11/13: Chondrocytes and Cartilage Flashcards
What is cartilage?
Specialized connective tissue
Avascular
What does cartilage contain?
Limited regenerative capacity
Gelatinous ground substance
Where is cartilage found?
Locations where support, flexibility, resistance to compression
What is cartilage important in?
Embryonic bone formation
What is important for longitudinal bone growth?
Growth plate cartilage
What makes up hyaline cartilage?
Protein fibers = predominantly collagen (II,X)
Where is hyaline cartilage found?
− 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
What is elastic cartilage?
Type II collagen with lots of elastic fibers (elastin), making it more flexible
Where is elastic cartilage found in?
− pharyngotympanic (eustachian) tubes
− epiglottis
− ear lobes
What is fibrocartilage made of?
Mixture of fibrous tissue (type I collagen containing) and hyaline cartilage
Where is fibrocartilage found in?
− Pubic symphysis
− Intervertebral disks
− Temporomandibular joint (TMJ)
What does the ECM of fibrocartilage contain?
Type I and Type II collagen
What are the steps of endoochondral bone formation?
- Mesenchymal condensation
- differentiation
- blood vessels initiate cartilage destruction/bone
formation in center of developing element - Secondary ossification centers formed following vascular invasion
Proliferation of columnar chondrocytes and expansion of chondrocyte size in hypertrophic region is the principle engine for?
Longitudinal bone growth
What is the master regulator of chondrocyte differentiation?
SOX9
What replaces SOX9 in cartilage differentiation?
RUNX2
OSX
What drives differentiation down chondrocyte pathway?
SOX9
What is expressed in chondroprogenitors/proliferating chondrocytes?
activation of SOX9
Why must SOX9 be downregulated?
To allow chondrocytes to mature
What does SOX9 inhibit?
RUNX2
What is expressed in prehypertrophic and hypertrophic chondrocytes?
RUNX2/OSX
What are important regulators of hypertrophy?
RUNX2/OSX
What does RUNX2 homozygous deletion cause?
Delayed chondrocyte maturation - failure to form bone
What are key regulators of chondrogenesis and are the two ligands chondrocytes bind to?
LHH and PTHrP
What are LHH and PTHrP receptors?
PTC1 and PTH1R
What regualtes chondrocyte proliferation/differentiation and determine length of the proliferating columns of chondrocytes?
Ihh and PTHrP
What determines when chondrocytes enter hypertrophy?
Ihh and PTHrP
What is the principle engine for bone growth?
Chondrocyte hypertrophy
What is Ihh/PTHrP axis very important in?
Regulating bone longitudinal bone growth
What is PTHrP produced by?
Early proliferative chondrocytes near ends of bone/growth plate
What does PTHrP act on/
PTH1R receptor in late proliferating/prehypertrophic dhoncroycytes to keep them proliferating
What happens when chondrocytes are far enough from source?
No longer stimulated by PTHrP -> stop proliferating -> become hypertrophic -> synthesize Ihh
What stimulates chondrocyte proliferation>
Ihh
What does Ihh act on to stimulate?
Early proliferating cells; producting more PTHrP
What cells does Ihh induce and what does this form?
Perioteal cells; mineralized bone collar
What does the feedback loop ensure?
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
What is a critical regulator of chondrocyte proliferation/differentiation?
FGF signaling
When is FGFR3 expressed?
In proliferating/prehypertrophic chondrocytes
What is FGFR3 signaling important in?
Regulatory step that limits chondrocyte proligeration
What does FGFR3 suppress?
Ihh
What is the major fibrillar collagen in cartilage?
Type II collagen
What is the major collagen expressed in hypertrophic cartilage?
Type X collagen
What are the 1st and 2nd suar residues in glycosaminoglycans?
1st = amino sugar
2nd = uronic acid
What are 4 main groups of GAGS?
Hyaluronan
Chondroitin sulfate and dermatan sulfate
Heparan sulfate and heparin
Keratan sulfate
What are the major proteoglycans of skeletal tissues?
Aggrecan
Versican
What are small leucine rich proteoglycans?
Decorin
Biglycan
Fibromodulin
Osteoglycin
What does the aggrecan core protein have?
Keratan sulphate
Chondroitin sulfate GAG chains
What may regulate calcification?
Aggrecan
What happens when there are
mutations in genes involved
with cartilage differentiation
and function?
Chondrodysplasias
What is a hereditary skeletal disorders characterized by abnormal growth plate function leading to skeletal
deformities/growth defects?
Chondrodysplasias
What is camplomelic dysplasia caused by?
Heterozygous loss of function mutation in SOX9
What does camplomelic dysplasia affect?
Development of skeleton/reproductive system
What does impaired PTHrP signaling lead to?
late proliferating/prehypertrophic chondrocytes
will enter hypertrophy too soon (premature growth plate
maturation/skeletal maturation)
What does impaired Ihh signaling lead to?
no replacement of proliferating cells once
they have gone into hypertrophy
(premature closing of the growth plate)
What happens when both PTHrP and IHH signaling goes wrong?
Growth retardation (dwarfism)
What is required for normal chondrocyte differentiation/bone development in humans?
Ihh/PTHrP signaling
What is the most common form of short limbed dwarfism?
Achondroplasia
What is achondroplasia caused by?
Mutation in FGF receptor 3 (FGFR3)
What are the types of clinical severity of type II collagen mutations?
Lethal
Severe
Mild
What are mutations in type II collagen linked to?
Chondrodysplasias
What is spondyloepiphyseal dysplasia (SED) a mutation in?
COL2A1 gene (type 2 collagen)
What is Schmid-type meetaphyseal chondrodysplasia a mutatoin in?
COL10A1 (type X collagen)
What are the 3 types of chondrodysplasias?
- Mutations in transcription factors
- SOX9 - Mutations in cartilage extracellular amtrix components
- Type II collagen
- Type X collagen
- aggrecan - Mutations in signaling molecules and their receptors
- PTHrP,IHH, PTH1R loss/gain of function
- FGFR3
