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Biochem > Lecture 45- Chondrocytes and Cartilage > Flashcards

Lecture 45- Chondrocytes and Cartilage Flashcards

1
Q

what is cartilage

A

specialized avascular connective tissue with limited regenerative capacity

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2
Q

what does cartilage contain

A

gelatinous ground substance with collagen and elastic protein fibers

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3
Q

where is cartilage found

A

in locations where support, flexibility, resistance to compression are important

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4
Q

what type of embyronic bone formation is cartilage important in

A

endochondral

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5
Q

what is growth plate cartilage important for

A

longitudinal bone growth

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6
Q

describe hyaline cartilage

A
  • predominantly type 2 collagen and 10
  • glossy appearance with evenly dispersed chondrocytes
    -most abundant type in body
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7
Q

where is hyaline cartilage found

A

-growth plate
-precursor to bone in embryonic skeleton
-joint articular surfaces
- costal cartilages
-cartilage in nose, ears, trachea, larynx, smaller respiratory tubes

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8
Q

describe elastic cartilage

A

-type 2 collagen with a lot of elastic fibers

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9
Q

where is elastic cartilage found

A

eustachian tubes, epiglottis, and ear lobes

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10
Q

describe fibrocartilage

A

mixture of type 1 collagen and hyaline cartilage with chondrocytes dispersed among fine collagen fibers in layered arrays

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11
Q

where is fibrocartilage found

A

pubic symphysis, intervertebral disks, TMJ

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12
Q

what is the principle engine for longitudinal bone growth

A

proliferation of columnar chondrocytes and expansion of chondrocyte size in hypertrophic region

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13
Q

what transcription factors are important in chondrocyte differentiation

A

mainly SOX9, also RUNX2, and OSX

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14
Q

what are the major signaling molecules in chondrocyte differentiation

A

IHH, PTHrP, FGFs and VEGF

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15
Q

what are the major receptors for signaling molecules in chondrocyte differentiation

A

PTC1, PTH1R, FGFR3

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16
Q

what are the major extracellular matrix components

A

COL2A1, ACAn, and COL10A1

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17
Q

what are the major enzymes/proteases involved in chondrocyte differentiation

A

TNSALP, and MMP13

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18
Q

what does SOX9 do

A

drives differentiation down chondrocyte pathway

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19
Q

where is SOX9 expressed

A

in chondroprogenitors/proliferating chondrocytes

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20
Q

what must happen to SOX9 for chondrocytes to mature

A

it must be downregulated

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21
Q

what does SOX9 inhibit

A

RUNX2

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22
Q

what is RUNX2/OSX expressed in

A

prehypertrophic and hypertrophic chondrocytes

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23
Q

what is RUNX2/OSX an important regulator of

A

hypertrophy

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24
Q

what happens in hypertrophy of chondrocytes

A

-chondrocytes swell in size
- express type 10 collagen
- express alkaline phosphatase
- express MMP13/VEGF
-eventually undergo apoptosis

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25
Q

what do Ihh and PTHrP regulate

A

chondrogenesis and longitudinal bone growth

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26
Q

what do coordinated actions of Ihh and PTHrP signaling through their receptors regulate

A

chondrocyte proliferation/differentiation and determine length of the proliferating columns of chondrocytes
- also determine when chondrocytes enter hypertrophy

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27
Q

how does the Ihh/PTHrP regulatory loop control chondrocyte differentiation kinetics (mechanism)

A
  • PTHrP produced by early proliferative chondrocytes near ends of bone/growth plate
  • this acts on PTH1R receptor in late proliferating/prehypertrophic chondrocytes to keep them proliferating
    -when chondrocytes are far enough away from source they are no longer stimulated by PTHrP -> stop proliferating -> become prehypertrophic -> synthesize Ihh
  • Ihh stimulates chondrocyte proliferation
  • Ihh diffuses to ends of bones and acts on early proliferating cells stimulating them to produce more PTHrP
  • Ihh also induces periosteal cells to form the mineralized bone collar
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28
Q

what does the feedback loop of chondrocyte differentiation kinetics ensure

A

once cells enter hypertrophy they produce Ihh and PTHrP to ensure proliferation of a continual supply of chondrocytes to replace them

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29
Q

what is FGF signaling a critical regulatory for

A

chondrocyte proliferation/differentiation

30
Q

how many FGF genes are there and how many FDF receptor genes

A

23 FGF genes and 4 FGF receptor genes

31
Q

what is FGFR3 important in and where is it expressed

A

important additional regulatory step that limits chondrocyte proliferation and expressed in proliferating/prehypertrophic chondrocytes

