Msk Week 1 Objective 11

Front 1

The pathology of osteoarthritis can be defined in 4 dimensions. What are they?

Back 1

1. gradual loss of articular cartilage
2. thickening of subchondral bone
3. osteophytes at the joint margins
4. mild, chronic non-specific synovial inflammation

Front 2

What are the 3 stages of cartilage (in general)?

Back 2

1. stage I - normal cartilage
2. Stage II - aging cartilage
3. Stage III - OA cartilage

Front 3

What are the 2 main components of normal cartilage?

Back 3

1. extracellular matrix - rich in collagens (**type II, IX, XI) and proteoglycans (mainly aggrecan)
2. Chondrocytes

Front 4

What is aggrecan?

Back 4

Central core protein with GAGs attached (chondroitin sulfate, keratan sulfate) that are capable of retaining H20.

Front 5

How does cartilage change as it ages?

Back 5

1. contains less H20
2. contains fewer chondrocytes which decreases capacity to synthesize matrix
3. altered collagens

Front 6

How does the matrix change in aging cartilage?

Back 6

1. GAGs become shorter
2. Type 6 keratan sulfate increases while type 4 decreases
3. Reduction in total total proteoglycan synthesis
4. Accumulation of advanced glycation end products (AGE's) leading to inferior mechanical properties

Front 7

How are chondrocytes affected in ageing cartilage?

Back 7

AGEs trigger RAGEs on chondrocytes (= receptors for AGE's), leading to increased catabolic activity and therefore cartilage degradation.

Front 8

What are the 3 histologic phases of OA?

Back 8

1. Phase I: Edema and microcracks
2. Phase II: Fissuring and Pitting
3. Phase III: Microerosion

Front 9

What constitutes Phase I of OA?

Back 9

- 1st recognizable change = edema of ECM
- cartilage looses smooth aspect
-microcracks appear
-focal loss of chondrocytes alternating with areas of chondrocyte proliferation

Front 10

What constitutes Phase II of OA?

Back 10

-microcracks deepen perpendicularly
-vertical clefts form in subchondral bone cartilage
-clusters of chondrocytes appear around these clefts and at the surface

Front 11

What constitutes Phase III of OA?

Back 11

-fissures cause fragments of cartilage to detach and "fall into" articular cavity (= loose bodies/joint mice)
-loose bodies cause mild synovial inflammation
-sclerosis of subchondral bone and osteophytes form around this zone (the surfaces of osteophytes are covered with fibrocartilage)
-subchondral sclerosis increases with disease progression

Front 12

What drives the pathogenesis of OA?

Back 12

- CHONDROCYTES!!!
- fail to synthesize a good quality matrix
- fail to maintain the balance between synthesis and degradation of ECM

Front 13

What is the initiating factor in the development of OA?

Back 13

We don't know!
-mechanical loading?
-microtrauma?

Front 14

What is the pathogenetic sequence of OA development?

Back 14

1. "insult" to chondrocyte
2. Chondrocyte releases IL-1, NO and Plasminogen activating factor (PAF)
3. increased release of NMP's (stromelysin & collagenase)by chondrocyte
4. these enzymes produce cartilage damage and thus altered biomechanics
5. secondary synovitis (due to joint mice) which cause the synoviocyte to release PGE2, NO, IL-1, and NMPs
6. this creates a feedback loop to the chondrocyte and further damage occurs

Front 15

What are TIMPs?

Back 15

Tissue Inhibitors of Metalloproteases.

These enzymes oppose the metalloproteases.

Front 16

What is the role of TIMPs in osteoarthritis?

Back 16

In OA, the balance between ECM synthesis and degradation is skewed.

- there is increased synthesis of NMPs

-there is decreased synthesis of TIMPs

Front 17

How is OA characterized clinically?

Back 17

1. joint pain
2. stiffness
3. decreased mobility and function

Front 18

How is OA characterized radiographically?

Back 18

1. joint space narrowing
2. subchondral bone sclerosis
3. subchondral cysts (not always present)
4. osteophytes

Front 19

What are osteophytes?

Back 19

Fibrocartilage extensions of "new bone" along margins of joint

Front 20

Where might you see/feel osteophytes in physical exam?

Back 20

-over DIP joints (Heberden's nodes)
-over PIP joints (Bouchard's nodes)
-1st MCP
-1st MTP (bunions)

Front 21

How can you classify the etiology of OA?

Back 21

1. Primary
2. Secondary

Front 22

What is Primary OA?

Back 22

Describes the condition in patients when no obvious underlying cause can be discerned.

