Chondrocytes and TMJ Flashcards
what is cartilage?
specialized connective tissue
is cartilage vascular?
no, avascular
cartilage has limited — capacity
regenerative
Cartilage contains — ground substance
predominantly proteoglycans
gelatinous
(2)
embedded in ground substance
Collagen and elastic protein fibers
where is cartilage found?
in locations where support,
flexibility, resistance to compression
are important.
cartilage is important in embryonic — —
bone formation (endochondral)
growth plate cartilage is important for
longitudinal bone growth
in hyaline cartilage, protein fibers are predominantly
collagen (2 and ten)
appearance of hyaline cartilage
glossy with evenly dispersed chondrocytes
hyaline cartilage is a — connective tissue
supportive
most abundant cartilage type in the body
hyaline
where is hyaline cartilage found (5)
− 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
type of fibers in elastic cartilage
type 2 collagen together with a lot of elastic fibers (elastin), making it more flexible
where is elastic cartilage found? (3)
pharngotympanic (Eustachian tubes)
epiglottis
ear lobes
fibrocartilage
mixture of fibrous tissue (type
I collagen containing) and hyaline cartilage
structure of fibrocartilage
Chondrocytes dispersed among fine collagen
fibers in layered arrays
fibrocartilage is —, making it a good — absorber
spongy
shock
where is fibrocartilage found? (3)
public symphysis
intervertebral disks
TMJ
ECM is fibrocartilage contains what type of cartilage?
type 1 and 2
Osteoblasts, Chondrocytes, Myoblasts and Adipocytes Differentiate from a Common — Precursor
Mesenchymal
what is the principle engine for longitudinal bone growth?
proliferation of columnar chondrocytes
and expansion of chondrocyte size (10-15 fold) in hypertrophic region
genes/markers importnat in chondrocyte differentiation: TF (3)
SOX9 SRY-box 9 (master regulator)
RUNX2 Runt related transcription factor 2
OSX Osterix
genes/markers importnat in chondrocyte differentiation: signaling molecules (4)
IHH Indian hedgehog
PTHrP Parathyroid hormone related protein
FGFs Fibroblast growth factors
(VEGF Vascular endothelial growth factor)
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
genes/markers importnat in chondrocyte differentiation: ECM components (3)
COL2A1 Type II collagen
ACAN Aggrecan
COL10A1 Type X collagen
genes/markers importnat in chondrocyte differentiation: enzymes/proteases (2)
TNSALP Tissue non specific alkaline phosphatase
MMP13 Matrix metalloproteinase 13
SOX9 is a master transcription factor which drives
differentiation down —- pathway
chondrocyte
where is SOX9 expressed?
in chondroprogenitors/ proliferating chondrocytes (not hypertrophic chondrocytes)
SOX 9 must be
downregulated to allow
chondrocytes to mature
SOX 9 inhibits RUNX2
where is RUNX2/OSX expressed?
in prehypertrophic and hypertrophic chondrocytes
RUNX2/OSX is an important regulator of
hypertrophy
RUNX2 homozygous deletion results in (2)
delayed chondrocyte maturation, failure to form bone
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)
key regulators of chondrogenesis (2)
Ihh
PTHrP
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
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
principle engine for bone
growth
chondrocyte hypertrophy
Ihh/PTHrP axis is very important
in regulating
bone longitudinal bone growth
PTHrP produced by early proliferative
chondrocytes near
ends of bone/growth plate
PTHrP then acts on PTH1R receptor in late
proliferating/prehypertrophic chondrocytes to
keep
them proliferating (stops them entering
hypertrophy)
When chondrocytes are far enough away from
source they are no longer stimulated by PTHrP, they (3)
stop proliferating → become prehypertrophic →
synthesize Ihh
what does Ihh stimulate?
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
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
critical regulator of chondrocyte proliferation/differentiation
FGF signaling
– FGF genes and – FGF receptor genes
23
4
many FGF and FGFr genes are expressed in
cartilage
Complete story of which
ligands/receptors are important
not fully determined, however — is very important
FGFR3
where is FGFR3 expressed?
in proliferating/prehypertrophic chondrocytes
FGFR3 also suppresses —
Ihh
Major fibrillar collagen in cartilage, vitreous humor, inner ear
type 2 collagen
structure of type 2 cartilage
encoded by
Homotrimer of α1(II) chains (encoded by COL2A1 gene)
Major collagen expressed in hypertrophic cartilage
type 10 cartilage
structure of type 10 cartilage
encoded by
Homotrimer of α1(X) chains (encoded by COL10A1 gene)
GAGs
Unbranched polysaccharide chains composed of repeating
disaccharide units
1st sugar residue =
amino sugar (N-acetylglucosamine or N-acetylgalactosamine)
2nd sugar residue =
uronic acid (glucuronic or iduronic)
GAGs are usually highly —-, and — charged
sulffonated
highly
4 main groups of GAGS:
hyaluronan
chondroitin sulfate and dermatan sulfate
heparan sulfate and heparin
keratan sulfate
Most GAGs found covalently attached to a protein core in the form of —
proteoglycans
Major proteoglycans of skeletal tissues: (2)
aggrecan
versican
small leucine rich proteoglycans (SLRPs) (4)
decorin
biglycan
fibromodulin
osteoglycin
Major proteoglycan in cartilage – produced in large amounts by proliferating and prehypertrophic chondrocytes
aggrecan
Aggrecan core protein has (2) GAG chains
keratan sulphate and chondroitin sulfate
aggrecan assembles with hyaluronan to form
huge aggregates (hyaluronan disaccharide chains can be as long as 50,000 repeats)
aggrecan binds high amounts of — due to negative charge (cartilage is hydrated, resilient)
water
aggrecan may regulate —
calcification
What happens when there are
mutations in genes involved
with cartilage differentiation
and function?
