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M2 Musculoskeletal > 4/11 Devptal Disorder of Bone/Cartilage - Corbett > Flashcards

4/11 Devptal Disorder of Bone/Cartilage - Corbett Flashcards

1
Q

functions of bone

A
  • mechanical support
  • transmission of force
  • protection of viscera
  • mineral homeostasis
  • acid-base balance
  • niche for production of blood cells
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2
Q

two processes of bone formation

A

1. intramembranous ossification

  • bone tissue laud down directly in embryonic connective tissue or mesenchyme
  • flat bones: skull, midface, jaw, clavicle

2. endochondral ossification

  • bone tissue REPLACES preexisting hyaline cartilage (template for future bone)
  • long bone
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3
Q

membranous bone devpt

A

bones of skull, midface, jaw, clavicle

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4
Q

woven bone vs lamellar bone

A

new bone = woven bone

remodeled into lamellar bone

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5
Q

long bone devpt

A

bones of limbs and girdle

endochondral ossification

type of collagen thats made changes (type 2 - type 10 - type 1)

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6
Q

zones of endochondral ossification

A
  1. proliferative zone
  2. hypertrophic zone
  3. vascular invasion zone
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7
Q

regulators of bone devpt

chondrocyte proliferation regulators?

A
  • growth hormone
  • thyroid hormone
  • Indian hedgehog
  • PTHrP
  • Wnt
  • Sox9
  • Runx2
  • FGF-receptor3 → inhibits chondrocyte prolif

chondrocyte proliferation regulators

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8
Q

FGFr3

A
  • regulates ability of chondrocytes to prolif/mature
  • negative reg of bone growth via inhibition of chondrocyte prolif
    • gain of fx mutation: activation of FGFr3 → short stature
    • achondroplasia
    • thanatrophic dysplasia
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9
Q

normal bone anatomy

A

diaphysis: in shaft

  • central trabecular portion surrounded by thick cortical layer

metaphysis

  • loose trabecular bone surrounded by thin cortical layer
  • adjacent to growth plate

epiphysis

  • end of bone, articular surface, contains subchondral regions under articular cartilage
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10
Q
A
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11
Q

cortical bone vs trabecular bone

A

cortical: outer periosteal surface + inner endosteal suface

  • periosteum contains vessels/nerves/osteoblasts/osteoclasts, aids in bone formation, appositional bone growth and fracture repair

trabecular: honey comb network of rods and plates

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12
Q

cortical vs trabecular

summary

A
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13
Q

bone matrix

A

1. osteoid

  • type I collagen
  • GAG
  • osteopontin (unique to bone)
    • serum measurements indicate osteoblast activity

2. mineral component (hydroxyapatite)

  • gives hardness
  • repositor for 99% of body Ca, 85% of P
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14
Q

osteoblasts

A
  • at surfaces of bone matrix, compose most of the flattened bone lining cells in endosteum and periosteum
  • main fx: SYNTHESIZE BONE MATRIX
    • cuboidal when synthesizing matrix

functions

  1. formation of new bone
  2. regulation of osteoclastogenesis (RANKL and OPG)
  3. comm with osteocytes to receive mechanotrasduction signals (anabolid)

regulated via

  • Runx2 (platform for hormone/cytokine action)
  • osterix (interaction with NFAT2)
  • Wnt-betacatenin
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15
Q

osteocytes

A

most abundant (90-95%) adult bone cells

derived from osteoblasts

fx: dendritic processes connect periosteal and endosteal surfaces

  • sense stress
    • load? → bone matrix synthesis
    • reduced load? → bone resorption
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16
Q

osteoclasts

A
  • 1-2%
  • derived from circulating monocytes
    • need two signals for maturation: RANKL (formation) & M-CSF (growth/survival/diff)
  • ​large, motile, multinucleated

fx: resorbing bone

clast contact w matrix → formation of “sealing zone” for isolation of acidification of bone matrix by cathepsin K

