Chondrocytes and TMJ Flashcards
How do we know that IHH acts back on the earlier stages of chondrocyte differentiation?
because its receptor PTC1 is present at earlier stages on earlier cells
Where would you find fibrocartilage in the body?
- pubic symphysis
- intervertebral discs
- TMJ
Why is the IHH/PTHrP regulatory loop important in chondrocyte differentiation?
because the feedback loop ensures that once cells enter hypertrophy, they produce enough IHH, and then PTHrP, to ensure a continual supply of chondrocytes to replace them
Stickler syndrome and early onset osteoarthritis are both ____ type II collagen mutations.
mild
When is type II collagen expressed in the ECM of cartilage?
from the mesenchymal cells until the prehypertrophic chondrocyte
Why is aggrecan so important in cartilage?
because its negative charge allows it to bind large amounts of water and contribute greatly to the gel-like consistency of cartilage
Which transcription factors turn on later, when chondrocytes become hypertrophic?
RUNX2
Osterix (OSX)
Does cartilage have a blood supply?
NO - it is avascular
What are some extracellular matrix components of chondrocyte differentiation?
COL2A1 (type II)
ACAN (aggrecan)
COL10A1 (type X)
Which syndrome results in short stature, cone-shaped epiphysis in the hands and hips, and premature fusion of the growth plates?
acrocapitofemoral dysplasia
Which receptors are expressed in prehypertrophic chondrocytes?
PTH1R
FGFR3
What are the classifications of TMJ disorders?
- articular disorders (intrecapsular)
- non-articular disorders (extracapsular)
Hyaline cartilage contains type __ and type __ collagen fibers.
II; X
What are 4 important signaling molecules involved in chondrocyte differentiation?
IHH
PTHrP
FGFs
VEGF
What are some mutations that can cause chondrodysplasias?
- mutations in transcription factors
- mutations in signaling molecules and their receptors
- mutations in cartilage ECM components
What are the 4 main groups of GAGs?
- hyaluronan
- chondroitin sulfate and dermatan sulfate
- heparan sulfate and heparin
- keratan sulfate
There are 23 FGF genes and 4 FGF receptor genes, many of them being expressed in ____.
endochondral bone formation
What are the attributes of Jansen’s metaphyseal chondrodysplasia or Eiken syndrome?
- delayed growth plate maturation
- delayed skeletal maturation
- short stature
- malpositioning of teeth
- hypercalcemia
- hypophosphatemia
Aggrecan may have a role in regulating what mineral?
calcium
In ____, patients present with shortened digits, short stature, and premature fusion of growth plates.
brachydactyly type A1
What is the syndrome that results from an inactivating mutation in the PTH1R receptor?
Blomstrand Lethal Chondrodysplasia
What acts as a brake on chondrocyte proliferation?
FGFR3
What is the major type of fibrillar collagen in cartilage?
Type II collagen
What are some features of patients with achondroplasia?
- short limbs
- short fingers/toes
- large head/prominent forehead
- flattened nasal bridge
- kyphosis or lordosis
- bowleg/knock knees
Where would you NOT find SOX9 contained in the cells of chondrocyte differentiation?
within the hypertrophic chondrocytes (only found in precursors or proliferating chondrocytes)
Mutations in PTHrP, IHH, PTH1R, and FGFR3 result in ____.
chondrodysplasias
What does the recruitment of blood vessels to newly forming bone do?
blood vessels initiate cartilage destruction and allow bone formation in the center of the developing mass
____ cartilage has primarily type II and type X collagen fibers and is the most abundant type of cartilage found in the body.
Hyaline
What amino acid is replaced in a lethal mutation of type II collagen called Achonrogenesis type II or hypochondrogenesis?
glycine (replaced by a much bulkier amino acid)
Fusion of the growth plates prematurely is indicative of a mutation in the ___ gene.
IHH
Where is hyaline cartilage found in the body?
- growth plates
- bone precursor in embryo
- joint articular surfaces
- costal cartilage
- nose, ear, trachea, larynx cartilage
Which zone at the epiphyseal growth plate contains swollen chondrocytes that attract capillaries and osteoblasts?
Hypertrophic Zone
What type of cartilage has type II collagen along with elastic fibers (elastin)?
elastic cartilage
Where would you find RUNX2 and OSX expressed?
in prehypertrophic and hypertrophic chondrocytes
What are the enzymes or proteases involved with the hypertrophic chondrocytes?
