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Biochem Exam 5 > 11/9: Osteoclasts/Osteoporosis and Fracture Healing > Flashcards

11/9: Osteoclasts/Osteoporosis and Fracture Healing Flashcards

1
Q

What are the 3 main bone cells?

A

Osteoclasts
Osteocytes
Osteoblasts

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2
Q

To repair damaged bone, it is continually being removed by ______ and rebuilt by _______

A

Osteoclasts; osteoblasts

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3
Q

What are osteoclasts derived from?

A

Same precursor as macrophages

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4
Q

How many nuclei are in mature osteoclasts?

A

Multinucleated

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5
Q

What do osteoclasts express to remove ECM proteins?

A

Proteases

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6
Q

What do osteoclasts express to generate H+ ions?

A

Proteins that act as proton pumps

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7
Q

What do active osteoclasts have that are specialized?

A

“ruffled border”

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8
Q

What does ruffled border do?

A

Increase surface area in resorption compartment

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9
Q

What is the lifespan of osteoclasts?

A

Short (days)

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10
Q

What are osteoclasts responsible for?

A
  • Bone resorption during normal bone growth and
    remodeling
  • Removal of alveolar bone during tooth eruption
  • Resorption of tooth roots of primary teeth
  • Removal of alveolar bone during orthodontic tooth
    movement
  • Bone loss in pathological conditions (osteoporosis,
    tumor associated osteolysis, etc.)
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11
Q

What is osteoclastic resorption important for?

A

Normal bone growth

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12
Q

Where does growth occur?

A

At epiphyseal plate

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13
Q

What does modeling occur to maintain?

A

Bone shape

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14
Q

What are the main factors that regulate osteoclastic differentiation?

A

M-CSF
RANKL

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15
Q

What inhibits M-CSF RANKL?

A

OPG

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16
Q

What inhibits RANKL?

A

OPG

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17
Q

What is an enzyme for mononucleated osteoclast?

A

NFATc1
C-fos
NFkB

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18
Q

What stimulates monocytes?

A

M-CSF

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19
Q

What stimulations mononucleated (prefusion) osteoclasts?

A

M-CSF RANKL

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20
Q

What stimulates multinucleated osteoclasts and resorbing osteoclasts?

A

RANKL

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21
Q

What is the master transcription factor?

A

NFATc1

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22
Q

What are downstream of NFATc1?

A

C-fos and NFkB

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23
Q

What are two factors produced by osteoblasts/osteoctes that are essential for OCL differentiation?

A

RANKL
M-CSF

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24
Q

What is a receptor activator of NFkB ligand?

A

RANKL

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25
Q

What is a macrophage colony stimulating factor?

A

M-CSF (aka CSF-1)

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26
Q

What promotes
proliferation/ survival of
osteoclast precursors?

A

M-CSF

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27
Q

What (member of TNF
superfamily) – required for
osteoclast fusion and
differentiation?

A

RANKL

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28
Q

What (natural inhibitor of RANKL– decoy receptor)?

A

OPG (osteoprotogerin)

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29
Q

What does an osteoclast need to do?

A
  • Differentiate/fuse
  • Adhere to the bone surface
  • Produce acid to dissolve mineral
  • Produce proteases to breakdown extracellular matrix
    components
  • Respond to factors that regulate osteoclast survival/
    activity
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30
Q

What are transcription factors for osteoclast marker proteins?

A

NFATc1
C-fos
NFkB

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31
Q

What are enzymes for osteoclast marker proteins?

A

Tartrate resistant acid phophatase (TRAP)

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32
Q

What are receptors for osteoclast marker proteins?

A

RANK
C-fms
Calcitonin receptor
Integrin alpha-v-beta-3

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33
Q

What generates protons/proton pump for osteoclast marker proteins?

A

Carbonic anhydrase II
Vacuolar-type ATPase

34
Q

What are proteases for osteoclast marker proteins?

A

Cathepsin K
MMP9, MMP13

35
Q

What do osteoclasts attach via to form a sealed zone?

A

Alphavbeta3

36
Q

What generates protons?

A

Carbonic anhydrase II (CAII)

37
Q

What pumps protons into resorption lacuna and what happens?

A

Vacuolar-type H+ ATPase; create acidic pH (Dissolves material)

38
Q

What removes excess bicarbonate?

A

Cl- and HCO3- exchanger on
basolateral surface

39
Q

What maintains charge
neutrality?

A

Chloride channel

40
Q

What is released into resorption lacuna?

A

Cathepsin K (and other proteases)

41
Q

What lead to osteopetrosis?

A

Impaired osteoclast function

42
Q

What is osteopetrosis due to?

A

Failure in osteoclast FORMATION or osteoclasts
form normally but have impaired resorptive FUNCTION

43
Q

What are two major clinical forms?

A

Autosomal dominant adult type - benign
Autosomal recessive child type - malignant

44
Q

What genes are association with osteopetrosis?

A

ATPase
Chloride Channel
Cathepsin K

45
Q

What gene mutations is associated with pycnodysostosis?

A

Cathepsin K

46
Q

What BMD does an osteoporosis patient have?

A

BMD >2.5 standard deviations below average

47
Q

What are anti-resorptives as treatment for osteoporosis?