Chondrodysplasias
Chondrodysplasias
hereditary skeletal disorders characterized by abnormal
growth plate function leading to skeletal
deformities/growth defects (often dwarfism)
sometimes skeletal dysplasia or osteochondrodysplasia are used
somewhat interchangeably with chondrodysplasia - these terms encompass
dysplasias of both cartilage and bone.
Camplomelic Dysplasia
Rare human syndrome caused by heterozygous loss of function mutation in SOX9 (haploinsufficiency)
camplomelic dysplasia is
autosomal dominant
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
camplomelic dysplasia is often threatening in
neonatal period
In mice - homozygous loss of Sox9 -
completely inhibits chondrogenesis
Impaired PTHrP signaling –
late proliferating/prehypertrophic chondrocytes will enter hypertrophy too soon (premature growth plate maturation/skeletal maturation)
Impaired Ihh signaling –
no
replacement of proliferating cells once
they have gone into hypertrophy
(premature closing of the growth plate)
Ihh/PTHrP Signaling is Required for Normal — in Humans
Chondrocyte Differentiation/Bone Development
Inactivating Mutations in PTHrP (loss of function)
Brachydactyly type E2
Brachydactyly type E2
shortened digits; short stature; delayed tooth eruption in some patients
Inactivating Mutations in IHH (loss of function) (2)
Brachydactyly type A1
Acrocapitofemoral Dysplasia
Brachydactyly type A1
shortened digits; short stature; premature fusion
of growth plates
Acrocapitofemoral Dysplasia
short stature; cone shaped epiphyses in
the hands, hips; premature fusion of growth plates
Mutations in PTH1R
Inactivating mutations (loss of function)- (1) Activating mutations (gain of function) – (2)
Blomstrand Lethal Chondrodysplasia
Jansen’s metaphyseal chondrodysplasia, Eiken Syndrome
Blomstrand Lethal Chondrodysplasia:
premature growth plate maturation; premature skeletal maturation; increased bone density; joint fusion; short stature (perinatal lethal)
Jansen’s metaphyseal chondrodysplasia, Eiken Syndrome:
delayed
growth plate maturation/delayed skeletal maturation/ossification; short
stature; malpositioning of teeth (also hypercalcemia, hypophosphatemia)
Activating point mutations in FGFR3 in humans –
associated with —
Achondroplasia
Achondroplasia
shortened, disorganized columns of chondrocytes in growth plate – FGFR3 signaling normally acting to limit chondrocyte proliferation
most common form of short limbed dwarfism (1 in 15,000-40,000)
achondroplasia
achondroplasia avg height in M and F
M: 4’4”
F: 4’1”
achondroplasia is caused by activating mutations in
FGFR3
constitutive ligand independent activation
achondroplasia is
autosomal dominant
80% of vases are sporadic mutation
prognosis for homozygous achondroplasia
severe disease
usually still born or die shortly after birth from respiratory failure
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
Type II collagen mutations - wide spectrum of
clinical severity ranging from:
lethal, severe, mild
Lethal -
Severe-
Mild-
achondrogenesis type II/hypochondrogenesis
spondyloepiphyseal dysplasia (SED),
spondyloepimetaphyseal dysplasia congenita, Marshall syndrome
Stickler syndrome and early onset osteoarthritis
Spondyloepiphyseal Dysplasia (SED) is from mutations in — gene
COL2A1
SED is
autosomal dominant
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
Type X Collagen Mutations Associated with
Schmid-Type Metaphyseal Chondrodysplasia
Mutations in — gene associated
with Schmid-type metaphyseal
chondrodysplasia
COL10A1
features/symptoms of schemed-type metaphysical chondrodysplasia
Short stature, bowing of the long
bones, widening/irregularity of growth
plates
TMJ has – articulation surfaces
3
why is TMJ a unique joint
articular surfaces dont come into contact with each other
TMJ is separated by
articular disk
articular disk
cushioning function - prevents bone on bone wear
— — splits the joint into two synovial joint cavities
articular disk
Articular surfaces of bones covered in
— rather than hyaline
fibrocartilage
TMJ enclosed in a — capsule
fibrous
— — surround joint
capsule (adds stability)
Thick ligaments
Upper head of — — muscle inserts onto articular disk
lateral pterygoid
Disk =
fibrous/avascular (fibrocartilage)
Composed of dense fibrous tissue containing
−Tightly packed collagen fibers
−Proteoglycans
−Elastic fibers
Central part of disk =
avascular
Some —like cells appear with age
chondrocyte
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
Partly due to unique anatomy, disorders of TMJ =
common
prevalence > 5% of population
Most common TMJ disorder is
disc displacement
disc displacement
disc is displaced
anteriorly, pulling vascularized/innervated retrodiscal tissue into the
joint (painful)
TMJ can lead to — — if disc degenerates
bone contact (wearing of joint surfaces)
TMJ is more prevalent in — than —
women
men
peak occurrence of TMJ
20-40 years
Temporomandibular disorder (TMD) -
thought to be a multifactorial
process secondary to muscle hyperfunction, traumatic injuries,
hormonal influences, articular changes (e.g. osteoarthritis)
— thought to be a contributing factor
Malocclusion
Symptoms of TMD/TMJ (3)
decreased mandibular range of motion
muscle/joint pain
functional limitation/deviation of the jaw opening
