11/13: Chondrocytes and Cartilage

Question 1

What is cartilage?

Answer 1

Specialized connective tissue
Avascular

Question 2

What does cartilage contain?

Answer 2

Limited regenerative capacity
Gelatinous ground substance

Question 3

Where is cartilage found?

Answer 3

Locations where support, flexibility, resistance to compression

Question 4

What is cartilage important in?

Answer 4

Embryonic bone formation

Question 5

What is important for longitudinal bone growth?

Answer 5

Growth plate cartilage

Question 6

What makes up hyaline cartilage?

Answer 6

Protein fibers = predominantly collagen (II,X)

Question 7

Where is hyaline cartilage found?

Answer 7

− Growth plate
− Precursor to bone in embryonic skeleton
− Joint articular surfaces (reduces
friction/acts as shock absorber)
− Costal (rib) cartilages
− Cartilage in nose, ears, trachea, larynx,
smaller respiratory tubes

Question 8

What is elastic cartilage?

Answer 8

Type II collagen with lots of elastic fibers (elastin), making it more flexible

Question 9

Where is elastic cartilage found in?

Answer 9

− pharyngotympanic (eustachian) tubes
− epiglottis
− ear lobes

Question 10

What is fibrocartilage made of?

Answer 10

Mixture of fibrous tissue (type I collagen containing) and hyaline cartilage

Question 11

Where is fibrocartilage found in?

Answer 11

− Pubic symphysis
− Intervertebral disks
− Temporomandibular joint (TMJ)

Question 12

What does the ECM of fibrocartilage contain?

Answer 12

Type I and Type II collagen

Question 13

What are the steps of endoochondral bone formation?

Answer 13

1. Mesenchymal condensation
2. differentiation
3. blood vessels initiate cartilage destruction/bone
   formation in center of developing element
4. Secondary ossification centers formed following vascular invasion

Question 14

Proliferation of columnar chondrocytes and expansion of chondrocyte size in hypertrophic region is the principle engine for?

Answer 14

Longitudinal bone growth

Question 15

What is the master regulator of chondrocyte differentiation?

Answer 15

SOX9

Question 16

What replaces SOX9 in cartilage differentiation?

Answer 16

RUNX2
OSX

Question 17

What drives differentiation down chondrocyte pathway?

Answer 17

SOX9

Question 18

What is expressed in chondroprogenitors/proliferating chondrocytes?

Answer 18

activation of SOX9

Question 19

Why must SOX9 be downregulated?

Answer 19

To allow chondrocytes to mature

Question 20

What does SOX9 inhibit?

Answer 20

RUNX2

Question 21

What is expressed in prehypertrophic and hypertrophic chondrocytes?

Answer 21

RUNX2/OSX

Question 22

What are important regulators of hypertrophy?

Answer 22

RUNX2/OSX

Question 23

What does RUNX2 homozygous deletion cause?

Answer 23

Delayed chondrocyte maturation - failure to form bone

Question 24

What are key regulators of chondrogenesis and are the two ligands chondrocytes bind to?

Answer 24

LHH and PTHrP

Question 25

What are LHH and PTHrP receptors?

Answer 25

PTC1 and PTH1R

Question 26

What regualtes chondrocyte proliferation/differentiation and determine length of the proliferating columns of chondrocytes?

Answer 26

Ihh and PTHrP

Question 27

What determines when chondrocytes enter hypertrophy?

Answer 27

Ihh and PTHrP

Question 28

What is the principle engine for bone growth?

Answer 28

Chondrocyte hypertrophy

Question 29

What is Ihh/PTHrP axis very important in?

Answer 29

Regulating bone longitudinal bone growth

Question 30

What is PTHrP produced by?

Answer 30

Early proliferative chondrocytes near ends of bone/growth plate

Question 31

What does PTHrP act on/

Answer 31

PTH1R receptor in late proliferating/prehypertrophic dhoncroycytes to keep them proliferating

Question 32

What happens when chondrocytes are far enough from source?

