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
What do osteoblasts produce?
Large amounts of ECM proteins (collagen type I) = osteoid, which then mineralize
26
What is the lifespan of osteoblasts?
weeks
27
What are osteoblast marker proteins that are transcription factors?
Runx2 Osterix
28
What are osteoblast marker proteins that are enzymes?
Alkaline phosphatase
29
What are osteoblast marker proteins that are ECM proteins?
* Type I collagen * Osteopontin * Osteocalcin * Bone sialoprotein (BSP)
30
What are the key transcriptional regulators of osteoblast differentiation?
Proliferation Maturation Terminal differentiation
31
What is the master transcription factor for bone?
Runx2
32
What is Runx2 essential for?
Bone and tooth development
33
What does a heterozygous mutation in Runx2 result in?
Cleidocranial dysplasia (CCD)
34
What transcription factor does Runx2 induce?
Osterix
35
What is osterix critical for?
Osteoblast differentiation
36
What does osterix control expression of?
Osteoblast genes: Type 1 collagen Osteocalcin Osteopontin
37
What does a human mutation in SP7 (osterix) associate with?
Osteogenesis imperfecta type XII
38
What are two key signaling pathways that regulate osteoblast differentiation?
BMPs and WNT/B-catenin signaling pathway
39
What are originally purified from bone extracts that induce bone formation when implanted in muscle?
BMPs
40
What are BMPs required for?
skeletal development/maintenance of adult bone homeostasis
41
What promotes differentiation from early osteoprogenitor cells?
BMPs
42
What does Naturally occurring mutations in BMPs or their receptors result in?
Inherited skeletal disorders in humans
43
What is FOP (fibrodysplasia ossificans progressiva)?
Heterotopic bone formation (bone forming in soft tissues)
44
What is FOP a result from?
Mutation in BMP type 1 receptor
45
What is Wnt-β-catenin signaling pathway important in determining?
Bone mass
46
What does activating mutations of Lrp5 lead to?
High bone mass in humans and vise versa
47
What is the first phase of mineralization initaited by?
Matrix vesicle
48
What does the second phase of mineralization involve?
Propagation of mineralization on collagen fibers
49
What are the stages in Matrix vesicle (MV) mediated mineralization?
Phosphate compounds -> pyrophosphate (PPi) -> monophosphate ion Pi (aka PO43-)
50
What enzyme highly expressed in osteoblasts/ odontoblasts?
Alkaline phosphotases
51
What does alkaline phosphotases hydrolyze?
Pyrophosphate
52
What is a natural inhibitor of mineralization, thereby increasing local phosphate concentration – promotes mineralization?
Pyrophosphate
53
What is mutations in alkaline phosphatase gene (TNSALP) associated with?
Hypophosphatasia
54
Mutations in what is associated with syndrome of spontaneous infantile artieral and periarticular calcification – similar phenotype in KO mice?
ENPP1
55
Mutations in what are associated with hypophosphatasia (impaired mineralization)?
TNSALP (TNAP)
56
What in knockout mice doesn't show abnormal skeletal development?
Anx5
57
Deletion of what in mice may cause impaired mineralization, including in MV?
PHOSPHO1
58
What are terminally differentiated osteoblasts?
Osteocytes
59
What is the lifespan of osteocytes?
Decades
60
What cells are embedded in the bone matrix?
Osteocytes
61
What are transcription factors in osteocytes?
Mef2c
62
What are early osteocyte markers?
* E11/gp38/podoplanin * Dentin matrix protein-1 (DMP1) * Matrix extracellular phosphoglycoprotein (MEPE) * Phosphate regulating endopeptidase homolog, X-Linked (PHEX)
63
What are late osteocyte markers?
Sclerostin (SOST)
64
What are functions of osteocytes?
* 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
What is highly expressed in mature osteocytes, cementocytes, odontoblasts?
Sclerostin
66
What is a Negative regulator of bone formation?
Sclerostin
67
What does Deletion or mutation of SOST gene results in?
Sclerosteosis or van buchem's disease
68
What is a key target cell for development of new treatments for diseases of bone loss and overgrowth?
Osteocyte
69
Osteocytes express several genes important in phosphate homeostasis:
FGF23 (fibroblast growth factor-23) DMP1 (dentin matrix protein-1) PHEX (phosphate regulating endopeptidase homolog, x-linked)
70
What play an endocrine role in regulation of phosphate homeostasis?
Osteocytes
71