Week 1 Flashcards
What are the bio functions of the skeleton
provides framework
uses joints - motion
provides muscle leverage
protects organs
what are examples of non-mineralized CT
notochord and cartilage
what are examples of mineralized CT
calcified cartilage and bone
what is the notochord in vertebrate adults
nucelus pulpose in each intervertebral disc
what is cartilage
non-mineralized (lacks hydroxyapatite)
flexible - stronger under compression
easily injured & difficult to repair
growth tissue in fetus
what is cartilage composed of
gel matrix
collagen or elastic fibers
chondrocytes
what is calcified cartilage
mineralized (hydroxyapatite)
unorganized microstructure
stronger than cartilage
transitional tissue (EO)
calcification can be pathogenic
bone is a composite tissue made of____ and ___ components
organic components (osteoids - type I collagen and cells)
inorganic components (hydroxyapatite and water)
what is bone capable of
growth - only at surface
and remodeled throughout life
what are the physiological functions of bone
mineral reservoir
calcium homeostasis
source of blood cells
energy storage/source
what are the endocrine functions of bone
osteocalcin hormone
- insulin regulation
- brain development & function
- testosterone formation & release
what are the classifications of bone
long, short, flat, irregular
where do osteocytes live
in lacunae
between lamella surrounding haversian canals
connected to adjacent osteocytes by canaliculi
what are osteons
made of haversian canals surrounding lamella
contains vessels and nerves
what percent do bones get of total cardiac output
5-10%
where does endochondral bone grow from
cartilage precursor
where does endochondral bone form in
mesenchyme
where does ossification begin
in utero
- first in diaphysis
- then in epiphyses
what are the two ways bone is added to shaft
- replacement of cartilage
- conversion of perichondrium to periosteum
all EO-dervived bones have periosteal bone that forms concomitantly via
intramembranous ossification
how does membrane bone grow
no cartilage precursor
intramembranous ossification
grow outward
what is a sesamoid bone
bones that form within tendons
prevent muscle from deforming
improve muscle leverage
how is the skeleton held together
ligaments
joint capsules
menisci
bursae
what do synovial joints include
synovial fluid
synovial membrane
fibrous outer layer
capsular ligaments
what is menisci
cartilage spaces or pads
what is bursae
protective cushions
have synovial membrane and synovial fluid
what are the three types of joints
synovial
fibrous
cartilaginous
what is the most mobile joint
synovial joint
what are the different shapes of synovial joints
flat (plane)
barrel-shaped (hinge)
pivot
ball-and-socket
what are the types of motions that can occur at synovial joints
flexion
extension
pronation
supination
abduction
adduction
overextension
circumduction
which joint allows limited motion
fibrous joints
what are the three types of fibrous joints
sutures
syndesmoses
gomphosis
what is the least mobile joint
cartilaginous joints
what is synchondrosis
connected by cartilage
what is symphysis
multiple tissues together (sandwich)
bone-cartilage-CT-cartilage-bone
what is connective tissue
complex of cells and extracellular matrix that provides supporting and connecting framework for all other tissues of the body
what are the components of ECM
fibers and ground substance
what are the types of fibers
collagenous or fibrillar
reticular (non-fibril-forming collagens)
elastic (elasin)
what is in ground substance
glycosaminoglycans (GAGs)/Proteoglycans (PGs)
&
Structural glycoproteins
how is CT types and subtypes defined
according to amount, type, and proportions of ECM components
what are the properties of an individual collagen molecule
- type II collagen
- trimeric
- rigid, rope-like
- (+) charged (basic aa’s)
what are the properties of collagen fibril
- composed of individual, quarter-staggered collagen molecules
- eosinophilic
what are in GAG molecules
-chondroitin sulfate
- keratin sulfate (contains sulfate groups); highly (-) charge
what are the effects of ground substance being (-) charged
- spread out
- hydrophilic
- basophilic
- metachromatic
what makes up ground substance
- hyaluronic acid (GAG)
- link protein
- core protein
- PG molecule
- GAG molecule
what is type II collagen
- trimeric molecule
- laterally aggregates into fibrils
- fibrils criss-cross randomly
- slightly basic, eosinophilic
- slight positive charge
- provides rigid structural support
what is PG/GAG aggregates
- hyaluronic acid backbone
- mainly chondroitin/keratan sulfate side chains (highly neg charge)
