11/8: Biochemistry of Bone Formation Flashcards

1
Q

What are the 4 phases of skeletal development?

A
  1. Migration of preskeletal cells to sites of future
    skeletogenesis
  2. Interaction of these cells with epithelial cells
  3. Interaction leads to mesenchymal condensation
  4. Followed by differentiation to chondroblasts or
    osteoblasts
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2
Q

What type of bone formation is indirect?

A

Endochondral

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3
Q

What bone formation is when mesenchyme forms cartilage template first,
which is later replaced by bone?

A

Endochondral

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4
Q

What bone formation occurs in most bones and during fracture repair?

A

Endochondral

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5
Q

What type of bone formation is direct?

A

Intramembranous

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6
Q

What bone formation occurs with the transformation of mesenchymal cells to
osteoblasts (no cartilage intermediate)?

A

Intramembranous

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7
Q

Where does intramembranous formation occur and contribute to?

A

Cranial vault, some facial bones; contribute to fracture repair

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8
Q

When does growth plate fusion occur?

A

age 14-20 in humans

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9
Q

What is produced by hypertrophic
chondrocytes attracts blood vessels to
invade?

A

Vascular endothelial
growth factor (VEGF)

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10
Q

When do secondary
ossification center
appears?

A

Time of birth

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11
Q

What do mesenchymal cells condense to produce?

A

Osteoblasts

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12
Q

What do osteblasts deposit?

A

Osteoid (unmineralized) bone matrix

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13
Q

What do some osteoblasts trapped in bone matrix become?

A

Osteocytes

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14
Q

What is the first type of bone produced developmentally?

A

Woven bone (aka primary bone)

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15
Q

When does woven bone get produced?

A

When osteoblasts need to form bone rapidly:
- embryonic development
- fracture healing
- disease states (e.g. Paget’s Disease)

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16
Q

What is immature woven bone remodeled and replaced with?

A

Lamellar bone (aka secondary bone)

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17
Q

Describe the structure of woven bone

A
  • Disorganized structure
  • Randomly oriented collagen
    fibrils (lower birefringence
    w/ polarized light)
  • Increased cell density
  • Reduced mineral content
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18
Q

Describe the structure of lamellar bone

A
  • Highly organized
  • Bone lamellae concentrically
    arranged around central canal
    (Haversian canal) containing
    blood vessels, nerves.
  • Parallel oriented collagen fibrils
    (more birefringence w/
    polarized light)
  • Mechanically stronger
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19
Q

What is secondary bone further classified into?

A

Compact (cortical) Bone and Cancellous
(trabecular/spongy) Bone

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20
Q

What is compact bone?

A

Cortical/haversion

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21
Q

What is cancellous bone?

A

Spongy/trabecular

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22
Q

What are the 3 main types of bone cells?

A

Osteoclasts
Osteoblasts
Osteocytes

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23
Q

What do osteoblasts, chondrocytes, myoblasts and adipocytes differentiate from?

A

A common mesenchymal precursor

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24
Q

What are osteoblasts derived from?

A

Mesenchymal stem cells

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25
Q

What do osteoblasts produce?

A

Large amounts of ECM proteins (collagen type I) = osteoid, which then mineralize

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26
Q

What is the lifespan of osteoblasts?

A

weeks

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27
Q

What are osteoblast marker proteins that are transcription factors?

A

Runx2
Osterix

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28
Q

What are osteoblast marker proteins that are enzymes?

A

Alkaline phosphatase

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29
Q

What are osteoblast marker proteins that are ECM proteins?

A
  • Type I collagen
  • Osteopontin
  • Osteocalcin
  • Bone sialoprotein (BSP)
30
Q

What are the key transcriptional regulators of osteoblast differentiation?

A

Proliferation
Maturation
Terminal differentiation

31
Q

What is the master transcription factor for bone?

A

Runx2

32
Q

What is Runx2 essential for?

A

Bone and tooth development

33
Q

What does a heterozygous mutation in Runx2 result in?

A

Cleidocranial dysplasia (CCD)

34
Q

What transcription factor does Runx2 induce?

A

Osterix

35
Q

What is osterix critical for?

A

Osteoblast differentiation

36
Q

What does osterix control expression of?

