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Biochemistry (Cole) > Lecture 43 Chondrocytes and TMJ > Flashcards

Lecture 43 Chondrocytes and TMJ Flashcards

1
Q

Does cartilage contain blood vessels?

A
  • no its avascular
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2
Q

what makes up cartilage gelatinous ground substance?

A
  • predominantly proteoglycans that have collagen and and protein fibers embedded in it
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3
Q

Where is cartilage typically located?

A
  • locations where support, flexibility, and resistance to compression are important
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4
Q

What type of bone formation is cartilage important in?

A
  • embryonic bone formation (endochondral)
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5
Q

Growth plate cartilage is important for?

A
  • longitudinal bone growth
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6
Q

What are the types of cartilage?

A
  • hyaline
  • elastic
  • fibrous
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7
Q

What protein fibers make up hyaline cartilage?

A
  • II and X
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8
Q

What is the most abundant type of cartilage found in body?

A
  • hyaline

supportive connective tissue

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9
Q

What is the appearance of hyaline cartilage?

A
  • glossy appearance w/evenly dispersed chondrocytes
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10
Q

Where is hyaline cartilage found in?

A
  • growth plate
  • precursor to bone in embryonic skeleton
  • joint articular surfaces (reduces friction/act as shock absorber)
  • costal rib cartilages
  • cartilage in nose ears trachea larynx and smaller respiratory tubes
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11
Q

_________ has type II collagen together with a lot of elastic fibers (elastin) making it more flexible

A
  • elastic cartilage
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12
Q

Elastic cartilage is found in what structures?

A
  • pharyngotympanic (eustachian) tubes
  • epiglottis
  • ear lobes`
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13
Q

_________ is a mixture of fibrous tissue (type I collagen containing) and hyaline cartilage

A
  • fibrocartilage

- (also has chondrocytes dispersed among fine collagen fibers in arrays)

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14
Q

What cartilage is spongy and a good shock absorber?

A
  • fibrocartilage
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15
Q

Where is fibrocartilage found?

A
  • pubic symphysis
  • intervertebral disks
  • Temporomandibular joint
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16
Q

ECM of _______ contains both type I and type II collagen?

A
  • fibrocartilage
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17
Q

What is the precursor of chondrocytes?

A
  • mesenchymal progenitors ( same precursor as osteoblasts)
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18
Q

What are the steps of endochondral bone formation?

A
  1. mesenchymal condensation
  2. differentiation
  3. blood vessels initiate cartilage destruction/bone formation in center of developing element (VEGF)
  4. secondary ossification centers formed following vascular invasion
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19
Q

What cells do mesenchymal differentiate into as it results to endochondral bone formation?

A
  • proliferating
  • prehypertrophic
  • perichondrium
  • periosteal bone collar
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20
Q

What are the zones of the epiphyseal growth plate?

A
  • resting zone (contains stem cells)
  • proliferating zone (columnar organization)
  • maturing chondrocytes (prehypertrophic)
  • hypertrophic zone (where length happens from swelling chondrocytes)
  • bone
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21
Q

What is the principle engine for longitudinal bone growth? 🦴

A
  • proliferation of columnar chondrocytes and expansion of chondrocyte (10-15 fold) in hypertrophic region
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22
Q

What are the transcription factors in chondrocyte differentiation?

A
  • SOX9
  • RUNX2
  • OSX (osterix)
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23
Q

what is the master regulator of chondrocyte differentiation?

A
  • SOX9
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24
Q

What are the signaling molecules for chondrocyte differentiation?

