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Concepts of Disease > Matrix biology and disease > Flashcards

Matrix biology and disease Flashcards

1
Q

What are the 6 major tissues of the synovial joint?

A 
Tendons
Ligaments
Meniscus
Bone
Synvoium and synovial fluid
Articular cartilage
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2
Q

What are the two weight bearing bones that meet at the knee joint?

A

Femur and Tibia

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3
Q

What is the function of tendon?

A

Link muscle with bone.
Transmit muscle forces with minimal elongation.
Highest tensile strength of all body soft tissues.

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4
Q

Which component of the knee synvoial joint has the highest tensile strength of all body soft tissues?

A

Tendons

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5
Q

Describe the collagen arrangement in tendons?

A

The collagens eist in a triple helix which pack into a fibre = tenidnous fibre which bundle together to form the tendon.
The collagen is spirally wound - long collagen spirals.

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6
Q

What are the cells that make up the bundles in a tendon?

A

Tenocytes - but tendonns are hypocellular.

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7
Q

Describe the structure of a tendon?

A

Tendons are made of lots of collagen which is arranged in a triple helix structure, these helices pack together to form tendinous fibres and these bundle together to form a tendon.
Tendons are hypocellular, they’re predominantly matrix.
Sometimes tendons are surrounded by thin sheaths which help lubricate the tendon movements.

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8
Q

What is the function of the thin sheaths surrounding a tendon?

A

To lubricate the tendon movements.

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9
Q

Describe the biochemical composition of a tendon?

A

95% type I collagen.
5% minor collagens,
The collagens give the tensile properties.
Small amounts of elastin confering elastic properties and the ability to recoil back to normal length, the elastin stores the energy during movement.
Proteoglycans - regulate collagen fibril size during growth and development and bind water and resist compression.

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10
Q

What is the function of collagen in a tendon?

A

Confers the tensile properties.

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11
Q

What is the function of elastin in a tendon?

A

Confers the elastic properties allowing recoil back to normal length.
The elastin stores energy during movement.

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12
Q

What is the function of proteoglycans in a tendon?

A

Regulate collagen fibril size during growth and development.
Bind water and resist compression.

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13
Q

What is the result of immobilisation of a tendon?

A

Decreased mechanical strength.

Decreased proteoglycan content.

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14
Q

What is the result of exercise and training on a tendon?

A

Increased collagen fibril size.

Increased strength and stiffness.

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15
Q

Where is the most common tendon injury site?

A

Site of insertion to the bone - this is the weakest link and is most likelly to rupture.

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16
Q

What is tendonitis?

A

A term describig any condition causing pain when a tendon is under tension.

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17
Q

What is the common cause of tendonitis?

A

Episodes of inflammation which cause high levels of cytokines around the tendons generating an inflammatory response.
Commonly associated with tendon injury is the formation of adhesions which aggrevates the tendonitis and leads to further inflammatory response.

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18
Q

Which tendon is affected in “tennis elbow”?

A

Lateral epicondyl tendon.

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19
Q

Which tendon is affected in “Jumper’s knee”?

A

Patellar tedon.

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20
Q

Which tendon is affected in “golfers elbow”?

A

Medial epicondyle.

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21
Q

What is the function of ligaments?

A

Connect bone to bone.
They have passive mechanical function in stabilising joints and body structures and guiding body movements.
Ligaments supply propioceptive information to the brain.

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22
Q

Describe the structure of a ligament?

A

Ligaments are dense, white, fibrillar, avascular structures.
Rich in nerve fibres and pain fibres.
Relatively hypocellular and the cells are fibroblastic (fibrocytes) but closer to the bone insertion site they resemble cartilage cells.

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23
Q

Which component of the synovial joint supplies proprioceptive information?

A

Ligaments - they are rich in nerve fibres, stretching activates muscle contractions preventing over-stretching.

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24
Q

What are the 4 major ligaments stabilising the knee joint?

A

Anterior cruciate ligament.
Posterior cruciate ligament.
Medial collateral ligament.
Lateral collateral ligament.

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25
Q

What is the difference between an ACL and MCL ligament injury?

A

ACL has very poor repair capacity whereas MCL repairs itself.

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26
Q

What effect does exercise have on ligaments?

A

Increases collagen content and therefore increases tensile strength.

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27
Q

Describe the biochemical composition of a ligament?

A 
90% type I collagen.
10% type III collagen.
70-80% dry weight is collagen.
Proteoglycans <5% dry weight. 
Elastin <5% dry weight. 
Water is 60-70% wet weight.
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28
Q

What is the function of the meniscus?