TNSALP
MMP13
What pathway also stimulates periosteal cells at the sides of the bone to form the mineralized bone collar?
IHH
What is the principle engine for longitudinal bone growth?
the proliferation of columnar chondrocytes in the Proliferation Zone and expansion of chondrocytes in the Hypertrophic Zone
How are most GAGs found? What are they attached to?
in the form of a proteoglycan (they are found covalently attached to a protein core)
Which is the major type of collagen expressed in hypertrophic cartilage?
Type X collagen
SOX9 inhibits ____, which is why SOX9 must be down-regulated in order to allow chondrocytes to mature.
RUNX2
___ stimulates chondrocyte proliferation.
IHH
What would happen if IHH signaling was impaired?
no replacement of proliferating cells would occur once they enter hypertrophy (premature closing of the growth plate)
What are the 3 articulation surfaces of the TMJ?
articular tubercle
mandibular fossa
mandibular head
How many synovial joint cavities does the TMJ have?
2
In which type of cartilage are the chondrocytes dispersed among fine, spongy collagen in layered arrays?
fibrocartilage
What is SOX9 expressed in?
chondroprogenitors and proliferating chondrocytes
What particular growth factor do hypertrophic chondrocytes attract?
VEGF
____ diffuses to the ends of bones and acts on early proliferating cells, stimulating them to produce more PTHrP.
IHH
_____ of TMJ are intracapsular and can be causes by inflammation, non-inflammatory factors, or disc displacement.
Articular disorders
What type of collagen is expressed in hypertrophic chondrocytes?
Type X collagen (before hypertrophy they were expressing type II)
____ signaling is a critical regulator of chondrocyte/cartilage proliferation and differentiation.
FGF
Impaired IHH and impaired PTHrP signaling lead to what condition?
dwarfism
Cartilage has a ____ regenerative capacity and is considered a specialized connective tissue.
limited
What might happen if SOX9 was not able to be downregulated?
the chondrocytes would not be able to mature since SOX9 inhibits RUNX2
What two pathways are very important in the regulation of longitudinal bone growth?
IHH
PTHrP
What gene suppresses IHH?
FGFR3
What muscle of the head and neck inserts onto the articular disc of the TMJ?
upper head of lateral pterygoid muscle
What type of cartilage typically covers articular joints?
hyaline cartilage
GAGs are usually ____ sulfated.
highly (= negatively charged)
Achondrogenesis type II/hypochondrogenesis is a ____ type II collagen mutation.
lethal
Of the IHH/PTHrP signaling-pathway associated syndromes, which are loss-of-function mutations?
- Blomstrand Lethal Chondrodysplasia
- brachydactyly type E2
- brachydactyly type A1
- acrocapitofemoral dysplasia
What happens when a patient is affected by autosomal recessive spondyloepimetaphyseal dysplasia, with aggrecan being affected?
these patients are very, very short (about 2 feet tall)
____, a transcriptional regulator, is working with the proliferative cells in cartilage differentiation: the mesenchymal cells, chondrocytes, and flat columnar chondrocytes.
SOX9
____ and ____ are transcription regulators associating with prehypertrophic chondrocytes, hypertrophic chondrocytes, and terminal hypertrophic chondrocytes.
RUNX2; OSX (Osterix)
In which type of bone formation is there the production of a cartilage template?
endochondral bone formation
What hereditary skeletal disorders are characterized by abnormal growth plate function leading to skeletal deformities and growth defects?
the chondrodysplasias
What is the structure called that mineralizes on the outside to essentially provide the outermost scaffold for endochondral bone formation?
periosteal bone collar
What are some unique characteristics of the TMJ?
- TMJ enclosed in a fibrous capsule
- thick ligaments surround it
- split synovium
- 3 articulation surfaces that do not touch
Does cartilage have a role in embryonic bone formation?
YES - endochondral bone formation (AKA the one with the precursor)
What is TNSALP?
tissue non-specific alkaline phosphatase
As chondrocytes move away from the growth plate, they become less and less exposed to PTHrP, which allows them to do what?
when they are no longer stimulated by PTHrP they stop proliferating and become prehypertrophic, which causes them to synthesize IHH
Achondroplasia is a ___-of-function mutation involving the FGFR3 signaling pathway.
gain
Mutations in Type II or Type X collagen, as well as aggrecan can result in ____.
chondrodysplasias
____ is a disease where the growth plate prematurely closes, the skeleton matures too quickly, bone density is increased, and joints fuse.