A

Amino bisphosphonates
Hormone replacement therapy
Selective estrogen receptor modulators
Denosumab
Cathepsin K inhibitors

48
Q

What are anabolic agents for osteoporosis?

A

PTH 1-84, Teriparitide
Anti-sclerostin antibodies

49
Q

What is widely used for treatment of osteoporosis?

A

Oral bisphosphonates

50
Q

What are used for treatment of myeloma/bone metastatic cancers?

A

I.V. bisphosphonates

51
Q

What are non-hydrolyzable analogs of pyrophosphate (PPi) – inhibit mineralization similarly to PPi?

A

Bisphosphonates

52
Q

What are nitrogen containing bisphosphonates?

A

Alendronate
Risedronate
Pamidronate
Zoledronate
Ibandronate

53
Q

What is the definition for Bisphosphonate associated osteonecrosis of the jaw (BONJ)?

A

(1) current or previous treatment with a bisphosphonate
(2) exposed, necrotic bone in the maxillofacial region that has been present for at least 8 weeks
(3) no history of radiation therapy to the jaws

54
Q

What is the pathogenesis of BONJ?

A

Not fully understood - attributed mainly to suppression of bone turnover due to BP inhibition of osteoclast activity

55
Q

What is skeletal healing essential for?

A
  • Resolution of orthopedic trauma that has
    caused fractures
  • Healing of corrective surgeries where bony
    injuries are created intentionally to correct
    bone deformities, etc
  • Bone regeneration in oral surgical
    procedures/tooth extractions, etc
56
Q

Fracture healing requires coordinated activity of severall cell types:

A
  • Inflammatory Cells
  • Chondroprogenitors/chondrocytes
  • Osteoprogenitors/osteoblasts
  • Osteoclasts
  • Vascular cells
57
Q

What are the three phases of fracture healing?

A

Inflammatory (reactive) phase
1. days to weeks
reparative phase
1. weeks to months
remodeling phase
1. months to years

58
Q

What is the process of reactive fracture repair?

A

1) formation of vascular hematoma

59
Q

What is the process of reparative fracture repair?

A

2) Formation of (fibrocartilage)
callus
3) Tissue metaplasia – callus
replaced by mineralized bone

60
Q

What is the process of remodeling fracture repair?

A

4) Bone remodeling and turnover

61
Q

Hematoma-associated cytokines
released:

A

Tumor necrosis factor-α (TNF-α )
Interleukins (IL-1,-6, -11 and -18)

62
Q

Cytokines lead to recruitment/infiltration
of

A

inflammatory cells

63
Q

What do inflammatory cells release?

A

more inflammatory cytokines and recruit mesenchymal stem cells (MSC)/osteogenic precursors to fracture site

64
Q

During the formation of fibrocartilagenous callus, what invades the hematoma?

A

MSC/connective tissue stem cells/blood vessels which degenerates/phagocytes clear debris

65
Q

What lays down a connective issue matrix?

A

Fibroblasts (granulation tissue)

66
Q

What do some MSC differentiate towards?

A

Chondrogenic/osteogenic lineages

67
Q

What happens at broken ends of bones where blood supply is disrupted?

A

Hypoxia/tissue necrosis occurs

68
Q

In hypoxic regions MSC differentiate into, which initiates?

A

chondrocytes – initiates endochondral bone formation

69
Q

What are cell sources of osteogenic precursors?

A
  • Periosteum
  • Muscle
  • Bone Marrow
  • Circulating?
70
Q

What are cell types of osteogenic precursors?

A
  • Mesenchymal Stem Cell (MSC)
  • Pericyte
  • Muscle satellite cell
71
Q

What contributes to a bony callus?

A

Intramembranous bone (formed where vascular supply intact)

72
Q

What does cartilage undergo

A

endochondral ossification (hypertrophy>calcification of
cartilage>removal by osteoclasts>
replacement with bone)

73
Q

When is the fracture considered healed?

A

when bone stability restored by bone tissue completely bridging the original fracture (“clinical union”)

74
Q

When is initial bone formed called?

A

Woven bone

75
Q

What is the function of osteoclasts/blasts in woven bone during remodeling?

A

Osteoclasts resorb woven bone in
fracture callous then osteoblasts lay down new lamellar bone (Haversian) = mechanically stronger

76
Q

Are genes expressed during fracture healing?

A

Yes

77
Q

What are the 3 main signaling molecules that are important in fracture healing?

A
  1. Pro-inflammatory cytokines
  2. TGF beta
  3. Angiogenic factors
78
Q

When TNF and Interleukins get released, what does their release cause?

A
  1. Recruitment of other inflammatory cells and mesenchymal stem cells differentiation
  2. Apoptosis of hypertrophic chondrocytes
  3. Osteoclast formation
79
Q

What does TGF, BMP, and GDF proteins do?

A
  1. Promote ECM synthesis and assembly
  2. Promote osteogenic differentiation
  3. Cell proliferation
80
Q

What angiogenic factors are released during fracture repair?

A

VEGF
PDGF
Angiopoietin

81
Q

What do these angiogenic factors do?

A

Cause the promotion of vascular ingrowth

Biochem Exam 5 (11 decks)

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