A

The menisci are C-shaped cups/discs of fibrocartilage interposed between the femoral and tibial condyles.
They perform load-bearing, shock absorption and joint stabilisation, load distribution, allows rolling movement of the joint, allows separate movement in two halves of the joint cavity, spreading of synovial fluid lubricates the joint.
The medial meniscus transmits 50% of compressive load of the knee.
Removing a small piece of the meniscus increases contact stress by 350%

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29
Q

Describe the biochemical composition/structure of the meniscus?

A

Collagens, type I (majority), II, III and IV.
Proteoglycan concentrations high.
Elastin <1% dry weight.
Collagen fibril orientation is circumferential - C-shape.
The outer region has blood supply and nerves = pain upon injury.

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30
Q

What % of compressive load of the knee does the medial meniscus transmit?

A

50%

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31
Q

Describe the structure of the bone in the synovial joint?

A

Mineral component is composed of calcium and phosphate containing hydroxyapatite crystals.
The major inorganic component is type I collagen, forms a 3D framework in which mineral crystals grow in and in which minerals are embedded.

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32
Q

Where is the synovial membrane found?

A

Surroundig the inner chamber of the synovial joint.

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33
Q

What is the function of the synovium?

A

Secretes synovial fluid, which contains hyaluronic acid and promotes joint movement and lubrication.
Synovial fluid contains nutrients supplied to cartilage because cartilage is avascular.

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34
Q

What is the main lubricant in synovial fluid?

A

Hyaluronic acid.

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35
Q

What are the 2 cell types of the synovium?

A

Type A - macrophage like - clears debris.

Type B - fibroblast-like synoviocytes - synthesise hyaluronic acid and lubric.

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36
Q

What are the two main components of synovial fluid?

A

Hyaluronic acid and lubricin.

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37
Q

How thick is the synovial membrane?

A

1-3 cells thick.

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38
Q

What are the general features of cartilage?

A
  1. Avascular.
  2. Aneural.
  3. Hypocellular.
  4. No lymphatics.
  5. No basement membrane.
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39
Q

What are the two major macromolecules present in cartilage?

A

Collagen.

Proteoglycans.

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40
Q

What is the key proteoglycan in cartilage?

A

Aggrecan

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41
Q

Describe the morphology of cartilage?

A

4 zones…
1. Superficial zone.
2 layers of flattened cells.
2. Intermediate/middle zone.
Chondrocytes are rounded in shape and randomly distributed.
3. Deep zone.
Chondrocytes form stacks/columns 2-3 cells.
4. Zone of calcified cartilage.
Cells in a chondroid matrix speckled with apatitic crystals/salts. This forms the interface to the subchondral bone/trabecular bone.

42
Q

What are the 4 zones of cartilage?

A
  1. Superficial zone
  2. Intermediate/middle zone.
  3. Deep zone.
  4. Zone of calcified cartilage.
43
Q

How does collagen morphology change throughout the articular cartilage and how does this relate to the chondrocyte morphology?

A

Collagen is arranged in arcades termed Beninghoff’s arcades, the shape of the collagen fibrils determines the orientation of the chondrocytes.
At the surface, the chondrocytes are flattened because the collagen fibrils are running parallel to the surface.
Moving down the tissue, chondrocytes become more randomly located and rounder in shape.
In the deep zone the chondrocytes begin to form columns lining up between the collagen fibrils.

44
Q

How many different types of collagen have been identified in vertebrates?

A

28

45
Q

What is the collaginous domain?

A

All alpha chains of collagen consist of repeating Gly-X-Y triplet repeats, repeated 100-400 times.

46
Q

What is the size of a collagen fibril?

A

300nm in length.

1.5nm in diameter.

47
Q

What are the major collagens of cartilage?

A

Type II - 94%
Type IX - 2%
Type XI - 3%
Type VI - 1%

48
Q

Describe the structure of the heterotypic fibrils in articular cartilage?

A

Type II collagen fibrils are interconnected to the fibrillar type XI collagen and decorated externally with the FACT type IX collagen.

49
Q

What are the properties of the heterotypic fibrils?

A

The heterotypic fibrils have a high tensile strength and shear sliding strength.

50
Q

What is the function of type VI collagen in cartilage?

A

Type VI collagen protects the chondrocytes from molecular load and is located in the pericellular matrix surrounding the chondrocyte in the lacuna.
Type VI collagen is globular (doesn’t form fibrils) it forms a meshwork in the lacunae.

51
Q

What is the function of type II collagen in cartilage?

A

Type II is the major collagen if cartilage, it is a fibrillar collagen that confers high tensile strength.

52
Q

What is the function of type XI collagen in cartilage?

A

Type XI is a fibrillar collagen involved in fibril nucleation with type II collagen, it self-assembles within the type II fibrils.

53
Q

What is the function of type IX collagen in cartilage?

A

Type IX collagen is a FACIT collagen located on the outside of the fibrils confering a high shear strength.

54
Q

What is the size of the protein core of an aggrecan monomer?

A

250-300 amino acids.

