Flashcards in MSK L18 and L19 Osteoarthritis I & II Deck (45):
o OA is one of the most common musculoskeletal Condition
o In he UK about 8 million people have OA
o Worldwide 9.6% men and 18% women over the age of 60 have symptomatic OA
o 80% OA patients have limitations of movement, 25% can not perform their daily activites
Weight and obesity
Gender → More Common in women than men
Evidence for a genetic cause of OA
1. Prevalence of OA is differnet in differnet races and populatinos
2. Women are 10 times more lilely to have Hebeden’s node than men (particular form of OA)
3. Increased production of certain cytokines that breakdown cartilage due to genetic variability of genes coding for the cytokines
1. The largest study of its kind ever undertaken
2. Screening DNA from 8,000 OA patients and 6,000 healthy people
3. This could lead to several potential breakthroughs
o Genetic testing
o Identify progressors
Prevent OA occuring
Pathogensis of OA
1. Joint Biomechanics (injury, overloading, instability – cruciate ligament etc.)
2. Systemic predisposition
Both cause biochemical change sin the joint tissues
o Increase cytokine -> Il17, TNF etc.
o Increase enzymes – proteases damage and destroy cartilage
Severity determined by joint i.e. load bearing or not etc.
Presence of other diseases can also effect the progress of disease.
Common sites of OA
Mechanisms involved in degradation of cartilage and inflammation is the same for all joint sbt the risk of OA occurring in different joints is different.
Pathogenesis of OA
Worn Cartilage – focal then throughout joint surfaces
Born Growth → osteophytes at edge of joint
Inflammation -> synovial lining
Changes in cartilage: cartilage surface changes
1. Fibrillation → cracks from surface to deeper zone
2. Erosion → of surface a maybe mid zone
Changes in Cartilage: other changes in cartilage
Cartilage Softening → loss of proteoglycan and damage to collagen therefore cartilage can maintain shape leading to increased hydration in early stages of disease.
Chondrocyte necrosis and apoptosis
Cell cluster → find in most OA but in normal cartilage can see this
Complete loss of superficial layer of cartilage
Fissures and cracks in cartilage
Cells → GAG from medial and superficial zones lost
Changes in the Bone
Joint space narrowing →loss of cartilage
Sclerosis → thickening of subchondral bone
Eburnation → shiny as over lying cartilage lost
Focal pressure necrosis and subarticular cysts → overlying cartilage absent transmission of articular pressure into marrow space.
Changes in the Bone:
Recent findings in bone matrix
1. Extracellular matrix with more protein and less mineral
2. MRI evidence of bone marrow lesions leading to cartilage
3. CT scan show changes in cancelous bone
4. Markers: Increased alkaline phosphatase, TGF-Beta and PGE in OA bone
5. Alteration in phenotypic structure of bone cells
OA grading →
→ Kellgren and Lawrence for knee and hand joints
o Grade 1 → normal
o Grade 2 → osteophytes and loss of joint space
o Grade 3 → lots od osteophytes and significant loss of cartilage
o Grade 4→ little of no joint space left (no cartilage) andlots of osteophytes
Mild to moderate inflammation → Marked infiltration of cells → neutrophils etc
Neovascularization (similar to RA tissue is proliferating to some degree)
Correct order unknown – can begin in any of the tissues?
Some evidence that ligaments and meniscus involved
cartilage Matric synthesis
Promotion → TGF-Beta and IGF-1
Inhibition → IL-1 and TNF
cartilage Matrix Degradation
Promotion → IL-1 and TNF
Inhibition → IGF-1 and TGF-beta
Chondrocytes (only cells in cartilage)
Responsible for synthesis and degradation
Mediators that stimulate synthesis of cartilage
IGF-1, TGF-beta and FGF-1
In OA increased concentrations of cytokines e.g. TNF and Il-1
Most cartilage is degraded by
Most of the cartilage is degraded by MMPs and Aggrecanases
Synthesis → of cartilage
1. Increased production of mediators they bind to corresponding receptors on chondrocytes which stimulates them to produce collgane and PGE.
2. Will also produce protease inhibitos which prevents degradation and damage
a. MMP’s → collagenases and stromelysin blocked
b. Serine proteases
Degradation → of cartilage
1. Stimulated by mediators found in other tissues in joint, chondrocytes
2. TNF, IL-1 e.g trauma or mechanical wear and tear (debris).
3. Triggers Chondrocytes to make more proteases, serine activators activated which activates latent stromelysin, which breaks down Proteoglycan.
4. Chondrocytes also make less tissue inhibitors
Proteoglycans can aggregate to
to hyaluronic acid and form → aggrecan
Specific enzyme that cleaves aggrecans (part of it) that proteoglycans use to form aggregates with hyaluronic acid = cartilage loss.
Cleaves between G1 and G2
staining procedure to look at distribution of Proteoglycans
Collagen →Degradation →
Uncoiling of triple helix via denature.
Collagen →Early Hydration in early OA →
Denaturation leads to soft cartilage. The cartilage fibres can maintain the shape of cartilage and so more water infiltration.
Collagen → Later stages→
Loss of water due to loss of proteoglycans.
Collagen →Cartilage Failure in OA:
1. Cartilage becomes “fibrillate” early in OA (loss of surface zones
2. Gross loss in advanced OA
3. OA cartilage has more denatured collagen and swells more. Its softer. PG’s normal but decreases?
Collagen →Final Result of cartilage loss
Joint space narrowing
Bone remodelling in OA →
1. Osteophyte formation → help distribute the load more easily
2. Sclerosis → thicker bone form osteoblasts
3. Eburnation →associated with sclerosis related to osteoblastic activity – bone is exposed with no overlying cartilage, friction causes shiny surface.
4. Increased bone mineral density → early stages some evidence of loss (slight)
5. Focal pressure necrosis (advanced feature) → overlying cartilage is missing therefore transmission of force from surface into marrow space.
6. Bone marrow odema-like lesions →
3 factors associated with OA:
o Cartilage loss
o Bone remodelling
o Synovial inflammation
pro-infammatory cells capable of producing mediators ROS, MMP1 and £, TNF, IL etc. causes articular fissures
Chondrocytes capable of producing
IL-1,6, PGE, leukotrienes which could trigger the synovium and cute inflammation leading to macrophages and fibroblasts aggregating in synovium
Bone → Osteoblasts can produce
all mediators, which stimulate it to produce subchondral bone leadin got sclerosis and eburnation. Some mediators eg. IL-6 and PGE may contribute to cartilage and synovium changes.
Young man, OA Hip
Middle aged man, OA knee
Mid aged women → knee and hand
Elderly women → generalised
2. Muscle wasting
3. Bony swelling
4. Joint effusions
7. Reduced motion
Onset slow and insidious
Joint stiffness after inactivity
Reduced range of joint motion
Factors affecting pain in OA
Radiographic severity (poor correlation between this and pain)
Gender → women worse
Pain in OA
No nerve endings in cartilage therefore coming from synovium maybe
Investigation and Management
1. Blood test (normal) → most common blood tests usually in normal ranges
4. Synovial fluid analysis
5. Animal models →
a. Guinea pig (dank and hartlley) spontaneous models of osteoarthritis.
b. Partial minisectomy model.
c. Cruciate ligament damage models
2. Relieve symptoms
3. Minimize handicap
4. Limit progression