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Musculoskeletal/Rheum > Congenital and Developmental Diseases of Bone > Flashcards

Congenital and Developmental Diseases of Bone Flashcards

1
Q

What are the two components of bone matrix?

A

osteoid (35%) and inorganic mineral component (65%)

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2
Q

What is the predominant collagen type in osteoid? What are the characteristics of it?

A

type 1 (triple helix composed of two alpha-1 chains and one alpha-2 chain)

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3
Q

What are the characteristics of type 1 collagen?

A

calcium hydroxyapatite

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4
Q

What is the role of calcium hydroxyapatite?

A

gives bone its hardness and also serves as a repository for 99% of the body’s calcium and 85% of its phosphorus (relevant to maintaining homeostasis of the blood levels of these elements).

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5
Q

What are the two histologic forms of bone matrix?

A

woven and lamellar

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6
Q

Describe woven bone. When is it made? What does it look like?

A

Woven bone is rapidly produced during fracture repair, fetal development and various diseases. It has haphazard arrangement of collagen fibers.

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7
Q

Is presence of woven bone in adults normal?

A

NO–always pathologic

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8
Q

How does lamellar bone differ from woven bone?

A

it is slowly produced, with collagen fibers in parallel array, which imparts more structural integrity to it than woven bone

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9
Q

What are the 4 cell types in bone?

A

osteoprogenitor cells, osteoblasts, osteoclasts and osteocytes

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10
Q

What is the function of osteoprogenitor cells?

A

pluripotential mesenchymal stem cells that become osteoblasts if signaled to do so.

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11
Q

Where are osteoblasts located?

A

surface of the matrix

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12
Q

What is the function of osteoblasts?

A

synthesize, transport and assemble bone matrix and initiate its mineralization

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13
Q

How long does mineralization take?

A

12-15 days

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14
Q

What are osteocytes?

A

former osteoblasts enclosed in the matrix they built and no longer actively building matrix are

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15
Q

What are bony canaliculi?

A

an intricate network of dendritic cytoplasmic processes through tunnels that connect osteocytes

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16
Q

What is the function of osteocytes?

A

help to control calcium and phosphate levels in the microenvironment; detect mechanical forces and translate them into biologic activity (mechanotransduction)

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17
Q

How do osteocytes regulate calcium and phosphate levels?

A

have parathyroid hormone (PTH) receptors and regulate serum calcium and phosphorous by mediating osteoclast activity

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18
Q

What are osteoclasts?

A

specialized multinucleated macrophages, derived from circulating blood monocytes

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19
Q

What is the function of osteoclasts?

A

carry out bone resorption and remodel it

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20
Q

How do osteoclasts resorb bone?

A

attach to bone matrix (via surface integrins) and create a sealed extracellular trench (resorption pit) into which they secrete acid and neutral proteases (predominantly MMPs), which dissolves both the inorganic/organic components of bone

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21
Q

What cells express transmembrane receptor RANK?

A

osteoclast precursors

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22
Q

What is RANK?

A

receptor activator for NF-kB

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23
Q

What cells express RANK ligand?

A

osteoblasts and marrow stromal cells

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24
Q

What is osteoprotegerin (OPG)? What does it do?

A

a secreted “decoy” receptor made by osteoblasts and several other types of cells that can bind RANKL and thus prevent its interaction with RANK

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25
Q

What happens when RANK is stimulated by RANK ligand?

A

activation of the transcription factor NF-kB, which is essential for the generation and survival of osteoclasts

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26
Q

What cells produce monocyte colony stimulating factor (M-CSF)?

A

osteoblasts

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27
Q

What is the role of monocyte colony stimulating factor (M-CSF) ?

A

Activation of the M-CSF receptor on osteoclast precursors stimulates a tyrosine kinase cascade that is crucial for the generation of osteoclasts

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28
Q

What is the WNT/beta-catenin pathway?

A

WNT proteins produced by osteoprogenitor cells bind to the LDL receptor related protein 5 and 6 (LRP5 and LRP6) receptors on osteoblasts and thereby trigger the activation of beta-catenin and the production of OPG (preventing RANK pathway)

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29
Q

What inhibits the WNT/beta-catenin pathway? What else does it do?