250,000-300,000 daltons.

55
Q

Describe the structure of a glycosaminoglycan?

A

Glycosaminoglycans are long negatively charged polysaccharides composed of repeating disaccharides that are polyanions.
Being polyanions means they have a strong affinity for binding water, the negative charge binds cations and this inbibes water.

56
Q

Describe the structure of aggrecan monomers?

A

There is series of GAG attachments, typically 100 chondroitin sulphate and 50 keratin sulphate.
The N-terminal region is comprised largely of 50 keratin sulphate and the chondroitin sulphate residues are dispersed throughout the aggrecan.
At the N-terminal there is a hyaluronan-binding domain/G1 globular domain.
Then an interglobular domain.
Then a second globular domian called the G2 domain.
The aggrecan monomer is 2.5 million Dalton.

57
Q

Describe the structure of aggrecan macromolecular aggregates?

A

30-50 aggrecan monomers are stabilised by a 1:1 interactions with link proteins.
Aggrecan aggregates are 80-100 million Daltons.
Aggrecan monomers bond non-covalently (electrostatic attraction) to a central filament of hyaluronic acid stabilised non-covalently by the link protein.
The interaction between the aggrecan and hyaluronic acid filamet ocurs through the G1 globular/hyaluronic acid binding domain at the N-terminal.

58
Q

Describe the wet weight composition of articular cartilage?

A 
Water 70%
Collagens 20%
Proteoglycans 7%
Cells 2%
Other proteins 1%
59
Q

Describe the dry weight composition of articular cartilage?

A

75% collagens
22% proteoglycans
3% other proteins

60
Q

What is the principle function of articular cartilage?

A

The principle function of articular cartilage is to provide a smooth lubricated surface for low friction articulation and to facilitate the transmission of loads to underlying subchhondral bone = biomechanical function.
Cartilage resists and dissipates compressive loads duing joint articulation.
The collagens provide high tensile and shear strength.
The proteoglycans draw in water.
This gives cartilage viscoelastic properties.

61
Q

What is the fluid phase of articular cartilage?

A

The water is the principle component containig inorganic ions e.g. sodium, calcium, chloride and potassium.

62
Q

What is the solid phase of articular cartilage?

A

Characterised by the extracellular matrix (collagen and proteoglycans) which is porous and permeable.

63
Q

What is the function of the solid and fluid phase?

A

The solid phase has low permeability due to high frinctional resistance to fluid flow.
The fluid phase gives high pressurisation contributing more than 90% of the load transmission of AC.
The combination of the low permeability of the solid phase and the high pressurisation of the fluid phase gives cartilage its stiffness and viscoelastic properties.

64
Q

What is the turnover rate of proteoglycans?

A

Months - 80-100 days.

65
Q

What is the turn over rate of collagen?

A

Years.

66
Q

What are teh main proteinases involved in cartilage matrix turnover?

A
  1. Matrix metalloproteinases.

2. Aggrecanases.

67
Q

What is meant by the term “metalloproteinase”

A

A metalloproteinase is a protease that requires zinc/calcium for its acitivity.

68
Q

What is the function of aggrecanases?

A

Aggrecanases degrade cartilage aggrecan.

69
Q

What induces the activity of aggrecanases?

A

Exposure of chondrocytes to cytokines e.g. IL-1 and TNF-a.

70
Q

What is the function of MMPs?

A

MMPs “collagenases” degrade the collagen triple helix and “gelatinases” degrade the denatured collagen.

71
Q

Which two aggrecanases can degrade cartilage aggrecan?

A

ADAMTS4 and ADAMTS5

72
Q

Describe the structure of matrix metalloproteinases?

A

They have a pro-peptide which must be cleaved.
They have a catalytic domain which contains the HExxH motif that binds zinc.
At the C-terminal end of the protein is a hemopexin domain involved in substrate recognition.

73
Q

What is the substrate recognition domain of matrix metalloproteinases?

A

Hemopexin domain.

74
Q

Which matrix metalloproteinases are collagenases?

A

MMP-1

MMP-13

75
Q

Which matrix metalloproteinases are gelatinases?

A

MMP-2

MMP-9

76
Q

Which matrix metalloproteinases are stromelysins?

A

MMP-3

MMP-10

77
Q

What is the function of collagenases?

A

Degrade the collagen triple helix.

78
Q

What is the function of gelatinases?

A

Degrade the denatured collagen triple helix.

79
Q

What is the function of stromelysins?

A

Degrade non-collagenous matrix proteins (excluding aggrecan).

80
Q

Describe the structure of aggrecanase?

A

Aggrecanases are - A disintegrin And Metalloproteinases with Thrombospondin motif.
They have a pro-domain that is cleaved by the furin protein intracellularly in the golgi apparatus.
They have a catalytic domai containing a HExxH motif which is zinc-binding.
They have a disintegrin domain and a thrombospondin domain which are potentially involved in substrate interaction.