- hydrophilic
- basophilic, metachromatic stain
what is in hyaline cartilage
- capillary
- perichondrium
- chondroblast
- chondrocyte
- collagen (type II) fibril
- ground substance (sulfated proteoglycans)
is hyaline cartilage vascular or avascular
avascular
explain hydrated sponge concept in hyaline cartilage
can withstand compressive forces due to stabilizing collagen matrix, and ability of PG aggregates to bind or release water and allow matric to compress/expand
explain the molecular sieve concept
nutrient and gas exchange occurs via ECM and perichondrial blood vessels; ECM selectively sequesters various molecules/ factors
what is the formation of cartilage process called
chondrogenesis
what is the start of chondrogenesis
mesenchymal condensation
what is the second step in chondrogenesis
chondroblasts form
- divide and secrete ECM
- distance between neighboring cells increases
what is the third step of chondrogenesis
chondrocyte form
- cells surround entirely by ECM
what is the last step of chondrogenesis
isogenic groups
- as cells divide, daughter cells remain in close proximity, forming chondrocyte clusters
what is the matrix called that immediately surrounds chondrocytes
territorial matrix
what is the matrix called that is further away from chondrocytes
interterritorial matrix
what are the two mechanisms that cartilage grows by
apositional and interstitial
what is apositional cartilage growth mechanism
differentiation of chondroprogenitors and chondroblasts on the inner surface of the perichondrium into chondrocytes
what is interstitial cartilage growth mechanism
involves division of pre-existing chondrocytes within a cartilage matrix, giving rise to isogenous groups
what are the three cartilage types
- hyaline cartilage
- elastic cartilage
- fibrocartilage
what is the function and location of hyaline cartilage
function: structural support, rapid growth, ability to withstand compression, temporary skeleton during embryogenesis
location: fetal skeleton, respiratory passages, cushioning of joints
what is the function and location of elastic cartilage
function: flexible support, ability to withstand deformation
location: external ear, auditory tubes, epiglottis, larynx cartilages
what is the function and structure of fibrocartilage
function: attachment to bone, provides restricted (type I and II) mobility under great mechanical stress
location: annulus fibrosus of intervertebral discs, pubic symphysis, bone-ligament junctions
where is fibrocartilage always found
in association with dense connective tissue
why does hyaline cartilage serve as a temporary skeleton during embyogenesis
- ECM composition
- enables hyaline cartilage to be firm and compressible
- provide protection and structural support
- grow increase rapidly by interstitial and apositional growth
how is this skeletal “blue-print” gradually replaced by trabecular bone and marrow
Endochondral ossification
why is endochondral ossification called the substitution process
ossification means formation of bone, endochondral means without cartilage
process is formation of bone within a cartilage blueprint within cartilage model
how are most skeletal elements neck down and a few skull bones formed in vertebrates
by EO
what is the EO outcome
gives rise to future skeletal elements that are going to have a bone marrow cavity where hematopoiesis takes place
describe the steps of EO in this picture
- skeleton initially comprised of hyaline cartilage that grows via intersitial and appositional growth
- at genetically predetermined stage, periosteal bony collage forms within perichondroum (via IO)
- as collar minerallizes, perichondrium becomes periostrum and compact bone is laid down on outer surface of shaft
describe steps of EO in this picture
- as periosteal bony collar extends to epiphysis, chondrocytes stack and then enlarge to ~10 fold in size (hypertrophy), hypertrophic cartilage beings to calcify
- presence of periosteal bony collar and calcified cartilage matrix inhibits oxygen and nutrient diffusion
describe EO in this picture
- diaphysis is penetrated by periosteal bud made up of blood vessels, mesenchymal cells, and chondro/osteoclasts - establishes the primary ossification center
- chondro/osteoclasts secrete enzymes that degrade hypertrophic cartilage, while mesenchymal cells differentiate into cells of primitve bone marrow and into osteoblasts
describe EO in this picture
- vascular invasion and gradual degradation of hypertrophic cartilage results in establishment of a marrow cavity and deposition of ostepblasts along hypertrophic cartilage remnants