A

Sclerostin (produced by osteocytes)- inhibits osteoblast activity in a paracrine manner

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30
Q

What is the consequence of mutations in the OPG, RANK, RANKL, and LRP5 genes?

A

cause congenital diseases of bone metabolism

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31
Q

What is the function of Osteopontin?

A

bridges bone cells and matrix (TRICK QUESTION) does TONS of things

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32
Q

What is osteocalcin?

A

plays a role in bone formation and mineralization and in calcium homeostasis.

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33
Q

Why are blood levels of osteocalcin useful?

A

sensitive and specific marker for osteoblast activity

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34
Q

Where is the growth flate in long bones?

A

epiphysis

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35
Q

What is the metaphysis?

A

are of long bone between diaphysis (shaft) and epiphysis

36
Q

How do bones develop in an embryo?

A

bones develop from a cartilage mold by a process of endochondral ossification

37
Q

What synthesizes the cartilage mold?

A

mesenchymal precursor cells

38
Q

What type of bone growth occurs at the primary center of ossification (midshaft)?

A

radial growth (widening it)

39
Q

What type of bone growth occurs that the secondary center of ossification (ends)?

A

centrifugal fashion

40
Q

How does the growth plate form?

A

Eventually, a plate of the cartilage anlage becomes entrapped between the two expanding centers of ossification

41
Q

Who is more likely to get osteomyelitis: adults or children? Why?

A

Children are more prone to osteomyelitis than adults because of the richer blood supply in growing bone

42
Q

How do flat bones develop?

A

Intramembranous ossification

43
Q

Do flat bones have a growth plate?

A

no

44
Q

How does intramembranous ossification work?

A

bone is made only by osteoblasts, the enlargement of bones is achieved by the deposition of new bone on a preexisting surface

45
Q

What hormone is secreted by the pituitary and acts on resting chondrocytes to induce and maintain proliferation?

A

Growth hormone

46
Q

What hormone is secreted by the thyroid and acts on proliferating chondrocytes to induce hypertrophy?

A

Thyroid hormone (T3)

47
Q

What is the name of the locally secreted regulator, made by prehypertrophic chondrocytes that coordinates chondrocyte proliferation and differentiation and osteoblast proliferation?

A

Indian hedgehog (Ihh)

48
Q

What is the name of the local factor, expressed by perichondrial stromal cells and early proliferating chondrocytes, that activates the PTH receptor and maintains proliferation of chondrocytes?

A

Parathyroid hormone related protein (PTHrP)

49
Q

What is the name of the family of secreted factors that are expressed at highest levels in the proliferating zone and bind to the receptors Frizzled and LRP5/6 to activate beta-catenin signaling (promote both proliferation and maturation of chondrocytes)?

A

Wnt

50
Q

What is the transcription factor expressed by proliferating but not hypertrophic chondrocytes that is essential for differentiation of precursor cells into chondrocytes?

A

SOX9

51
Q

What is the name of the transcription factor involved in chondrocyte and osteoblast differentiation?

A

RUNX2

52
Q

What chemical leads hypertrophic chondrocytes to inhibit proliferation and promote differentiation?

A

FGF3

53
Q

What is the term for genetic, congenital and developmental diseases that mess up bone development?

A

skeletal dysplasias

54
Q

True or False: Skeletal dysplasias lead to premalignant uncontrolled cell proliferation.

A

FALSE: not pre-malignant

55
Q

What is osteogenesis imperfecta?

A

a group of diseases primarily involving bone even though they relate to type I collagen, which is prevalent in many other organs.

56
Q

What causes achondroplasia?

A

gain-of-function mutations in the FGF receptor 3 (FGFR3)

57
Q

What causes AD type of osteopetrosis?

A

loss-of-function mutations of RANK ligand mess up recruitment and activation of osteoclasts

58
Q

What causes the AR type of osteopetrosis?

A

Mutations in LRP5 receptor, CA2, CLCN7, etc. that alter osteoclast function

59
Q

What do most of the AR mutations for osteopetrosis lead to?