A
  • indian hedgehog
  • PTHrP
  • Fibrolblast
    (VEGF is marker of prehypertrophic chondrocytes)
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25
Receptors for signaling molecules in chondrocyte differentiation?
- PTC1 (Patched Ihh receptor) - Fibroblast growth factor receptor 3 (FGFR3) - PTH1R receptor
26
What are the extracellular matrix components involved in chondrocyte differentiation?
- Type II Collagen - Aggrecan - Type X collagen
27
What enzymes or proteases are involved in chondrocyte differentiation?
- TNSALP (tissue non specific alkaline phosphatase) | - MMP13 ( matrix metalloproteinase 13)
28
What is the transcription factor in the proliferation phase of cartilage growth?
- SOX9
29
What transcription factors come into play during prehypertrophic and hypertrophic growth?
- OSX | - RUNX2
30
Why must you down regulate SOX9?
- it inhibits RUNX2 which is an important regulator of hypertrophy
31
What happens when RUNX2 is homozygous deleted?
- delayed chondrocyte maturation - failure to form bone
32
What cells express RUNX2/OSX?
- prehypertrophic and hypertrophic chondrocytes
33
What happens during the hypertrophy phase?
- chondrocytes swell in size (10-15 fold) - type X collagen is expressed - Alkaline phosphatase is expressed (mineralizes into bone) - MMP13/VEGF are expressed (promote cascular invasion) - eventually undergo apoptosis
34
______ and _______ are key regulators of chondrogenesis?
- Ihh and PTHrP
35
What do Ihh and PTHrP do?
- regulate chondrocyte proliferation/differentiation and determine length of the proliferating columns of chondrocytes - also determine when chondrocytes enter hypertrophy
36
What is the principle engine for bone growth?
- chondrocyte hypertrophy
37
Ihh/PTHrP axis is?
- very important in regulating longitudinal bone growth bc of its involvement with chondrocyte hypertrophy
38
Describe the feedback loop of PTHrp/Ihh
- feedback loop ensures 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
39
What is PTHrP role in the chondrocyte differentiation?
- acts on PTH1R receptor in late proliferating/prehypertrophic chondrocytes to keep them proliferating (prevents them from entering hypertrophy)
40
What happens when chondroctyes are far enough away from source they are no longer stimulated by PTHrP
- stop proliferating and become prehypertrophic and synthesize Ihh
41
What does ihh do?
- stimulates chondrocyte proliferation by telling early proliferating cells to produce more PTHrP
42
What is the other function of ihh?
- induces periosteal cells to form the mineralized bone collar
43
What is FGFR3 role?
- FGFR3 signaling is important additional regulatory step that limits chondrocyte proliferation - (also suppresses Ihh)
44
What type of collagen is expressed in the proliferative phase of cartilage growth?
- type 2 collagen (COL2A1 gene) | - and aggrecan
45
What type of collagen is expressed in the hypertrophic part of growth?
- type X collagen (COL10A1 gene)
46
What is the major fibrillar collagen in cartilage, vireous humor, and inner ear?
- type II collagen
47
_ what is the structure of type II collagen?
- homotrimer of a1(II) chains encoded by the COL2A1 gene
48
What is the collagen expressed in hypertrophic cartilage?
- type x collagen
49
What is the structure of type X collagen?
- homotrimer of a1(X) chains (encoded by COL10a1 gene)
50
Unbranched polysacccharide chains composed of repeating disaccharide units are?
- glycosaminoglycans (GAGs)
51
what is the structure of GAGs)
- 1st sugar residue is an amino sugar (N-acetylglucosamine or N- acetylgalactosamine) - 2nd sugar residue is uronic acid (glucuronic or iduronic) - usually highly sulfated i.e negatively charged
52
What are 4 main groups of GAGS:
- hyaluronan - chondroitin sulfate and dermatan sulfate - heparan sulfate and heparin - keratan sulfate
53
What are the major proteoglycans of skeletal tissues?
- aggrecan | - versican
54
Most GAGS are found covalently attached to what?
- a protein core in the form of proteoglycans
55
What is the major proteoglycan found in cartilage?
- aggrecan | produced in large amounts of proliferating and prehypertrophic chondrocytes
56
Aggregan core protein has _______ and _____ sulfate GAG chains
- keratan sulphate | - chondroitin
57
What does aggrecan assemble with to form huge aggregates?
- hyaluronan
58
What is the function of aggrecan?
- binds high amounts of water due to negative charge (cartilage is hydrated, resilient) - may regulate calcification
59
