Chondrocytes and TMJ Flashcards
1
Q
what is cartilage?
A
specialized connective tissue
2
Q
is cartilage vascular?
A
no, avascular
3
Q
cartilage has limited — capacity
A
regenerative
4
Q
Cartilage contains — ground substance
predominantly proteoglycans
A
gelatinous
5
Q
(2)
embedded in ground substance
A
Collagen and elastic protein fibers
6
Q
where is cartilage found?
A
in locations where support,
flexibility, resistance to compression
are important.
7
Q
cartilage is important in embryonic — —
A
bone formation (endochondral)
8
Q
growth plate cartilage is important for
A
longitudinal bone growth
9
Q
in hyaline cartilage, protein fibers are predominantly
A
collagen (2 and ten)
10
Q
appearance of hyaline cartilage
A
glossy with evenly dispersed chondrocytes
11
Q
hyaline cartilage is a — connective tissue
A
supportive
12
Q
most abundant cartilage type in the body
A
hyaline
13
Q
where is hyaline cartilage found (5)
A
− 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
14
Q
type of fibers in elastic cartilage
A
type 2 collagen together with a lot of elastic fibers (elastin), making it more flexible
15
Q
where is elastic cartilage found? (3)
A
pharngotympanic (Eustachian tubes)
epiglottis
ear lobes
16
Q
fibrocartilage
A
mixture of fibrous tissue (type
I collagen containing) and hyaline cartilage
17
Q
structure of fibrocartilage
A
Chondrocytes dispersed among fine collagen
fibers in layered arrays
18
Q
fibrocartilage is —, making it a good — absorber
A
spongy
shock
19
Q
where is fibrocartilage found? (3)
A
public symphysis
intervertebral disks
TMJ
20
Q
ECM is fibrocartilage contains what type of cartilage?
A
type 1 and 2
21
Q
Osteoblasts, Chondrocytes, Myoblasts and Adipocytes Differentiate from a Common — Precursor
A
Mesenchymal
22
Q
what is the principle engine for longitudinal bone growth?
A
proliferation of columnar chondrocytes
and expansion of chondrocyte size (10-15 fold) in hypertrophic region
23
Q
genes/markers importnat in chondrocyte differentiation: TF (3)
A
SOX9 SRY-box 9 (master regulator)
RUNX2 Runt related transcription factor 2
OSX Osterix
24
Q
genes/markers importnat in chondrocyte differentiation: signaling molecules (4)
A
IHH Indian hedgehog
PTHrP Parathyroid hormone related protein
FGFs Fibroblast growth factors
(VEGF Vascular endothelial growth factor)
25
genes/markers importnat in chondrocyte differentiation: receptors for signaling molecules (3)
PTC1 Patched (Ihh receptor)
PTH1R PTH/PTHrP receptor
FGFR3 Fibroblast growth factor receptor 3
26
genes/markers importnat in chondrocyte differentiation: ECM components (3)
COL2A1 Type II collagen
ACAN Aggrecan
COL10A1 Type X collagen
27
genes/markers importnat in chondrocyte differentiation: enzymes/proteases (2)
TNSALP Tissue non specific alkaline phosphatase
| MMP13 Matrix metalloproteinase 13
28
SOX9 is a master transcription factor which drives
| differentiation down ---- pathway
chondrocyte
29
where is SOX9 expressed?
in chondroprogenitors/ proliferating chondrocytes (not hypertrophic chondrocytes)
30
SOX 9 must be
| downregulated to allow
chondrocytes to mature
| SOX 9 inhibits RUNX2
31
where is RUNX2/OSX expressed?
in prehypertrophic and hypertrophic chondrocytes
32
RUNX2/OSX is an important regulator of
hypertrophy
33
RUNX2 homozygous deletion results in (2)
delayed chondrocyte maturation, failure to form bone
34
Hypertrophy:
• Chondrocytes --- in size (10-15 fold)
• Express type -- collagen
• Express --- ----, which promotes mineralization
• Express ---. which promotes vascular invasion
• Eventually undergo ---
```
swell
10
alkaline phosphatase
MMP13/VEGF (vascular endothelial growth factor)
apoptosis (programmed cell death)
```
35
key regulators of chondrogenesis (2)
Ihh
| PTHrP
36
Co-ordinated actions of Ihh and PTHrP signaling
| through their receptors (PTC1 and PTH1R) regulate
chondrocyte proliferation/differentiation and determine length of the proliferating columns of chondrocytes
37
Co-ordinated actions of Ihh and PTHrP signaling
through their receptors (PTC1 and PTH1R) regulate
chondrocyte proliferation/differentiation and determine length of the proliferating columns of chondrocytes
• Also determines when chondrocytes enter ---
hypertrophy
38
principle engine for bone
| growth
chondrocyte hypertrophy
39
Ihh/PTHrP axis is very important
| in regulating
bone longitudinal bone growth
40
PTHrP produced by early proliferative
| chondrocytes near
ends of bone/growth plate
41
PTHrP then acts on PTH1R receptor in late
| proliferating/prehypertrophic chondrocytes to
keep
them proliferating (stops them entering
hypertrophy)
42
When chondrocytes are far enough away from
| source they are no longer stimulated by PTHrP, they (3)
stop proliferating → become prehypertrophic →
| synthesize Ihh
43
what does Ihh stimulate?