- formation of secondary ossification center at the epiphyses defines 5 distinct growth plate cartilage zones
what are the 5 growth plate zone
- resting zone
- zone of proliferation
- zone of hypertrophy
- zone of degradation
- zone of ossification
describe EO in this picture
transition from hypertrophic cartilage to bone and marrow continues within growth plate and responsible for longitudinal growth
describe EO in this picture
- growth plate closure results in termination of longitudinal growth
- in adults the only cartilage (hyaline) that remains is the articular cartilage at the outer ends of (epiphyses) of bone
- carilage lacks perichondrium
what is the clinical significance of cartilage lacking perichondrium
reduced ability to repair itself
osteoarthritis
what is the purpose of articular cartilage
- low friction gliding surface
- transmits weight bearing forces to underlying bone
- withstand high cyclic loads
what are the two ways articular cartilage can be damaged
- abnormal loading (physical): cyclic trauma & direct
- biochemical damage: inflammation
what is an example of a predisposition to cartilage injury
canine hip dysplasia
some animals more predisposed
what is canine hip dysplasia
- improper alignment of the femoral head within the acetabulum
- 3 mutations in glycoproteins, PG, fibrillar structure
- abnormal mechanical stress
- articular cartilage damage
injury starts a cascade of inflammation and increase in ____
catabolism/degradation
what are chondrocytes activated by
imbalance due to injury
stress
what do chondrocytes act as
imbalance due to injury
their own inflammatory mediators
what gets released when imbalance is caused due to injury
cytokines
catabolic enzymes are released by ____
chondrocytes
what do catabolic enzymes cause
- collagen breakdown
- proteoglycan breakdown
what do catabolic enzymes result in
degradation of ECM
what two processes happen in tissue repair
- replacement of damaged cells and matrix
- regeneration
what are the general phases of tissue healing
- inflammation
- repair
- remodeling
what is inflammation
tissue healing
- vascular response
- cellular infiltration
- scaffold for repair
- 3-5 days
what is repair
tissue healing
- cellular infiltration - fibroblasts
- local cellular repsonse
- 3 days - 2 weeks
what is remodeling
tissue healing
- removal of inferior tissue, replacement
- 2 weeks - 1 year
why is cartilage being avascular a problem in response to injury
- different inflammatory phase
- no scaffold
- no cellular infiltration
- limited repair
why is fibrocartilage a problem in cartilage response to injury
- GAG concentration decreased
- Type 1 collegen put in
- biomechanically inferior - reduced funtion
what is intrinsic cartilage repair
- no vascular ingrowth
- relies on local chondrocytes
- sub-par
what is matrix flow
- forms lips of cartilage from perimeter that migrates towards center of defect
- surface chondrocytes are more fibroblast like
- fibroblast > hyaline cartilage
- heal small defects
what is extrinsic cartilage repair
- vascular ingrowth from surrounding tissue (bone)
- mesenchymal elements from subchondral bone
- helps form new CT
what are the two major limitations of cartilage
- avascular
- inferior repair tissue
osteoprogenitors
“stem cells” for bone
spindle shaped
found near bone surfaces in periosteum and endosteum
bone lining cells
flattened
line bone surfaces
quiescent osteoblasts
osteoblasts
“bone forming”
proliferative
cuboidal
appear as sheets on bone surface
deposit osteoid (unmineralized bone ECM)
osteocyte
“mature” bone cells
non-proliferative
encased in mineral
extensive filopodia for monitoring Ca levels and communicating with osteoblasts and osteoclasts
osteoclasts
“breakdown” or resorb bone
large
multinucleate
found on bone surface
not mesenchymal cells
inorganic phase of bone is ___
mineral (hydroxyapatite) - 75%
organic phase of bone is
type 1 collagen
small PG and glycoproteins - 25%
in bone, initial mineral deposition occurs where
in hole zones of type 1 collagen molecules in a collagen fiber from 1/4 staggered arrangement
do collagen fibers mineralize
no - this is why bones are able to bend
osteogenesis
formation of bone; proceeds through EO and IO
endochondral ossification
- involves a hyaline cartilage model, which serves as a blueprint for the future skeleton and marrow
- cartilage undergoes hypertrophy and is replaced by trabecular (spongy) bone, and bone marrow
intramembranous ossification
- involves a direct differentiation of mesenchymal/osteoprogenitor cells to osteoblasts, which secrete bone matrix
- bone forms through appositional growth
- end result: compact bone (membranous) without a marrow cavity