Answer 32

No longer stimulated by PTHrP -> stop proliferating -> become hypertrophic -> synthesize Ihh

Question 33

What stimulates chondrocyte proliferation>

Answer 33

Ihh

Question 34

What does Ihh act on to stimulate?

Answer 34

Early proliferating cells; producting more PTHrP

Question 35

What cells does Ihh induce and what does this form?

Answer 35

Perioteal cells; mineralized bone collar

Question 36

What does the feedback loop ensure?

Answer 36

Once cells enter hypertrophy (a one way trip eventually resulting in apoptosis!) they produce Ihh then PTHrP to ensure proliferation of a continual supply of chondrocytes to replace them

Question 37

What is a critical regulator of chondrocyte proliferation/differentiation?

Answer 37

FGF signaling

Question 38

When is FGFR3 expressed?

Answer 38

In proliferating/prehypertrophic chondrocytes

Question 39

What is FGFR3 signaling important in?

Answer 39

Regulatory step that limits chondrocyte proligeration

Question 40

What does FGFR3 suppress?

Answer 40

Ihh

Question 41

What is the major fibrillar collagen in cartilage?

Answer 41

Type II collagen

Question 42

What is the major collagen expressed in hypertrophic cartilage?

Answer 42

Type X collagen

Question 43

What are the 1st and 2nd suar residues in glycosaminoglycans?

Answer 43

1st = amino sugar 2nd = uronic acid

Question 44

What are 4 main groups of GAGS?

Answer 44

Hyaluronan Chondroitin sulfate and dermatan sulfate Heparan sulfate and heparin Keratan sulfate

Question 45

What are the major proteoglycans of skeletal tissues?

Answer 45

Aggrecan Versican

Question 46

What are small leucine rich proteoglycans?

Answer 46

Decorin Biglycan Fibromodulin Osteoglycin

Question 47

What does the aggrecan core protein have?

Answer 47

Keratan sulphate Chondroitin sulfate GAG chains

Question 48

What may regulate calcification?

Answer 48

Aggrecan

Question 49

What happens when there are mutations in genes involved with cartilage differentiation and function?

Answer 49

Chondrodysplasias

Question 50

What is a hereditary skeletal disorders characterized by abnormal growth plate function leading to skeletal deformities/growth defects?

Answer 50

Chondrodysplasias

Question 51

What is camplomelic dysplasia caused by?

Answer 51

Heterozygous loss of function mutation in SOX9

Question 52

What does camplomelic dysplasia affect?

Answer 52

Development of skeleton/reproductive system

Question 53

What does impaired PTHrP signaling lead to?

Answer 53

late proliferating/prehypertrophic chondrocytes will enter hypertrophy too soon (premature growth plate maturation/skeletal maturation)

Question 54

What does impaired Ihh signaling lead to?

Answer 54

no replacement of proliferating cells once they have gone into hypertrophy (premature closing of the growth plate)

Question 55

What happens when both PTHrP and IHH signaling goes wrong?

Answer 55

Growth retardation (dwarfism)

Question 56

What is required for normal chondrocyte differentiation/bone development in humans?

Answer 56

Ihh/PTHrP signaling

Question 57

What is the most common form of short limbed dwarfism?

Answer 57

Achondroplasia

Question 58

What is achondroplasia caused by?

Answer 58

Mutation in FGF receptor 3 (FGFR3)

Question 59

What are the types of clinical severity of type II collagen mutations?

Answer 59

Lethal Severe Mild

Question 60

What are mutations in type II collagen linked to?

Answer 60

Chondrodysplasias

Question 61

What is spondyloepiphyseal dysplasia (SED) a mutation in?

Answer 61

COL2A1 gene (type 2 collagen)

Question 62

What is Schmid-type meetaphyseal chondrodysplasia a mutatoin in?

Answer 62

COL10A1 (type X collagen)

Question 63

What are the 3 types of chondrodysplasias?

Answer 63

1. Mutations in transcription factors - SOX9 2. Mutations in cartilage extracellular amtrix components - Type II collagen - Type X collagen - aggrecan 3. Mutations in signaling molecules and their receptors - PTHrP,IHH, PTH1R loss/gain of function - FGFR3