17
Q

dysostosis

A

localized problem in migration and/or condensation of mesenchyme

  • absence of bone/digit (aplasia)
  • extra bone/digit
  • abnl bone fusion (syndactyly or craniosynostosis)
18
Q

dysplasia

A

abnormal growth; global disorganization of bone and/or cartilage

  • mutation in genes controlling devpt or remodeling of entire skeleton
19
Q

role of tf in bone/cartilage devpt

Sox9 mutation

A

fx: tf regulating commitment to chondrogenic lineage (Col2) in resting zone of growth plate

mutation → camptomelic dysplasia

  • auto dom
  • short limbed dwarfism
  • neonatal death
  • bowing of long bones, small thoracic cage, failure of scapulae to form; defects in all endochondral bones
  • ambiguous genitalia
20
Q

role of tf in bone/cartilage devpt

Runx2 mutation

A

fx: tf regulating commitment to osteoblast lineage

  • required for maturation of hypertrophic chondrocytes

loss of Runx2 → ossification defects - cartilage skeleton but NO BONE

mutation of Runx2 → cleidocranial dyslplasia

  • auto dom
  • char ft: clavicular hypoplasia
  • open sutures in skull
  • dental abnormalities (hyperdontia)
21
Q

role of tf in bone/cartilage devpt

GDF5

A

growth/differentiation factor 5

fx: promotes chondrogenesis

  • increases size of initial chondrocyte condensations
  • incr chondrocyte prolif

diminished GDF5 or heter/homozygous GDF5 →

  • shortening of appendicular skeleton
  • incr severity prox to distal
  • loss of some joints
22
Q

achondroplasia

A

most common short-limb dwarfism

paternal allele is site → related to paternal age

activating mutation in FGF3R → inhibits chondrocyte proliferation

decreased ENDOCHONDRAL (not membranous) OSSIFICATION

  • decr chondrocyte prolif and matrix affecting long bones
  • relatively normal head size

clinical features

  • shortened prox extremities
  • relatively normal trunk
  • enlarged head/bulging forehead (frontal bossing, flattened nasal bridge)
  • spinal deformities (spinal canal stenosis, intervertebral foramen stenosis → over 50% lower ext radiculopathy
23
Q

thanatorphic dysplasia

A

most common lethal skeletal dysplasia

mutation in FGF3R

  • auto dom
  • de novo activating mutations with 100% penetrance

“like an excessive form of achondroplasia”

clinical features

  • severe shortening of limbs (curved long bones are worst affected)
  • nl trunk length
  • macrocephaly
  • narrow bell-shaped thorax, shortened limbs
24
Q

osteogenesis imperfecta

A

pathologic changes occuring in tussues in which type 1 collagen is an important constituent

  • problems seen in bone, ligament, dentin, sclera
  • why? type 1 collagen makes up 90% of bone
    • caused by QUALITATIVE or QUANTITATIVE reduction in type 1 collagen

80% cases due to mutation in one of two genes for type 1 collagen

25
Q

type 1 collagen

structure

A

triple helix

  • two pro alpha1 (chr17)
  • one pro alpha2 (chr7)

mutations that sub a.a.s in for Gly are v disruptive to structure

26
Q

qualitative and quantitative defects of OI

mutations

defect comparison

A

qualitative (COL1A1, COL1A2)

  • COL1A1 mutations are more severe than COL1A2
  • mutations at COOH terminus are more severe
  • size/polarity determine severity of mut

quantitative (from nonsense mutations, mostly COL1A)

  • haploinsufficiency effect (reduced levels of normal collagen)

defect comparison?

27
Q

osteogenesis imperfecta type 2

A

pernatal lethal (most severe form of OI)

  • due to QUALITATIVE DEFECT
  • auto rec/dom

skeletal deformity with numerous fractures

28
Q

osteogenesis imperfecta type 1

A

mildest, most common form of OI

male = female

auto dom

  • blue sclera (sclera is thin, so you can see the choroid! blue)
  • varying bone fragility/deformity
    • 20% kyphosis, scoliosis
    • later fractures
  • hearing loss
  • normal stature
29
Q

osteopetrosis

A

incr bone mass and mineralization

  • failure of osteoclasts to resorb bone → skeletal fragility

etiologies:

  1. decreased numbers of osteoclasts
    * genetic defects in: RANKL, RANK, osteopregenerin
  2. defective acidification
  • carbonic anhydrase 2
  • CLCN7 (proton pump)
30
Q

most severe osteopetrosis

A

severe AR infantile osteopetrosis

increased OC numbers with secondary genetic defects:

  • carbonic anhydrase II → renal tubule acidosis, cerebral calcification
  • CLCN7 (osteoclast Cl ion channel)

M2 Musculoskeletal (21 decks)

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