-increasingly prevalent with advancing age. (Some arthritic changes are part of the normal aging process, as evidenced by the decreased range of motion of virtually all joints, even in people who are asymptomatic.)
- after the age of 75 years, >80% of persons symptomatic and limited to some degree by OA in one or more joints.

Front 23

What is secondary OA, and what are some causes?

Back 23

Secondary OA is degenerative joint disease that is secondary to specific conditions that cause accelerated erosion of articular cartilage:

1. trauma
2. inflammatory - following any chronic jt arthropathy (RA; Ank. Spon; etc)
3. neurologic
4. metabolic/endocrine: DM, acromegaly, hemochromatosis, ochronosis
5. Subchondral Bone too stiff (Paget's disease)
6. Subchondral Bone too weak (avascular necrosis)
7. Congenital: CHD
8. Mechanical: total menisectomy, etc.

Front 24

What is the significance of increased synthesis of NMPs in OA?

Back 24

If the collagen arcade is interruped, then the NMPs can degrade the hydrophilic PG's and ECM loses its ability to retain H20.

Front 25

Chondrocytes are hypermetabolic in OA. True or false?

Back 25

True! They are just fighting a losing battle.

Chondrocytes in OA undergo a lot of cell division (not normal) and so increase in numbers and activity.

Front 26

Simple way of classifying pathogenesis of OA:

Back 26

1. abnormal force on normal cartilage
2. normal force on abnormal cartilage
3. normal force on normal cartilage with WEAKENED subchondral bone
4. normal force on normal cartilage with STIFFENED subchondral bone

Front 27

What are some common sites of OA?

Back 27

- DIP & PIP joints of the fingers
-carpometacarpal joint of the thumb
-cervical and lumbar spine
-the hip
-the knee
-metatarsophalangeal joint of the great toe.

Front 28

What is premature primary OA?

Back 28

Premature primary OA is seen as severe degenerative changes in one or more joints by 50 to 60 years of age, without apparent predisposing events.

Front 29

How is the early pathologic process of OA (ie. increased degradative and hypermetabolic processes demonstrated by early proteoglycan loss and subsequent increased proteoglycan synthesis) characterized with histologic staining?

Back 29

-changes manifest as:
-loss of basophilic staining,
-appearance of chondrocyte clones,
-fibrillation of the superficial cartilage.

The increased synthesis of functionally impaired building blocks ultimately fails to rescue and restore the diseased matrix. The altered and weakened hyaline cartilage is susceptible to further erosion under load-bearing conditions and becomes ineffective in buffering the subchondral trabeculae against impact loading and microfracture.

Eventually, full-thickness loss of hyaline cartilage occurs from the combined effect of biochemical breakdown of the matrix and abnormal biomechanical forces.

Front 30

Collagen is relatively preserved in the early stages of OA. True or False?

Back 30

True.

Front 31

Catabolic enzymes such as interleukin-1, neutral proteases, and metalloproteinases are increased and are a factor in progressive OA. True or False?

Back 31

True.

Front 32

Patients with OA present with local signs and symptoms that are specific to the affected joint. True or False?

Back 32

True.

Front 33

What are the clinical symptoms of OA?

Back 33

Of note, symptoms expressed by patients with arthritic disease are generally independent of etiology and generally focus toward pain, limitation of motion, and impaired function.

Front 34

What causes pain in OA?

Back 34

Pain is initially provoked by load-bearing activity, is relieved by rest, and then is aggravated on resumption of activity after rest.

As symptoms progress, the pain may become constant, being present even at rest and awakening the patient at night.

Examination shows variable functional limitations and loss of joint motion.

Front 35

What is GOA (generalized osteoarthritis), and which joints are affected?

Back 35

GOA is characterized by visible osteophytes at the DIP joints of the fingers (Heberden nodes) and other arthritic joints, specifically, the PIP joints of the fingers and the carpometacarpal joint of the thumb.

Involvement of the weight-bearing joints of lower extremities is less common but causes greater functional disability.

Knee arthritis is associated with GOA and hand arthritis.

Hip arthritis has only a weak association with GOA.

Front 36

Where does OA cause the greatest functional limitation?

Back 36

OA of the knee is most likely to cause functional impairment. The reported incidence of OA of the knee is 30% or greater after the age of 65 years. Associated factors in knee OA include female gender and obesity.

In contrast, OA of the hip is less common than that of the knee and exhibits neither a female predilection nor meaningful association with obesity.

Front 37

Pathology of OA.

Back 37

Front 38

Clinical signs of OA.

Back 38