81
Q

Where do pathological aggrecanases cleave aggrecan?

A

Between the glutamate and alanin peptide bond in the interglobular domain of aggrecan.

82
Q

Why doesn’t initial loss of cartilage cause pain?

A

Because cartilage is aneural.

83
Q

What causes rheumatoid arthritis?

A

Deposition of immune complexes in the joint space cause influx of inflammatory cells that secrete cytokine which induce cartilage degradation.
This is an autoimmune disease.

84
Q

What is the main cytokine involved in rheumatoid arthritis?

A

TNF-a.

85
Q

What are the treatments for arthritic disease?

A 
Steroids. 
NSAIDs.
Surgery. 
Anti-cytokine antibodies. 
Neutraceuticals.
86
Q

What is primary osteoarthritis?

A

Primary osteoarthritis is idiopathic meaning the cause/origins are unknown.

87
Q

What is secondary osteoarthritis?

A

Caused by post-traumatic injury, congenital malposition of the joint, post-operative surery, metabolic, endocrine disorders, aseptic osteonecrosis.

88
Q

What are some endogenous risk factors for osteoarthritis?

A

Age, sex, heredity, ethnic origins, post-menopausal.

89
Q

What are some exogenous causes of osteroarthritis?

A

Microtrauma, repetitive microtrauma, being overweight, lifestyle, resective joint surgery.

90
Q

What are the 4 most common knee sport injuries?

A
  1. Anterior cruciate ligament injuries.
  2. Collateral ligament injuries.
  3. Meniscal cartilage tears.
  4. Cartilage lesions e.g. osteochondrosis dissecans.
91
Q

What is osteochondrosis dissecans?

A

OCD can precede OA.
Affects 15-29 per 100,000.
It is an idiopathic focal joint disorder affecting the subchondral bone in which a fragment of cartilage or subchondral bone separates from the articular surface.

92
Q

Which stages of osteochondrosis dissecans are non-displaced?

A

1, 2, 3

93
Q

What are the 4 stages of osteochondrosis dissecans?

A

There is initiation,an event where there is fragmentation of small focuses of subchondral bone.
This creates a defect between the osteochondral lesion and the permanent bone.
Through time there is small microtraumas and decrease vascularisation to that part of the bone.
Ultimatley there is necrosis which progresses up to the articular cartilage.
Eventually, at stage IV there is displacement of the subchondral bone cartilage fragment which is released into the synovial joint.

94
Q

What are the symptoms of osteochondrosis dissecans?

A

Pain
Inflammation, oedema, swelling, soreness in joint.
Catching and locking in the joint during movement.
Reduced range of motion.
Creptius, grating, cracking, popping sound.

95
Q

Who pioneered the process of autologous chondrocyte transplanation?

A

Mats Brittberg

96
Q

What is the methodology for autologous chondrocyte transplantation?

A

300-500mg of cartialge is harvested from low-weight bearing regions (usually upper medial femoral condyle).
Cartilage is digested (collagenases) to release cells yielding 180000-450000 cells.
Cells are seeded into tissue culture flasks at a density of 5000-10000 cells per cm2 and maintained in media containing autologous sera - this is culture expansion/ex vivo expansion in culture.
Transplantatio 12-14 days after initial surgery.
Chondrocytes are trypsin treated, washed and resuspended at which point they number 2-5-5m.
The chondral lesion is excised to eliminate damaged tissue and the cartilge defect is covered with a periosteal flap taken from the tibial bone of a patient.
The periosteal flap is sutered to the normal cartilage and acts as a source of growth factors and stem cells.
The autologous chondrocyte are injcted under the periosteal flap to initiate repair and remodelling of the cartilage ECM.

97
Q

Why is the periosteal flap important in ACT?

A

Potential source of growth factors and stem cells.

98
Q

What are the drawbacks of first generation ACT?

A

Limitations include defect size, geometry and inefficient cell retention within the defect.
Early surgeries invovled completely opening up the joint in multiple surgeries, this can now be performed arthroscopically meaning less damage and less trauma.
A defect size >4-6cm won’t be efficiently repaired with ACT.

99
Q

What is second generation ACI?

A

Development of 3D constructs using nativ and synthetic biomaterials, e.g. capsules to retain and hold cells.
Use of a collagen membrane (instead of a periosteum).
Use of cell-seeded membranes (MACI).
Use of 3D scaffolds (e.g. hyaluronic acid) seeded with chondrocytes.

100
Q

What is third generation ACI?

A

Use of chondroprogenitor cells and biofunctionalised biomaterials for more extesnive and permanent repairs.
This may be mesenchymal stem cells, the chondroprogenitors don’t need to be autologous.

Concepts of Disease (11 decks)

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