Blomstrand Lethal Chondrodysplasia
What condition(s) results from an inactivating mutation in IHH?
Brachydactyly type A1
Acrocapitofemoral dysplasia
What are the 3 transcription factors important in chondrocyte differentiation?
SOX9
RUNX2
Osterix (OSX)
What type of structures are formed following vascular invasion of bone in endochondral bone formation?
secondary ossification centers called growth plates
When is ACAN (aggrecan) expressed in the ECM of cartilage?
from the chondrocyte until the prehypertrophic chondrocyte
What is the master transcription factor/regulator of chondrocyte differentiation?
SOX9 (SRY-box 9)
Coordinated actions of ___ and ___ signaling through their receptors PTC1 and PTH1R regulate chondrocyte proliferation and differentiation determining the length of the columns of chondrocytes.
IHH; PTHrP
Schmid-type (spondylo)metaphyseal chondrodysplasia is caused by mutations in the ____ collagen gene.
COL10A1
What is the most common TMJ arthropathy?
disc displacement
Spondyloepiphyseal dysplasia is causes by a mutation in the ____ collagen gene.
COL2A1
Which receptors are expressed in chondrocytes and flat columnar chondrocytes?
PTC1
FGFR3
What receptor is expressed in chondrocytes, flat columnar chondrocytes, and prehypertrophic chondrocytes?
FGFR3
___ and ___ are important regulators of hypertrophy.
RUNX2; OSX
What is the first sugar residue of a GAG?
amino sugar (N-acetylglucoasamine OR N-acetylgalactosamine)
What are IHH’s and PTHrP’s receptors?
PTC1
PTH1R
What two pathways act as key regulators of chondrogenesis?
IHH
PTHrP
COL2A1, Aggregan, and COL10A1 are all produced in large amounts by ___.
chondrocytes
What do chondrocytes originate from?
mesenchymal progenitors
In _____, patients present with shortened digits, short stature, and delayed tooth eruption.
brachydactyly type E2
How many articulation surfaces does the temporomandibular joint have?
3
Which zone at the epiphyseal growth plate contains stem cells?
Resting Zone
What two pathways determine when chondrocytes enter hypertrophy?
IHH + PTC1 receptor
PTHrP + PTH1R receptor
Which two GAG chains does the aggrecan core protein contain?
keratan sulfate
chondroitin sulfate
The extracellular matrix of fibrocartilage contains type __ and type __ collagen.
I; II
What condition results from an inactivating mutation in PTHrP?
brachydactyly type E2
Is the central part of the TMJ articular disc vascular or avascular?
avascular
What is the syndrome that results from an activating mutation in the PTH1R receptor?
Jansen’s metaphyseal chondrodysplasia OR Eiken syndrome
Aggrecan assembles with ____ to form giant aggregates.
hyaluronan
This is the major proteoglycan in cartilage, since it is produced in such large amounts by proliferating and prehypertrophic chondrocytes.
Aggrecan (ACAN)
___ are unbranched polysaccharide chains composed of repeating disaccharide units.
Glycosaminoglycans (GAGs)
What is the gelatinous ground substance of cartilage primarily composed of? What is embedded in the ground substance?
proteoglycans; collagen and elastic protein fibers
What is the most common form of short-limbed dwarfism?
achondroplasia
What are the TMJ articular surfaces separated by?
an articular disc
Where is elastic cartilage found in the body?
- Eustacian (pharyngotympanic) tubes
- epiglottis
- ear lobes
Decorin, biglycan, fibromodulin, and osteoglycin are all ____.
SLRPs (small leucine rich proteoglycans)
What happens after the formation of the periosteal bone collar?
chondrocytes become hypertrophic
What are the primary components of elastic cartilage?
type II collagen fibers elastic fibers (elastin)
What are the two mutations that can happen to the PTH1R receptor and cause loss-of-function or gain-of-function mutations?
inactivating mutations
activating mutations
Patients with ____ have shortened and disorganized columns of chondrocytes in their growth plates.
achondroplasia
What allows us to expand our bones from the growth plate?
the massive swelling of hypertrophic chondrocytes
What are 3 important receptors for signaling molecules in chondrocyte differentiation?
