Osteoarthritis Flashcards
What is OA? and What does it affect?
A degenerative disorder affecting the articular cartilage
Molecules involved in OA?
1) TGF-β (in OA TGF-β will be down-regulated)
2) Wnt-3a
3) Indian hedgehog pathways
4) Signaling molecules:
- Smad3
- β-catenin (in OA β-catenin will be down-regulated)
- HIF-2α
Population affected by OA?
more common in Women and Elderly
Can OA be caused by Sports-related traumatic injuries at all ages?
Yes, sports can lead to post-traumatic OA
OA is characterized by what?
1) Progressive erosion (degeneration, loss) of articular cartilage and
2) Associated reactive changes at the margin of the joints and in the subchondral bone
Epidemiology of OA?
- Age dependent
- After 65 years
- More common in women
Joints involved in OA?
Weight bearing joints > Hips, knees, cervical and lumbosacral spine
Other joints > DIP & PIP
What are the types of OA?
Primary > aging phenomenon > older individuals
Secondary > a predisposing condition > younger individuals
List Risk factors of OA (Dr,Ouban slide)
Trauma
Obesity
Ochronosis
Hemochromatosis
List Risk factors of OA (Modifiable & Non-modifiable)
Modifiable - Obesity - Trauma - Repetitive use (e.g., heavy labor) Non-modifiable - Age - Female gender - Family history
State the pathology mechanism of Age as a risk factor in OA
Aging chondrocytes > elevated oxidative stress > promotes
1) cell senescence
2) alters mitochondrial function
Disease progression > associated with mitochondrial dysfunction and cell death.
Why there is a reduced repair response in aging chondrocytes?
Due to alteration of the receptor expression pattern.
Discuss the pathological mechanism in OA related to age
1) In chondrocytes from aged and osteoarthritic cartilage, the ratio of TGF-β receptor ALK1 to ALK5 was increased
2) Leading to down-regulation of the TGF-β pathway and
3) Shift from matrix synthesis activity to catabolic matrix metalloproteinase (MMP/collagenases) expression.
Discuss the pathological mechanism in OA related to obesity
Low-grade systemic inflammation through secretion of
- Adipokines
- Pro-inflammatory cytokines > IL-1β, IL-6, IL-8 and TNF-α
These inflammatory factors may trigger NF-κB signaling pathway > stimulate an articular chondrocyte catabolic process > ECM degradation through the upregulation of MMPs
What causes epigenetic alteration in OA chondrocytes?
Changes in expression of Dnmts (methylation) and Tets (de-methylation) enzymes.
Does inflammation found in OA contributes to disease development and progression?
Yes
What structures are involved in inflammation of OA?
Entire synovial joint, including:
- Cartilage,
- Subchondral bone
- Synovium
What is the mechanism of inflammation in aging and diabetic patients?
IL-1β, TNF-α & chemokines > contribute to the systemic inflammation > activation of NF-κB signaling in both synovial cells and chondrocytes.
What innate inflammatory signals are involved in OA?
- DAMPs
- Dlarmins (S100A8 and S100A9)
- Complement
What are the role of innate inflammatory signals in OA?
DAMPs and alarmins were abundant in OA joints, signaling through either
- TLR or
- The canonical NF-κB pathway
> to modulate the expression of MMPs and ADAMTS in chondrocytes
How complement can be activated in OA chondrocytes and synovial cells?
By,
- DAMPs,
- ECM fragments
- Dead-cell debris.
What does systemic inflammation do in OA?
Re-program chondrocytes through inflammatory mediators toward hypertrophic differentiation and catabolic responses
What inflammatory mediators involved in systemic inflammation in OA?
- NF-κB pathway
- ZIP8/Zn+/MTF1 axis
- Autophagy mechanisms
How Genetic predisposition contributes in OA?
- Alterations in TGF-β, Wnt/β-catenin
- Ihh, Notch and FGF pathways > contribute to OA development and progression by primarily inducing catabolic responses in chondrocytes
Such responses converge on
1) HIF-2α
2) Runx2
3) Inflammatory mediators > cartilage ECM degradation through increased expression of MMPs and ADAMTS activity
What is the role of RUNX2? and what happens if it’s down-regulated?
Key transcription factor associated with osteoblast differentiation & to maintain ECM.
RUNX2 down-regulation > no maintenance of ECM
Recent studies of genome-wide association screens (GWAS) revealed what?
Over 80 gene mutations or single-nucleotide polymorphisms (SNPs) involved in OA pathogenesis.
Some genes are
1) important structural and ECM-related factors (Col2a1, Col9a1, and Col11a1), and
2) critical signaling molecules in the Wnt (Sfrp-3), BMP (GDF5), & TGF-β (Smad3) signaling pathways
Discuss knee joint changes/findings in OA
1) Thinning of articular cartilage
2) Development of cracks & fibrillation
3) Erosion and loss of cartilage
4) Formation of : Loose bodies (Joint mice) & Subchondral cyst
5) Eburnation (conversion of the sub-chondral bone to an ivory-like surface at the site of the cartilage erosion)
6) Sclerosis
7) Osteophyte (bony outgrowths at joint margins) develop due to bone remodeling, seen in
- DIP joint as Heberden nodes
- PIP joint as Bouchard nodes
8) Narrowing of joint space
9) Degeneration of ligaments and menisci of the knee
10) Hypertrophy of the joint capsule
State function of cartilage
Cartilage lubricated by synovial fluid, cushions the bones and allows friction less motion
State gross & microscopic appearance of advanced cases in OA
Gross: Eburnated bone which is shiny and smooth
Microscopic: sclerotic
List OA Clinical findings
1) Pain with passive motion of joint, due to secondary synovitis
2) Joint stiffness
3) Crepitus
4) Heberden’s nodes
5) Bouchard’s nodes
What are the radio-graphic findings of OA?
1) Presence of osteophytes at joint margins
2) Subchondral bone cysts
3) Joint space narrowing
4) No ankylosis* (fusion) of joint
Loss of articular cartilage is due to?
- Genetic
- Chemical
- Inflammatory
Describe stiffness in OA
It worsens throughout the day because OA itself is an activity & movement related