what is primary bone
- first bone that is laid down, regardless of whether it is formed by EO or IO - temporary immature skeleton
- not well organized
- greater cell-to-matrix ratio
primary bone is replaced by mature ______ through ____ and _____
secondary bone, modeling, remodeling
what is another term for secondary bone
lamellar bone
lamellar bone is organized in functional units called ___
osteons
what do osteons consist of
- central Haversian canal w/ blood vessels and nerves
- concentric lamellae of bone matrix
- inhabiting cells
what is bone remodeling
- balance between osteoclasts degrading bone and osteoblasts depositing bone
- OCLs create resorption pits
- blood vessels invate pits and import osteoprogenitors that differentiate into osteoblasts
- OBs align along exposed bone surface and secrete osteoid in lamellae around haversian canals
what stage is bone in during skeletogenesis
modeling
- bone change width and shape
- primary to secondary
what stage is bone in during adult-homeostasis
remodeling
- bone adapt to mechanical pressure
- Ca storage and release
what stage is bone in during pathology
remodeling
- fracture repair
- Ca imbalance
- OB/OCL dysfunction
what is woven bone
immature bone/temporary
- highly cellular
- random matrix organization
- rapid formation
- poorly mineralized
- weak
what is lamellar bone
mature bone
- low cellularity
- organized
- slow formation
- strong
- well mineralized
what is the difference between structure of lamellar and woven bone
rate of formation (time)
where are sites of new “repair” bone formation
- periosteum
- endosteum
traumatic fracture
normal bone broken by excessive force
pathologic fracture
abnormal (diseased) bone broken by minimal trauma or during normal weight bearing forces
avulsion
fractures that occur at site of ligament/tendon insertion
articular
worse prognosis because of incongruent joint surface - secondary DJD
what is direct (primary) healing
- contact healing (surgical fixation)
- gap healing (<1mm)
- required rigid fracture stabilization
what is indirect (secondary) healing
- biomechanical environment dictates which type takes place
- rigid, stable fixation vs limited intervention
what are the stages of indirect bone healing
- inflammation
- repair (soft callus and bony callus)
- remodel
what will low O2 tension result in
hyaline cartilage formation which eventually turns into EO and radiopaque
what are the 3 complications of fracture healing
- excessive motion (fibrous non-union)
- inadequate blood supply
- infection = osteomyelitis
necrotic (dead) bone is called
sequestrum
the embryo develops in 3 germ layers ___
ectoderm, mesoderm, endoderm
the ectoderm is responsible for forming the ___
nervous system and skin
the mesoderm is responsible for forming the ____
musculoskeletal system and circulatory system
the ectoderm is responsible for the ___
GI tract and other organs
the ectoderm creates the ___ and ___ via ____
neural tube; neural crest cells; neurulation
the mesoderm is divided into___
paraxial, intermediate, and lateral plate mesoderm
somites form as sections of ___
paraxial mesoderm
lateral plate mesoderm has two players called?
splanchnic and somatic
the sternum is formed from
somatic player of lateral plate mesoderm
what are somitocoels
“holes” form in the center of somites
the somitocoel expants to cut somite into dorsal and ventral parts called
dermatomyotome and sclerotome
the dermomyotome divides again into
dermatome, myotome, syndetome
dermatome
makes skin
myotome
makes muscle
syndetome
makes tendon
the sclerotome doesn’t divide and makes ___
bone via EO around neural tube and notochord
vertebrae and ribs are created from
sclerotome
there is a ___ and ___ portion of sclerotomes
rostral; caudal
what is resegmentation
when the caudal portion of somite is fused with the rostral portion - allows intervertebral space for spinal nerves
the sclerotome makes structures including:
- vertebral arches w/ spinous process
- vertebral body
- transverse process
- intervertebral discs
what happens after resegmentation
each myotome becomes associated with 2 adjacent vertebrae and crosses the intervertebral space
what is the intervertebral space
- where the spinal nerve passes through and can innervate the muscles created by that myotome and provides sensory innervation to the skin
- can trace sensory nerve fibers to spine
what is the dorsolateral part of the myotome and what does it create
epimere; epaxial muscles (deep back muscles)
what is the ventralmedial part of the myotome and what does it create
hypomere; hypaxial muscles (trunk/limb muscles)
what are HOX genes