chondrocyte proliferation
44
Ihh diffuses to ends of bones and acts on early
| proliferating cells, stimulating them to
produce
| more PTHrP
45
Ihh also induces periosteal cells to
form the
| mineralized bone collar
46
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
47
critical regulator of chondrocyte proliferation/differentiation
FGF signaling
48
-- FGF genes and -- FGF receptor genes
23
| 4
49
many FGF and FGFr genes are expressed in
cartilage
50
Complete story of which
ligands/receptors are important
not fully determined, however --- is very important
FGFR3
51
where is FGFR3 expressed?
in proliferating/prehypertrophic chondrocytes
52
FGFR3 also suppresses ---
Ihh
53
Major fibrillar collagen in cartilage, vitreous humor, inner ear
type 2 collagen
54
structure of type 2 cartilage
| encoded by
Homotrimer of α1(II) chains (encoded by COL2A1 gene)
55
Major collagen expressed in hypertrophic cartilage
type 10 cartilage
56
structure of type 10 cartilage
| encoded by
Homotrimer of α1(X) chains (encoded by COL10A1 gene)
57
GAGs
Unbranched polysaccharide chains composed of repeating
| disaccharide units
58
1st sugar residue =
```
amino sugar (N-acetylglucosamine or
N-acetylgalactosamine)
```
59
2nd sugar residue =
uronic acid (glucuronic or iduronic)
60
GAGs are usually highly ----, and --- charged
sulffonated
| highly
61
4 main groups of GAGS:
hyaluronan
chondroitin sulfate and dermatan sulfate
heparan sulfate and heparin
keratan sulfate
62
Most GAGs found covalently attached to a protein core in the form of ---
proteoglycans
63
Major proteoglycans of skeletal tissues: (2)
aggrecan
| versican
64
small leucine rich proteoglycans (SLRPs) (4)
decorin
biglycan
fibromodulin
osteoglycin
65
Major proteoglycan in cartilage – produced in large amounts by proliferating and prehypertrophic chondrocytes
aggrecan
66
Aggrecan core protein has (2) GAG chains
keratan sulphate and chondroitin sulfate
67
aggrecan assembles with hyaluronan to form
```
huge aggregates (hyaluronan
disaccharide chains can be as long as 50,000 repeats)
```
68
aggrecan binds high amounts of --- due to negative charge (cartilage is hydrated, resilient)
water
69
aggrecan may regulate ---
calcification
70
What happens when there are
mutations in genes involved
with cartilage differentiation
and function?
Chondrodysplasias
71
Chondrodysplasias
hereditary skeletal disorders characterized by abnormal
growth plate function leading to skeletal
deformities/growth defects (often dwarfism)
72
sometimes skeletal dysplasia or osteochondrodysplasia are used
somewhat interchangeably with chondrodysplasia - these terms encompass
dysplasias of both cartilage and bone.
73
Camplomelic Dysplasia
```
Rare human syndrome caused by
heterozygous loss of function mutation
in SOX9 (haploinsufficiency)
```
74
camplomelic dysplasia is
autosomal dominant
75
camplomelic dysplasia affects development of skeleton/reproductive system, such as (8)
* 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
76
camplomelic dysplasia is often threatening in
neonatal period
77
In mice - homozygous loss of Sox9 -
completely inhibits chondrogenesis
78
Impaired PTHrP signaling –
```
late
proliferating/prehypertrophic chondrocytes
will enter hypertrophy too soon
(premature growth plate
maturation/skeletal maturation)
```
79
Impaired Ihh signaling –
no
replacement of proliferating cells once
they have gone into hypertrophy
(premature closing of the growth plate)
80
Ihh/PTHrP Signaling is Required for Normal --- in Humans
Chondrocyte Differentiation/Bone Development
81
Inactivating Mutations in PTHrP (loss of function)
Brachydactyly type E2
82
Brachydactyly type E2
shortened digits; short stature; delayed tooth eruption in some patients
83
Inactivating Mutations in IHH (loss of function) (2)
Brachydactyly type A1
| Acrocapitofemoral Dysplasia
84
Brachydactyly type A1
shortened digits; short stature; premature fusion
| of growth plates
85
Acrocapitofemoral Dysplasia
short stature; cone shaped epiphyses in
| the hands, hips; premature fusion of growth plates
86
Mutations in PTH1R
```
Inactivating mutations (loss of function)- (1)
Activating mutations (gain of function) – (2)
```
Blomstrand Lethal Chondrodysplasia
Jansen’s metaphyseal chondrodysplasia, Eiken Syndrome
87
Blomstrand Lethal Chondrodysplasia:
premature growth plate maturation; premature skeletal maturation; increased bone density; joint fusion; short stature (perinatal lethal)
88
Jansen’s metaphyseal chondrodysplasia, Eiken Syndrome:
delayed
growth plate maturation/delayed skeletal maturation/ossification; short
stature; malpositioning of teeth (also hypercalcemia, hypophosphatemia)
89
Activating point mutations in FGFR3 in humans –
| associated with ---
Achondroplasia
90
Achondroplasia
shortened, disorganized columns of chondrocytes in growth plate – FGFR3 signaling normally acting to limit chondrocyte proliferation
91
most common form of short limbed dwarfism (1 in 15,000-40,000)
achondroplasia
92
achondroplasia avg height in M and F
M: 4'4"
F: 4'1"
93
achondroplasia is caused by activating mutations in
FGFR3
| constitutive ligand independent activation
94
achondroplasia is
autosomal dominant
| 80% of vases are sporadic mutation
95
prognosis for homozygous achondroplasia
severe disease
| usually still born or die shortly after birth from respiratory failure
96
Achondroplasia Features: (6)
```
• Short stature w/
disproportionately short limbs
(trunk relatively normal)
• Short fingers/toes
• Large head/prominent forehead
• Small midface/flattened nasal
bridge
• Spinal kyphosis (convex
curvature) or lordosis (concave
curvature)
• Varus (bowleg) or valgus (knock
knee) deformities
```
97
Type II collagen mutations - wide spectrum of
| clinical severity ranging from:
lethal, severe, mild
98
Lethal -
Severe-
Mild-
achondrogenesis type II/hypochondrogenesis
spondyloepiphyseal dysplasia (SED),
spondyloepimetaphyseal dysplasia congenita, Marshall syndrome
Stickler syndrome and early onset osteoarthritis
99
Spondyloepiphyseal Dysplasia (SED) is from mutations in --- gene
COL2A1
100
SED is
autosomal dominant
101
SED features (5)
• Short stature from birth - height reaches 2– 4.5ft
• Kyphoscoliosis (curved spine) / vertebral defects
(e.g. flattened vertebrae)
• Short trunk, neck, limbs
• Hands/feet less affected
• Hip deformities/clubfoot
102
Type X Collagen Mutations Associated with
Schmid-Type Metaphyseal Chondrodysplasia
103
Mutations in --- gene associated
with Schmid-type metaphyseal
chondrodysplasia
COL10A1
104
features/symptoms of schemed-type metaphysical chondrodysplasia
Short stature, bowing of the long
bones, widening/irregularity of growth
plates
105
TMJ has -- articulation surfaces
3
106
why is TMJ a unique joint
articular surfaces dont come into contact with each other
107
TMJ is separated by
articular disk
108
articular disk
cushioning function - prevents bone on bone wear
109
--- --- splits the joint into two synovial joint cavities
articular disk
110
Articular surfaces of bones covered in
| --- rather than hyaline
fibrocartilage
111
TMJ enclosed in a --- capsule
fibrous
112
--- --- surround joint
| capsule (adds stability)
Thick ligaments
113
Upper head of --- --- muscle inserts onto articular disk
lateral pterygoid
114
Disk =
fibrous/avascular (fibrocartilage)
115
Composed of dense fibrous tissue containing
−Tightly packed collagen fibers
−Proteoglycans
−Elastic fibers
116
Central part of disk =
avascular
117
Some ---like cells appear with age
chondrocyte
118
Opening and Closing of the TMJ (3)
• First 20mm opening involves rotational
movement of the joint in the socket
• To open mouth wider, the condyle and disc
have to move out of the socket, forward and
down the articular eminence
• Disc = avascular and lacking innervation –
cushions joint
119
Partly due to unique anatomy, disorders of TMJ =
common
| prevalence > 5% of population
120
Most common TMJ disorder is
disc displacement
121
disc displacement
disc is displaced
anteriorly, pulling vascularized/innervated retrodiscal tissue into the
joint (painful)
122
TMJ can lead to --- --- if disc degenerates
```
bone contact
(wearing of joint surfaces)
```
123
TMJ is more prevalent in --- than ---
women
| men
124
peak occurrence of TMJ
20-40 years
125
Temporomandibular disorder (TMD) -
thought to be a multifactorial
process secondary to muscle hyperfunction, traumatic injuries,
hormonal influences, articular changes (e.g. osteoarthritis)
126
--- thought to be a contributing factor
Malocclusion
127
Symptoms of TMD/TMJ (3)
decreased mandibular range of motion
muscle/joint pain
functional limitation/deviation of the jaw opening