A

Osteoblast genes:
Type 1 collagen
Osteocalcin
Osteopontin

37
Q

What does a human mutation in SP7 (osterix) associate with?

A

Osteogenesis imperfecta type XII

38
Q

What are two key signaling pathways that regulate osteoblast differentiation?

A

BMPs and WNT/B-catenin signaling pathway

39
Q

What are originally purified from bone extracts that induce bone
formation when implanted in muscle?

A

BMPs

40
Q

What are BMPs required for?

A

skeletal development/maintenance of adult bone
homeostasis

41
Q

What promotes differentiation from early osteoprogenitor cells?

A

BMPs

42
Q

What does Naturally occurring mutations in BMPs or their receptors result
in?

A

Inherited skeletal disorders in humans

43
Q

What is FOP (fibrodysplasia ossificans progressiva)?

A

Heterotopic bone formation (bone forming in soft tissues)

44
Q

What is FOP a result from?

A

Mutation in BMP type 1 receptor

45
Q

What is Wnt-β-catenin signaling pathway
important in determining?

A

Bone mass

46
Q

What does activating mutations of Lrp5 lead
to?

A

High bone mass in humans and vise versa

47
Q

What is the first phase of mineralization initaited by?

A

Matrix vesicle

48
Q

What does the second phase of mineralization involve?

A

Propagation of mineralization on collagen fibers

49
Q

What are the stages in Matrix vesicle (MV) mediated mineralization?

A

Phosphate compounds -> pyrophosphate (PPi) -> monophosphate ion Pi (aka PO43-)

50
Q

What enzyme highly expressed in osteoblasts/
odontoblasts?

A

Alkaline phosphotases

51
Q

What does alkaline phosphotases hydrolyze?

A

Pyrophosphate

52
Q

What is a natural inhibitor of mineralization,
thereby increasing local phosphate
concentration – promotes mineralization?

A

Pyrophosphate

53
Q

What is mutations in alkaline phosphatase gene (TNSALP) associated with?

A

Hypophosphatasia

54
Q

Mutations in what is associated with syndrome
of spontaneous infantile
artieral and periarticular
calcification – similar
phenotype in KO mice?

A

ENPP1

55
Q

Mutations in what are associated
with hypophosphatasia
(impaired
mineralization)?

A

TNSALP (TNAP)

56
Q

What in knockout mice doesn’t show abnormal skeletal development?

A

Anx5

57
Q

Deletion of what in mice may cause impaired
mineralization, including
in MV?

A

PHOSPHO1

58
Q

What are terminally differentiated osteoblasts?

A

Osteocytes

59
Q

What is the lifespan of osteocytes?

A

Decades

60
Q

What cells are embedded in the bone matrix?

A

Osteocytes

61
Q

What are transcription factors in osteocytes?

A

Mef2c

62
Q

What are early osteocyte markers?

A
  • E11/gp38/podoplanin
  • Dentin matrix protein-1 (DMP1)
  • Matrix extracellular phosphoglycoprotein
    (MEPE)
  • Phosphate regulating endopeptidase
    homolog, X-Linked (PHEX)
63
Q

What are late osteocyte markers?

A

Sclerostin (SOST)

64
Q

What are functions of osteocytes?

A
  • Mechanosensors (control responses of bone cells
    to mechanical loading)
  • Control bone resorption and bone formation (by
    regulating osteoclast and osteoblast activity)
  • Regulate mineralization
  • Regulators of mineral homeostasis-both calcium
    and phosphorus
65
Q

What is highly expressed in mature osteocytes, cementocytes, odontoblasts?

A

Sclerostin

66
Q

What is a Negative regulator of bone
formation?

A

Sclerostin

67
Q

What does Deletion or mutation of SOST gene results in?

A

Sclerosteosis or van buchem’s disease

68
Q

What is a key target
cell for development of new treatments for
diseases of bone loss and overgrowth?

A

Osteocyte

69
Q

Osteocytes express several genes important in
phosphate homeostasis:

A

FGF23 (fibroblast growth factor-23)
DMP1 (dentin matrix protein-1)
PHEX (phosphate regulating endopeptidase homolog, x-linked)

70
Q

What play an endocrine role in regulation of
phosphate homeostasis?

A

Osteocytes

71
Q
A