PTC1
FGFR3
PTH1R (PTH/PTHrP receptor)
____ and ____ are both major proteoglycans of skeletal tissues.
Aggrecan; versican
Camplomelic dysplasia is causes by a mutation in the _____ regulation of the SOX9 genes.
transcriptional
Where do we find cartilage in the body?
in locations where support, flexibility, and resistance to compression are important
What happens when the coordinated system of chondrocyte proliferation and hypertrophy is mutated or altered?
chondrodysplasias can occur
PTHrP acts on the ___ receptor in late proliferation or prehypertrophic chondrocytes to keep them proliferating (but preventing them from becoming hypertrophic).
PTH1R
____ is a mixture of fibrous tissue (type I collagen) and hyaline cartilage.
Fibrocartilage
What would happen if PTHrP signaling was impaired?
the late proliferating or prehypertrophic chondrocytes would enter hypertrophy too soon leading to premature growth plate maturation
What are some manifestations of camplomelic dysplasia?
- hypoplasia of skeletal elements
- bowing
- underdeveloped shoulder blades
- clubfoot
- 11 ribs instead of 12
- ambiguous genitalia
____ of TMJ are extracapsular and may arise from clenching and bruxism.
Non-articular disorders
What is growth plate cartilage important for?
longitudinal bone growth
IHH is produced by ___ chondrocytes in chondrocyte differentiation.
prehypertrophic
What is the movement of the TMJ called when the joint migrates downward to allow the jaw to open?
translation
What are the 4 zones of differentiation at the epiphyseal growth plate?
Resting Zone
Proliferative Zone
Maturing Chondrocytes
Hypertrophic Zone
____ is expressed in the proliferating and prehypertrophic chondrocytes and its signaling is very important additional regulatory step that limits chondrocyte proliferation.
FGFR3
Why do GAGs bind such high amounts of water and create a gel-like matrix?
because the highly-sulfated nature of GAGs makes them negatively charged, so they bind water readily
What is the layer around the cartilage cells called in endochondral bone formation?
perichondrium
Spondyloepiphyseal dysplasia, spondyloepimetaphyseal dysplasia congenita, and Marshall syndrome are all _____ type II collagen mutations.
severe
When is type X collagen expressed in the ECM of cartilage?
from the prehypertrophic chondrocyte until the terminal hypertrophic chondrocyte
What does the recruitment of blood vessels to bone initiate?
brings in osteoclasts that resorb away the extra hypertrophic cartilage and allow osteogenic precursors to build bone
Do the articular surfaces of the TMJ contact each other?
NO
What is the second sugar residue of a GAG?
uronic acid (glucuronic OR iduronic)
Which type of cartilage has a glossy appearance with evenly dispersed chondrocytes?
hyaline cartilage
____ is an enzyme present in chondrocyte hypertrophy that promotes mineralization.
Alkaline phosphatase
What do hypertrophic chondrocytes express that promotes vascular invasion?
MMP13
VEGF
PTHrP is produced by ____ cells in chondrocyte differentiation.
early proliferative
Of the IHH/PTHrP signaling pathway-associated syndromes, which are gain-of-function mutations?
- Jansen’s metaphyseal chondrodysplasia
- Eiken syndrome
____ is the rare human syndrome caused by SOX9 haploinsufficiency that affects the development of the skeleton and reproductive system.
Camplomelic dysplasia
What happens when there are mutations in genes involved with cartilage differentiation and function?
chondrodysplasias result
What is happening regarding the activating mutation of FGFR3 gene in achondroplasia?
the FGFR3 gene is being activated, even in the absence of a ligand, so FGFR3 is severely restricting the proliferation of chondrocytes
What structure separates the two synovial joints of the TMJ?
articular disc
Are the receptors produced in the same place as the ligands in chondrocyte differentiation?
NO - they’re from different places
How is FGFR3 signaling normally acting?
it limits chondrocyte proliferation
What transcriptional regulator is the main driver of the cartilage differentiation/chondrocyte pathway?
SOX9
___ is produced by early proliferative chondrocytes near the ends of bone at the growth plates.
PTHrP
What do mesenchymal progenitors eventually produce in their lineage?
myocytes
adipocytes
chondrocytes
osteoblasts
What type of cartilage covers the articular surfaces of the TMJ?
fibrocartilage
How many genes encode type II collagen?
1 - COL2A1
What is thought to be a contributing factor to temporomandibular disorder (TMD)?
malocclusion