responsible for establishing patterning of vertebrae and limbs
what are some consequences of homeotic mutations of HOX genes
- flawed differentiation
- polydactyly
- syndactyly
what are fibroblast growth factors (fgf) and what can result from mutations
cell signaling proteins; abnormal growth plate function (dwarfism)
what can mutations in fibroblast growth factor receptors (fgfr) result in
- FGFR3 = achondroplasia
- FGFR1/2 = premature cranial synostosis
what are TBX genes
determine which limbs are upper and lower (TBX 4 & 5)
what does FGF10 lead to
continued growth of limb buds
limb buds first grow from ___ and then from ___
ectoderm; somatic lateral of lateral plate mesoderm
what is the thickened area on the tip of a limb bud called and what is it stimulated by and what does it secrete
apical ectodermal ridge (AER); FGF10; FGF4/8
what is the part of the lateral plate mesoderm that is closest to the AER called
progress/proliferating zone (PZ)
what is bone differentiation
- as limb bud grows, growth factors are not as saturated in lateral plate mesoderm that is furthest away from AER
- differentiate into cartilage then into bone (EO)
- creates stylopod, zeuopod, and autopod
some tissue at AER starts to undergo apoptosis because…
- high levels of bone morphogenic protein (BMP) and retinoic acid
- forms fingers
- AER still proliferates to make digits
AER dies off so they stop ___
proliferating and start differentiating into phalanges
how do you get differentiation of the autopod
- on dorsal portion of autopod there is zone of polarizing activity (ZPA)
- drives directional development of autopod by releasing molecules that create a gradient (Sonic Hedgehog protein)
how are limb muscles developed
- myotome migration into ventral and dorsal condensation (portions)
- syndetome migrates to make tendons
- dermatome migrates to make skin
what does ventral condensation create
forelimb
- flexor
- pronator
hindlimb
- extensor
- adductor
- digital extensor
what does dorsal condensation create
forelimb
- extensor
- supinator
hindlimb
- flexor
- abductor
- digital flexor
what are the somites toward the cranial end of the neural tube called
occipital somites
neural crest cells and occipital somites create ___ around ______ with the brain
neurocranium; rostral end of neural tube
what are the two types of bone in the skull
endochondral and membrane bone
what does endochondral bone make up
- chondrocranium
- splanchnocranium
what does membrane bone make up
dermatocranium
how is membrane bone made
intramembranous ossification
how is membrane bone made
intramembranous ossification
what is chondro(osteo)dysplasia
- congenital with defects present at birth
–> cartilage/bone formation impacted (ex: chondrodsyplastic dwarfism vs OI)
–> remodeling impacted (ex: OCL defect) - clinical manifestations can be immediate or delayed
what are the causes of congenital skeletal abnormalities
- genetic (HOX gene)
- in utero exposures (toxin/nutritional)
what is generalized chondrodysplasia
congenital defects involving the cartilage template and generalized defect in EO
what are the origins of chondrodysplasias
- defect in cartilage template required for EO (spontaneous or heritable mutations)
- defects can be generalized or regional
what does heritable mutations in chondrodysplasias cause
disproportionate (chondrodysplastic) dwarfism
- early DJD from malformations in shape of epiphysis = joint instability and incongruence
what is K9 chondrodysplasia
- chondrodysplastic
- CFA18-FGF4
- disproportionate dwarfism
(shortened limbs/breed standard)
what is K9 Chondrodystrophy
- chondrodystrophic
-CFA12-FGF4 - shortened limbs
-IVDD - IVD herniation - Neurologic signs
what is bovine chondrodysplasia (Bulldog Calf syndrome)
- shorted malformed limbs
- skull malformations
what are generalized osteodysplasia
- cartilage ok
- bone not ok
- generalized deformities, monostotic or polyostotic malformations
what is osteogenesis imperfecta
- affects puppies, calves, lambs, humans
- osteopenic disease (decreased bone density and increased bone fragility)
- mutation in Type 1 collagen synthesis
what is focal chondrodysplasias
- developmental defects in EO at focal, repeatable sites
- osteochondrosis (OC) and osteochondritis dissecans (OCD)
what is OC and OCD
- heterogeneous lesions in growth cartilage (epiphyseal)
- dogs, horses, pigs, cattle, poultry
- focal defect (delay or failure) of EO
- bilaterally symmetrical (50%)
- secondary osteoarthritis common
what are the causes of OC/OCD
damage to vasculature in growth cartilage
Equine OC is:
vascular necrosis - focal retained necrotic cartilage core - cartilage folds - subchondral bone trauma
