Lecture 45- Chondrocytes and Cartilage Flashcards
what is cartilage
specialized avascular connective tissue with limited regenerative capacity
what does cartilage contain
gelatinous ground substance with collagen and elastic protein fibers
where is cartilage found
in locations where support, flexibility, resistance to compression are important
what type of embyronic bone formation is cartilage important in
endochondral
what is growth plate cartilage important for
longitudinal bone growth
describe hyaline cartilage
- predominantly type 2 collagen and 10
- glossy appearance with evenly dispersed chondrocytes
-most abundant type in body
where is hyaline cartilage found
-growth plate
-precursor to bone in embryonic skeleton
-joint articular surfaces
- costal cartilages
-cartilage in nose, ears, trachea, larynx, smaller respiratory tubes
describe elastic cartilage
-type 2 collagen with a lot of elastic fibers
where is elastic cartilage found
eustachian tubes, epiglottis, and ear lobes
describe fibrocartilage
mixture of type 1 collagen and hyaline cartilage with chondrocytes dispersed among fine collagen fibers in layered arrays
where is fibrocartilage found
pubic symphysis, intervertebral disks, TMJ
what is the principle engine for longitudinal bone growth
proliferation of columnar chondrocytes and expansion of chondrocyte size in hypertrophic region
what transcription factors are important in chondrocyte differentiation
mainly SOX9, also RUNX2, and OSX
what are the major signaling molecules in chondrocyte differentiation
IHH, PTHrP, FGFs and VEGF
what are the major receptors for signaling molecules in chondrocyte differentiation
PTC1, PTH1R, FGFR3
what are the major extracellular matrix components
COL2A1, ACAn, and COL10A1
what are the major enzymes/proteases involved in chondrocyte differentiation
TNSALP, and MMP13
what does SOX9 do
drives differentiation down chondrocyte pathway
where is SOX9 expressed
in chondroprogenitors/proliferating chondrocytes
what must happen to SOX9 for chondrocytes to mature
it must be downregulated
what does SOX9 inhibit
RUNX2
what is RUNX2/OSX expressed in
prehypertrophic and hypertrophic chondrocytes
what is RUNX2/OSX an important regulator of
hypertrophy
what happens in hypertrophy of chondrocytes
-chondrocytes swell in size
- express type 10 collagen
- express alkaline phosphatase
- express MMP13/VEGF
-eventually undergo apoptosis
what do Ihh and PTHrP regulate
chondrogenesis and longitudinal bone growth
what do coordinated actions of Ihh and PTHrP signaling through their receptors regulate
chondrocyte proliferation/differentiation and determine length of the proliferating columns of chondrocytes
- also determine when chondrocytes enter hypertrophy
how does the Ihh/PTHrP regulatory loop control chondrocyte differentiation kinetics (mechanism)
- PTHrP produced by early proliferative chondrocytes near ends of bone/growth plate
- this acts on PTH1R receptor in late proliferating/prehypertrophic chondrocytes to keep them proliferating
-when chondrocytes are far enough away from source they are no longer stimulated by PTHrP -> stop proliferating -> become prehypertrophic -> synthesize Ihh - Ihh stimulates 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
what does the feedback loop of chondrocyte differentiation kinetics ensure
once cells enter hypertrophy they produce Ihh and PTHrP to ensure proliferation of a continual supply of chondrocytes to replace them
what is FGF signaling a critical regulatory for
chondrocyte proliferation/differentiation
how many FGF genes are there and how many FDF receptor genes
23 FGF genes and 4 FGF receptor genes
what is FGFR3 important in and where is it expressed
important additional regulatory step that limits chondrocyte proliferation and expressed in proliferating/prehypertrophic chondrocytes
what does FGFR3 suppress
Ihh
where is type 2 collagen found
major fibrillar collagen in cartilage, vitreous humor, and inner ear
describe the makeup of type 2 collagen and what gene encodes it
homotrimer of alpha1 (II) chains encoded by COL2A1 gene
where is type 10 collagen expressed
hypertrophic cartilage
describe the makeup of type 10 collagen and what gene encodes it
homotrimer of alpha1 (X) chains encoded by COL10A1 gene
what is the 1st sugar residue in a GAG
amino sugar such as N-acetylglucosamine or N- acetylgalactosamine
what is the 2nd sugar residue in a GAG
uronic acid such as glucuronic or iduronic
what are the 4 main groups of GAGs
- hyaluronan
- chondroitin sulfate and dermatan sulfate
- heparan sulfate and heparin
- keratan sulfate
what are the major proteoglycans in skeletal tissues
aggrecan and versican
what are the SLRPs in proteoglycans
decorin, biglycan, fibromodulin, osteoglycin
what is aggrecan produced by
proliferating and prehypertrophic chondrocytes
what does aggregan core protein have
keratan sulphate and chondroitin sulfate GAG chains
what does aggrecan assemble with
hyaluronan
what does aggregan regulate
calcification
what happens when there are mutations in genes involved with cartilage differentiation and function
chondrodysplasias
what is camplomelic dysplasia
rare human syndrome caused by heterozygous loss of function mutation in SOX9
what type of disorder is camplomelic dysplasia
autosomal dominant
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
-ambiguous genitalia
- craniofacial abnormalities
what happens in impaired PTHrP signaling
late proliferating/prehypertrophic chondrocytes will enter hypertrophy too soon resulting in premature growth plate maturation/skeletal maturation
what happens in impaired Ihh signaling
no replacement of proliferating cells once they have gone into hypertrophy resulting in premature closing of the growth plate
what do impaired PTFrP and Ihh signaling both lead to
dwarfism
what happens in inactivating mutations in PTHrP
brachydactyly type E2
- loss of function
what results in inactivating mutations in IHH
-brachydactyly type A1
- acrocapitofemoral dysplasia
- loss of function
what results in inactivating mutations in PTH1R
-Blomstrand lethal chondrodysplasia
-loss of function
what results in activating mutations in PTH1R
jansen’s metaphyseal chondrodysplasia
- gain of function
what is the result of activating point mutations in FGFR3
achondroplasia
-gain of function
what is the most common form of short limbed dwarfism
achondroplasia
what type of disorder is achondroplasia
autosomal dominant
what are the features of achondroplasia
-short stature with disproportionately short limbs
- short fingers/toes
- large head/prominent forehead
-small midface/flattened nasal bridge
- spinal kyphosis or lordosis
- varus (bowleg) or valgus ( knock knee) deformities
what is the lethal type 2 collagen mutation
achondrogenesis type 2/hypochondrogenesis
what are the severe type 2 collagen mutations
spondyloepiphyseal dysplasia, spondyloepimetaphyseal dysplasia congenita, Marshall syndrome
what are the mild type 2 collagen mutations
stickler syndrome and early onset osteoarthritis
what do mutations causing ACGII- HCG involve
replacement of glycine by bulkier amino acid in triple helical region of alpha1(II) chain
what is spondyloepiphyseal dysplasia caused by
mutations in COL2A1 gene
what type of disorder is SED
autosomal dominant
what are type 10 collagen mutations associated with
Schmid type metaphyseal chondrodysplasia
what mutation is associated with Schmid type metaphyseal chondrodysplasia
COL10A1
what are symptoms Schmid type metaphyseal chondrodysplasia
short stature, bowing of the long bones, widening/irregularity of growth plates
what is the autosomal recessive form of aggrecan associated chondrodysplasias
spondyloepiphyseal dysplasia - aggrecan type
what is the autosomal dominant form of aggregan associated chondrodysplasias
spondyloepiphyseal dysplasia - type Kimberly - milder form