A

interfere with the process of acidification of the osteoclast resorption pit, which is required for the dissolution of the calcium hydroxyapatite within the matrix

60
Q

What does deletion of CA2 cause is AR osteopetrosis?

A

prevents osteoclasts from acidifying the resorption pit and solubilizing hydroxyapatite

61
Q

What does a mutation in CLCN7 cause in AR osteopetrosis?

A

altered proton pump located on the surface of osteoclasts.

62
Q

Are osteopetrosis bones hard?

A

NO- they are “rock-like” but are actually more like chalk

63
Q

Is there a treatment for osteopetrosis?

A

hematopoietic stem cell transplantation, which is effective because osteoclasts are derived from hematopoietic precursors. The normal osteoclasts produced from donor stem cells reverse many of the skeletal abnormalities.

64
Q

What disease is caused by mutation in the homeobox HOXD13 gene?

A

Brachydactyly

65
Q

What does Brachydactyly do?

A

produces short, broad terminal phalanges of thumbs and first toes

66
Q

What disease is caused by mutation in transcription factor SOX9 gene?

A

Campomelic dysplasia

67
Q

What are characteristics of campomelic dysplasia?

A

causes short bowing long bones, small chest cavity, respiratory failure and sex reversal (46XY with female phenotype)

68
Q

What disease is caused by loss-of-function mutations in the RUNX2 gene?

A

Cleidocranial dysplasia

69
Q

What are characteristics of Cleidocranial dysplasia?

A

patent fontanelles, delayed closure of cranial sutures, Wormian bones (extra bones that occur within a cranial suture), delayed eruption of secondary teeth, primitive clavicles and short stature

70
Q

What disease is caused by TBX5 mutation?

A

Holt-Oram syndrome

71
Q

What are characteristics of Holt-Oram syndrome?

A

thumb, wrist and forearm bone hypoplasias, and commonly a cardiac atrial septal defect

72
Q

What disease is caused by LMX1B gene mutation ?

A

Nail-patella syndrome

73
Q

What are characteristics of nail-patella syndrome?

A

hypoplastic nails, hypo- or aplastic patellas, dislocated radial head and progressive nephropathy

74
Q

What disease is caused by PAX3 gene mutation?

A

Waardenburg syndrome

75
Q

What are characteristics of Waardenburg syndrome?

A

different colored eyes, partial albinism, patches of white hair or early graying, hearing loss and constipation

76
Q

What disease is caused by COL2A1 gene for type II collagen (prominent in cartilage)?

A

achondrogenesis

77
Q

What is the characteristic finding in achondrogenesis?

A

short trunk

78
Q

What disease is caused by mutations in the COL10A1 gene for type X collagen?

A

Metaphyseal dysplasia

79
Q

What is the characteristic finding in metaphyseal dysplasia?

A

short stature

80
Q

What is the most common lethal form of dwarfism?

A

Thanatophoric dysplasia

81
Q

What disease is caused by a somatic gain-of-function mutation during development in GNAS1?

A

Fibrous dysplasia

82
Q

What is it called when a GNAS1 mutation occurs during embryogenesis?

A

McCune-Albright syndrome

83
Q

How do the skeletal manifestations of Fibrous Dysplasia occur?

A

G s-cAMP mediated interruption of normal osteoblast differentiation from precursors

84
Q

What is it called when a GNAS1 mutation occurs in an osteoblast precursor?

A

monostotic fibrous dysplasia.

85
Q

What are characteristics of McCune Albright syndrome?

A

polyostotic fibrous dysplasia plus café-au-lait skin pigmentations and endocrine abnormalities, especially precocious puberty

86
Q

Chromosomal rearrangement fusing USP6 gene to promoters leads to what?

A

produces excess USP6 protease, excess NF-kB transcription factor and excess MMPs resulting in cystic reabsorption of bone.

87
Q

What is an aneurysmal bone cyst?

A

tumors characterized by multiloculated blood-filled cystic spaces like a sponge filled with blood

Musculoskeletal/Rheum (12 decks)

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