Pathogenesis of Osteoarthritis Flashcards
What is Osteoarthritis?
> What kind of disease is it? (Heterogenous/ Homogenous)?
> How does osteoarthritis often clinically present?
- Bone - Joints - Inflammation
> most common arthritic disease
A whole-organ disease of the joint including cartilage, bone, synovium, capsule, ligaments and muscles
* OA is a heterogeneous disease with multiple causes and clinical phenotypes
* gradual loss of cartilage, development of bony spurs (osteophytes), development of subchondral bone cysts and sclerosis (increased subchondral bone density)
What is the structure of a normal synovial joint?
- What is synovium? What does it look like when healthy? (+2 cells it contains?)
- What is synovial sublining?
- Connective tissue between the fibrous joint capsule and the joint space, lines all inner joint surfaces, excluding the cartilage
- Thin lining layer facing the joint space, typically 1-2 cells thick :
- Consists of macrophage-like synovial cells (synoviocytes type 1/type A) &
fibroblast-like synovial cells (synoviocytes type 2/type B)
> Synovial Sublining is loose connective tissue with numerous blood and lymphatic vessels, nerves, scattered macrophages and fibroblasts
What happens to synovial joint in OA?
- Fibrous joint capsule becomes thickened
- Synovium becomes inflamed (called synovitis),
- Articular cartilage becomes prematurely degraded, the cartilage comes fibrillated, bony spurs occur (called osteophytes)
- Bone turnover is altered (sclerosis). In sclerosis the subchondral bone is thickened, and subchondral bone cysts are formed.
How is the pathogenesis of OA initiated?
- Acquired risk factors lead to structural damage to cartilage > alters chondrocyte function > This releases cytokines, which cause synovial inflammation and bone remodelling.
> Note that cytokine release (which occurs due to alteration in chondrocyte function) further increases alteration in chondrocyte function. In addition, synovial inflammation and bone remodelling further damage the cartilage in a negative feedback loop.
What are the cellular and tissue changes associated with early OA?
- Chondrocytes
- ECM
- Trabecular bone
1: Chondrocytes > proliferate > become more active > form clusters > produce proteinases (MMPs and ADAMTS) degrade the cartilage > increased expression of hypertrophy markers > upregulate NF-κB activity
2: Gradual loss of aggrecan > followed by type II collagen degradation > cracks develop in cartilage (fibrillation)
- Disturbs the delicate balance between ECM synthesis and degradation.
3: Increased activity of the osteoclasts which mediate continuous bone destruction >
Becomes thicker > less mineralised
> contains more Howships lacunae
What are the cellular and tissue changes associated with late OA?
- Chondrocytes fill cracks with fibrocartilage
1 - bone osteophytes (non weight bearing)
2 - bone cysts (weight bearing)
How is the synovitis imaged?
- Synovitis is detectable by imaging arthroscopy or histology.
- Synovitis often predates the development of radiographic damage in OA.
Describe the type of inflammation in OA?
Chronic and low-grade
> Involve an innate immune response
1. DAMP-TLR signalling
2. Complement system
3. Macrophages and mast cells
* The resulting cellular signalling cascade leads to the production of inflammatory mediators (PURPLE BOX)
Describe DAMPs as a key inflammatory pathways implicated in OA?
- Products of ECM breakdown, which occurs at sites of inflammation;
- Plasma proteins that exude from blood vessels;
- Intracellular proteins released from stressed, damaged or necrotic cells;
- Microscopic crystals released from cartilage into synovium by injury or wear and tear e.g. fibronectin
Describe complement as a key inflammatory pathways implicated in OA?
- C3 and C5a promote inflammation and tissue damage. DAMPs in OA joints bind and activate complement. OA synovium expresses higher levels of complement effectors than healthy synovium
Describe Macrophages and mast cells as a key inflammatory pathways implicated in OA?
- Activated by DAMPs and complement in OA synovium;
> macrophages produce pro-inflammatory cytokines and contribute to cartilage breakdown and osteophytosis;
> mast cells release tryptase and histamine which stimulate proliferation of fibroblast-like cells in synovium
What are the Molecular mediators of inflammation in OA?
-Cytokines
-Chemokines
-Growth factors
-Adipokines
-Prostaglandins/leukotrienes
-Neuropeptides
What are some risk factors of OA?
- Ageing (late 40s or older)
- Heredity (parents have had OA)
- Gender (female)
- Obesity
- Previous joint injury
- Joint abnormality
- Occupation
- Ageing (late 40s or older)
- Most prominent risk factor
- Reduced muscle mass and increased fat mass alter joint loading and can result in ageing-related inflammation.
- Elevated levels of reactive oxygen species can cause oxidative damage and disruption of cell signalling.
- Chondrocytes have reduced levels of ECM gene expression and can undergo cellular senescence with age (metabolically active but unable to proliferate)
- Heredity (parents have had OA)
What genetic mutations cause Hand OA + Hip OA?
- Late onset OA is thought to be a complex disorder as it is the culmination of many gene variants with modest effects, e.g. GDF5, RUNX2.
- However early onset OA is caused by a single gene mutation which has a large effect on protein function e.g. COL2A1, ACAN.
- The prevalence of late onset OA is much greater than early onset OA.
-Polygenic : changes in multiple genes not 1 , hip and knee have different genetic aetiologies
Describe the phenotype manifestation for the following genes if they are mutated.
- Obesity
How does adipose tissue promote low grade inflammation?
- Endocrine organ secreting adipokines and cytokines
- Contains M1 macrophages, dendritic cells, T and B lymphocytes and neutrophils
- Adipocytes and immune cells secrete cytokines and growth factors:
1. TNFα and IL-6 inhibit production of ECM components (proteoglycans and collagen II) and upregulate expression of MMPs
2. VEGF stimulates angiogenesis in synovium
