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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
What is a macrophage colony stimulating factor?
M-CSF (aka CSF-1)
26
What promotes proliferation/ survival of osteoclast precursors?
M-CSF
27
What (member of TNF superfamily) – required for osteoclast fusion and differentiation?
RANKL
28
What (natural inhibitor of RANKL– decoy receptor)?
OPG (osteoprotogerin)
29
What does an osteoclast need to do?
* 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
30
What are transcription factors for osteoclast marker proteins?
NFATc1 C-fos NFkB
31
What are enzymes for osteoclast marker proteins?
Tartrate resistant acid phophatase (TRAP)
32
What are receptors for osteoclast marker proteins?
RANK C-fms Calcitonin receptor Integrin alpha-v-beta-3
33
What generates protons/proton pump for osteoclast marker proteins?
Carbonic anhydrase II Vacuolar-type ATPase
34
What are proteases for osteoclast marker proteins?
Cathepsin K MMP9, MMP13
35
What do osteoclasts attach via to form a sealed zone?
Alphavbeta3
36
What generates protons?
Carbonic anhydrase II (CAII)
37
What pumps protons into resorption lacuna and what happens?
Vacuolar-type H+ ATPase; create acidic pH (Dissolves material)
38
What removes excess bicarbonate?
Cl- and HCO3- exchanger on basolateral surface
39
What maintains charge neutrality?
Chloride channel
40
What is released into resorption lacuna?
Cathepsin K (and other proteases)
41
What lead to osteopetrosis?
Impaired osteoclast function
42
What is osteopetrosis due to?
Failure in osteoclast FORMATION or osteoclasts form normally but have impaired resorptive FUNCTION
43
What are two major clinical forms?
Autosomal dominant adult type - benign Autosomal recessive child type - malignant
44
What genes are association with osteopetrosis?
ATPase Chloride Channel Cathepsin K
45
What gene mutations is associated with pycnodysostosis?
Cathepsin K
46
What BMD does an osteoporosis patient have?
BMD >2.5 standard deviations below average
47
What are anti-resorptives as treatment for osteoporosis?
Amino bisphosphonates Hormone replacement therapy Selective estrogen receptor modulators Denosumab Cathepsin K inhibitors
48
What are anabolic agents for osteoporosis?
PTH 1-84, Teriparitide Anti-sclerostin antibodies
49
What is widely used for treatment of osteoporosis?
Oral bisphosphonates
50
What are used for treatment of myeloma/bone metastatic cancers?
I.V. bisphosphonates
51
What are non-hydrolyzable analogs of pyrophosphate (PPi) – inhibit mineralization similarly to PPi?
Bisphosphonates
52
What are nitrogen containing bisphosphonates?
Alendronate Risedronate Pamidronate Zoledronate Ibandronate
53
What is the definition for Bisphosphonate associated osteonecrosis of the jaw (BONJ)?
(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
What is the pathogenesis of BONJ?
Not fully understood - attributed mainly to suppression of bone turnover due to BP inhibition of osteoclast activity
55
What is skeletal healing essential for?
* 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
Fracture healing requires coordinated activity of severall cell types:
* Inflammatory Cells * Chondroprogenitors/chondrocytes * Osteoprogenitors/osteoblasts * Osteoclasts * Vascular cells
57
What are the three phases of fracture healing?
Inflammatory (reactive) phase 1. days to weeks reparative phase 1. weeks to months remodeling phase 1. months to years
58
What is the process of reactive fracture repair?
1) formation of vascular hematoma
59
What is the process of reparative fracture repair?
2) Formation of (fibrocartilage) callus 3) Tissue metaplasia – callus replaced by mineralized bone
60
What is the process of remodeling fracture repair?
4) Bone remodeling and turnover
61
Hematoma-associated cytokines released:
Tumor necrosis factor-α (TNF-α ) Interleukins (IL-1,-6, -11 and -18)
62
Cytokines lead to recruitment/infiltration of
inflammatory cells
63
What do inflammatory cells release?
more inflammatory cytokines and recruit mesenchymal stem cells (MSC)/osteogenic precursors to fracture site
64
During the formation of fibrocartilagenous callus, what invades the hematoma?
MSC/connective tissue stem cells/blood vessels which degenerates/phagocytes clear debris
65
What lays down a connective issue matrix?
Fibroblasts (granulation tissue)
66
What do some MSC differentiate towards?
Chondrogenic/osteogenic lineages
67
What happens at broken ends of bones where blood supply is disrupted?
Hypoxia/tissue necrosis occurs
68
In hypoxic regions MSC differentiate into, which initiates?
chondrocytes – initiates endochondral bone formation
69
What are cell sources of osteogenic precursors?
- Periosteum - Muscle - Bone Marrow - Circulating?
70
What are cell types of osteogenic precursors?
- Mesenchymal Stem Cell (MSC) - Pericyte - Muscle satellite cell
71
What contributes to a bony callus?
Intramembranous bone (formed where vascular supply intact)
72
What does cartilage undergo
endochondral ossification (hypertrophy>calcification of cartilage>removal by osteoclasts> replacement with bone)
73
When is the fracture considered healed?
when bone stability restored by bone tissue completely bridging the original fracture (“clinical union”)
74
When is initial bone formed called?
Woven bone
75
What is the function of osteoclasts/blasts in woven bone during remodeling?
Osteoclasts resorb woven bone in fracture callous then osteoblasts lay down new lamellar bone (Haversian) = mechanically stronger
76
Are genes expressed during fracture healing?
Yes
77
What are the 3 main signaling molecules that are important in fracture healing?
1. Pro-inflammatory cytokines 2. TGF beta 3. Angiogenic factors
78
When TNF and Interleukins get released, what does their release cause?
1. Recruitment of other inflammatory cells and mesenchymal stem cells differentiation 2. Apoptosis of hypertrophic chondrocytes 3. Osteoclast formation
79
What does TGF, BMP, and GDF proteins do?
1. Promote ECM synthesis and assembly 2. Promote osteogenic differentiation 3. Cell proliferation
80
What angiogenic factors are released during fracture repair?
VEGF PDGF Angiopoietin
81
What do these angiogenic factors do?
Cause the promotion of vascular ingrowth

Biochem Exam 5 (11 decks)

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