32
Q

what does FGFR3 suppress

A

Ihh

33
Q

where is type 2 collagen found

A

major fibrillar collagen in cartilage, vitreous humor, and inner ear

34
Q

describe the makeup of type 2 collagen and what gene encodes it

A

homotrimer of alpha1 (II) chains encoded by COL2A1 gene

35
Q

where is type 10 collagen expressed

A

hypertrophic cartilage

36
Q

describe the makeup of type 10 collagen and what gene encodes it

A

homotrimer of alpha1 (X) chains encoded by COL10A1 gene

37
Q

what is the 1st sugar residue in a GAG

A

amino sugar such as N-acetylglucosamine or N- acetylgalactosamine

38
Q

what is the 2nd sugar residue in a GAG

A

uronic acid such as glucuronic or iduronic

39
Q

what are the 4 main groups of GAGs

A
  • hyaluronan
  • chondroitin sulfate and dermatan sulfate
  • heparan sulfate and heparin
  • keratan sulfate
40
Q

what are the major proteoglycans in skeletal tissues

A

aggrecan and versican

41
Q

what are the SLRPs in proteoglycans

A

decorin, biglycan, fibromodulin, osteoglycin

42
Q

what is aggrecan produced by

A

proliferating and prehypertrophic chondrocytes

43
Q

what does aggregan core protein have

A

keratan sulphate and chondroitin sulfate GAG chains

44
Q

what does aggrecan assemble with

A

hyaluronan

45
Q

what does aggregan regulate

A

calcification

46
Q

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

A

chondrodysplasias

47
Q

what is camplomelic dysplasia

A

rare human syndrome caused by heterozygous loss of function mutation in SOX9

48
Q

what type of disorder is camplomelic dysplasia

A

autosomal dominant

49
Q

what are the symptoms of camplomelic dysplasia

A

-hypoplasia of skeletal elements
- bowing of limbs
- shortened limbs/dislocated hips
- underdeveloped shoulder blades
- 11 pairs of ribs instead of 12
- clubfoot
-ambiguous genitalia
- craniofacial abnormalities

50
Q

what happens in impaired PTHrP signaling

A

late proliferating/prehypertrophic chondrocytes will enter hypertrophy too soon resulting in premature growth plate maturation/skeletal maturation

51
Q

what happens in impaired Ihh signaling

A

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

52
Q

what do impaired PTFrP and Ihh signaling both lead to

A

dwarfism

53
Q

what happens in inactivating mutations in PTHrP

A

brachydactyly type E2
- loss of function

54
Q

what results in inactivating mutations in IHH

A

-brachydactyly type A1
- acrocapitofemoral dysplasia
- loss of function

55
Q

what results in inactivating mutations in PTH1R

A

-Blomstrand lethal chondrodysplasia
-loss of function

56
Q

what results in activating mutations in PTH1R

A

jansen’s metaphyseal chondrodysplasia
- gain of function

57
Q

what is the result of activating point mutations in FGFR3

A

achondroplasia
-gain of function

58
Q

what is the most common form of short limbed dwarfism

A

achondroplasia

59
Q

what type of disorder is achondroplasia

A

autosomal dominant

60
Q

what are the features of achondroplasia

A

-short stature with disproportionately short limbs
- short fingers/toes
- large head/prominent forehead
-small midface/flattened nasal bridge
- spinal kyphosis or lordosis
- varus (bowleg) or valgus ( knock knee) deformities

61
Q

what is the lethal type 2 collagen mutation

A

achondrogenesis type 2/hypochondrogenesis

62
Q

what are the severe type 2 collagen mutations

A

spondyloepiphyseal dysplasia, spondyloepimetaphyseal dysplasia congenita, Marshall syndrome

63
Q

what are the mild type 2 collagen mutations

A

stickler syndrome and early onset osteoarthritis

64
Q

what do mutations causing ACGII- HCG involve

A

replacement of glycine by bulkier amino acid in triple helical region of alpha1(II) chain

65
Q

what is spondyloepiphyseal dysplasia caused by

A

mutations in COL2A1 gene

66
Q

what type of disorder is SED

A

autosomal dominant

67
Q

what are type 10 collagen mutations associated with

A

Schmid type metaphyseal chondrodysplasia

68
Q

what mutation is associated with Schmid type metaphyseal chondrodysplasia

A

COL10A1

69
Q

what are symptoms Schmid type metaphyseal chondrodysplasia

A

short stature, bowing of the long bones, widening/irregularity of growth plates

70
Q

what is the autosomal recessive form of aggrecan associated chondrodysplasias

A

spondyloepiphyseal dysplasia - aggrecan type

71
Q

what is the autosomal dominant form of aggregan associated chondrodysplasias

A

spondyloepiphyseal dysplasia - type Kimberly - milder form

Biochem (34 decks)

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