_________ are hereditary skeletal disorders characterized by abnormal growth plate function leading to skeletal deformities/growth defects (often dwarfism)
- chondroysplasias
60
What condrodysplasia is associated by a heterozygous loss of function mutation in SOX9?
- camplomelic dysplasia | often life threating in neonatal period
61
Is campolimelic dysplasia AD or AR?
- Autosomal dominant
62
What happens to mice if they have homozygous loss os SOX9?
- completely inhibits chondrogenesis
63
What are the symptoms of camplomelic dysplasia?
- hypoplasia of skeletal elements - bowing of limbs - shortened limbs/dislocated hips - underdeveloped shoulder blades - 11 pairs of ribs instead of 12 - clubfoot - ambigous genitalia - craniofacial abnormalities
64
What happens with impaired PTHrP signaling?
- late proliferating/prehypertrophic chondrocytes will enter hypertrophy too soon (premature growth plate maturation/skeletal maturation)
65
What happens with Impaired Ihh signaling?
- no replacement of proliferating cells once they have gone into hypertrophy (premature closing of the growth plate)
66
Both impaired PTHrP and Ihh signaling lead to?
- Growth retardation (DWARFISM)
67
What do inactivating mutations in PTH1R lead to?
- Blomstrand lethal chondrodysplasia
68
What is blomstrand lethal chondrodysplasia?
- premature growth plate maturation; premature skeletal maturation, increased bone density, joint fusion; short stature (perinatal lethal)
69
What do activating mutations in PTH1R cause?
- Jansens metaphyseal chondrodsplasia, Eiken syndrome
70
What are symptoms of jansens metaphyseal chondrodsplasia, Eiken syndrome?
- delayed growth plate maturation/delayed skeletal maturation/ossification; short staure; malpositioning of teeth
71
What do inactivating mutations of PTHrP cause?
- Bradhydactlyly type e2 (shortened digits; short stature; delayed tooth eruption in some patients)
72
What do inactivating mutations in Ihh cause?
- brachydactyly type A1 | - Acrocapitofemoral dysplasia
73
Brachydactyly type A1
- caused by inactiving mutations in Ihh | - shortened digits, short stature, premature fusion of growth plates
74
Acrocapitofemral dysplasia
- caused by inactivating mutations in Ihh | - short stature; cone shaped epiphyses in hands, hips; premature fusion of growth plates
75
What are activating point mutations in FGFR3 associated with?
- Achondroplasia
76
Achondroplasia
- shortened disorganized columns of chondrocytes in growth plate
77
What is the most ocmmon form of short limbed dwarfism?
- achondroplasia
78
What causes achondroplasia?
- activating mutations in FGF receptor 3 gene (FGFR3) | - (constituitve ligand independent activation)
79
Is achondroplasia AR or AD?
- autosomal dominant | - (homozygotes have severe disease usually still born or die shortly after birth form respiratory failure)
80
What are the lethal type II collagen mutations?
- ahcondrogenesis type II/hypochondrogenesis
81
What are the severe type II collagen mutations?
- spondyloepiphyseal dysplasia (SED) - spondyloepimetaphyseal dysplasia congenita - marshall syndrome
82
What are the mild type II collagen mutations?
- stickler syndrome and early onset osteoarthritis
83
There are over 10 mutations causing ACGII-HCG reported and all involve replacement of ________ by a bulkier amino acid in triple helical region of a1(II) chain?
- glycine
84
Spondyloepiphyseal Dysplasia (SED)
- mutations in COL2A1 gene - AD - short stature from birth (2-4.5ft) - kyphoscoliosis (curved spine)/ vertebral defects (e.g. flatttened vertebrae) - short trunk, neck, limbs - hands/feet less affected - hip deformities/clubfoot
85
What causes shmid type metaphyseal chondrodysplasia?
- type X collagen mutation | results in short stature bowing of the long bones, widening/irregularity of growth plates
86
autosomal recessive spondyloepimetaphyseal dyslplasia
- aggrecan type - pretty severe - height 2'2 - 2'4
87
What type of cartilage covers the TMJ?
- fibrocartilage
88
______ thought to be a multifactoral process secondary to muscle hyperfunction traumatic injuries hormonal influences articular changes
- Temporomandibular disorder
89
Articular disorders of TMJ
- Inflammation related - Rhuematoid arthritis - non - inflammatory - Osteoarthristis joint damage from trauma/ surgery - disc displacement (most common)
90
Non-articular disorders
- extracapsular - myofascial pain in muscles of mastication fibromyalgia, muscle strain - myopathies- may arise from clenching/bruxism

Biochemistry (Cole) (25 decks)

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