chondrocytes is very low. When does it occur?
In response to injury or disease
What cells make the ECM of cartilage?
Chondrocytes
What are the three components of this ECM?
Water (80%)
Collagen
Proteoglycans
What type of collagen is in cartilage ECM?
Mainly type II (90-95%)
What is the role of collagen in cartialge ECM?
How is it arranged?
3D network of fibrils, give overall framework and shape of cartilage. Makes pockets filled with proteoglycan complexes. Collagen fibres - right up edges of lacunae..
What is the role of proteoglycans in cartilage ECM?
Draw water into cartilage to regulate compressibility
Describe the blood supply, nerve supply and lymphatic drainage of cartilage ECM.
Lacks blood supply and lymphatic vessels
No nerve supply
If the ECM has no blood supply or lymphatics, what does survival and synthetic activity depend on?
Diffusion of nutrients (e.g. oxygen and glucose) and metabolites through matrix (from synovial fluid). Fine balance of anabolism and catabolism.
How is collagen oriented in the different layers of cartilage and why?
Superficial layer - parallel with surface. Highest tensile properties, allows gliding.
Intermediate layer - criss-crossed oblique. Allows compression.
Deep layer - perpendicular to surface, follow stacks of chondrocytes.
It is mainly type II collagen in articular cartilage, but what other types are there? (3)
Types IX, X and XI
Where are the levels of type II collagen higher?
More superficial layers
Where are the levels of type X collagen higher?
Calcified deeper layers
What % of the dry weight does collagen make up?
40-70%
Describe the structure of aggrecan.
100s of proteoglycan monomers locked onto a central hyaluronic acid filament linked by glycoproteins: Hyaluronan molecule (core protein) with keratin sulfate and chondroitin sulfate (glycosaminoglycan side chains), and link proteins attached.
What are GAGs?
Linear polysaccharides of repeating disaccharide units
Most proteoglycans exist as…? Give the main one.
What % of the total dry weight do these make up?
Aggregates
Aggrecan
15-40%
Proteoglycans are negatively charged. What does this mean?
Highly hydrophilic
What is the role of proteoglycans? (2)
Trap water forming ground substance
Contributes to shock absorbing properties
List the problems that occur with an osteoarthritic joint. (10)
Fibrosis Synovitis Cartilage failure/loss of articular cartilage HA depolymerised Osteophytes Subchondral cysts Vascular engorgement Trabecular fracture Subchondral bone sclerosis Loss of joint space on x-ray
What systemic factors affect joint vulnerability? (5)
Increased age Female gender Racial/ethnic factors Genetic susceptibility Nutritional factors
What intrinsic joint vulnerabilities affect susceptibility to OA? (5)
Previous damage (e.g. meniscectomy) Bridging muscle weakness Increasing bone density Malaligment Propioceptive deficiencies
What use/loading factors acting on joints are there? (2)
Obesity
Injurious physical activities
What cytokines are involved in the pathophysiology of OA? (4)
IL-1 beta
IL-6
IL-17
TNF
What do cytokines do in OA?
They stimulate proteinases to cause cartilage destruction and they also act directly on osteoclasts, osteoblasts and chondrocytes.
In the affected joint, there is a failure in maintaining the homeostatic balance of the cartilage matrix _______ and _______, resulting from…?
Synthesis and degradation
reduced formation or increased catabolism.
What are the matrix metalloproteinases? Give an example. How are they affected in OA?
E.g. collagenase
Enzymes that catalyse both collagen and proteoglycan degradation
Found in increased concentrations
What cells produce matrix metalloproteinases (MMPs)? What stimulates their synthesis?
Chondrocytes
IL-1
Give an example of a catabolic cytokine and an anabolic cytokine. How are they altered in OA?
IL-1 - a catabolic cytokine, increased in OA
IGF-1, an anabolic cytokine, decreased in OA
What is seen in the initiation/early stage of OA?
Repetitive excess mechanical loading, causes stress-induced signals and quiescent chondrocytes. Characterized by loss of superficial zone and changes to the ECM of the articular cartilage, and cell clusters emerge.
What is seen in the late stage of OA?
Cytokines and chemokines are released, causing:
Matrix loss, tidemark duplication, osteophyte formation, microfractures, angiogenesis, chondrocyte hypertrophy and cloning.
Characterized by continued loss of ECM and chondrocyte hypertrophy.
What is HMGB2?
High mobility group protein 2 (chromatin protein)
Where is HMGB2 uniquely expressed? What does it support?
Superficial zone chondrocytes
Chondrocyte survival and regulates the specific differentiation status of superficial zone cells, including progenitor cells
What does loss of HMGB2 lead to? (3)
Superficial zone cell death
Loss of progenitor cells
Reduced synthesis of ECM components
What are the 3 phases of degeneration in OA?
Fibrillation
Erosion and cracking
Eburnation (complete loss of cartilage)
What can be seen microscopically in OA? (6)
- Chondrocyte necrosis throughout (more marked in superficial layers)
- Focal clumps or clones of increased proliferation (large Isogenic clusters)
- Change to fibrocartilage rather than hyaline (type I collagen rather than type II)
- Reduced thickness of articular cartilage
- Duplicated tidemark
- Thickening of calcified cartilage merging with subchondral bone
What is the biochemical pathophysiology of OA? (5)
- In early stages of OA articular cartilage thickens and swells - increased water
- But loss of proteoglycans make it less compressible, 3. Water moves in and out faster
- Collagen network breaks down as enzymes are released from stressed chondrocytes and synovial membrane cells (MMPs, collagenases and ADAMTS)
- Cartilage softens (chondromalacia) and progresses to fibrillation
What is ADAMTS?
A disintegrin and metalloproteinase with thrombospondin motifs
What happens to the subchondral bone in OA?
As articular cartilage is eroded underlying bone is exposed. There are microfractures of trabeculae, subchondral sclerosis, subarticular cysts and bone marrow oedema.
What causes subchondral sclerosis?
Increased osteoblastic activity and new bone formation
What causes subarticular cysts?
Surface undergoes focal pressure necrosis
What causes bone marrow oedema?
Vascular engorgement - this slows blood flow
Describe the disease of OA (the cycle).
Proteolytic destruction of cartilage matrix and chondrocyte death
Remodelling of bone (osteophytosis, angiogenesis, subchondral sclerosis)
Abnormal synovial fluid (reduced viscosity)
Phasic synovial inflammation and angiogenesis
Peripheral and central sensitisation, nocioceptor activation
Reduced exercise, muscle weakness, impaired proprioception, joint laxity
Altered mechanical loading of cartilage, bone and ligaments
CYCLE STARTS AGAIN
What are the health outcomes of OA? (8)
Joint destruction Severe pain Loss of joint function Disability Social isolation Depression Reduced QOL Major economic burden
What are the therapeutic targets for early OA? (3)
Regenerate joint resurfacing (with cartilage stem/progenitor cells)
Increase ECM production (with TGF-beta, bone morphogenic protein)
Inhibit ECM degradation (tissue inhibitor of MMPs, IL-1 receptor antagonist)
