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Biochem Exam 5 > Osteoclasts, Osteoporosis, and Fracture Healing > Flashcards

Osteoclasts, Osteoporosis, and Fracture Healing Flashcards

1
Q

What type of precursors do osteoclasts come from?

A

the same ones as macrophages
(hematopoietic lineage)

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2
Q

Mature osteoclasts are…

A

multinucleated

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3
Q

What do osteoclasts express?

A

-proteases for removing ECM proteins
-proteins that act as proton pumps to generate H+ ions

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4
Q

What type of cells have a ruffled border?

A

active osteoclasts

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5
Q

What do the ruffled borders of active osteoclasts do?

A

increase the surface area in resportion compartment

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6
Q

What is the lifespan of osteoclasts?

A

short (days)

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7
Q

What are osteoclasts responsible for?

A

-bone resorption during 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

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8
Q

Where does the growth of bone occur?

A

at the epiphyseal plate

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9
Q

What must happen to main the bone shape?

A

modeling of the bone

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10
Q

What is the master transcription factor of osteoclast formation/function?

A

NFATc1

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11
Q

What are the two downstream factors of NFATc1 that are also important?

A

C-fos and NFkB

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12
Q

What is RANKL?

A

receptor activator of NFkB ligand
-required for osteoclast fusion and differentiation

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13
Q

What is M-CSF?

A

macrophage colony stimulating unit
-promote proliferation/survival of osteoclast precursor

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14
Q

What is OPG?

A

natural inhibitor of RANKL
(decoy receptor)

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15
Q

What do osteoclasts need to do?

A

-differentiate/fuse
-adhere to 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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16
Q

What is the enzyme of osteoclasts?

A

TRAP

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17
Q

What are the receptors for osteoclasts?

A

-RANK
-C-fms
-calcitonin receptor
-integrin alpha-v-beta-3

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18
Q

What are the proton pumps of osteoclasts?

A

-carbonic anhydrase II
-vacuolar-type ATPase

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19
Q

What are the proteases of osteoclasts?

A

-cathepsin K
-MMP9
-MMP13

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20
Q

What do osteoclasts attach to to form the sealed zone?

A

alpha-v-beta-3

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21
Q

What does vacuolar type H+ ATPase do?

A

pump protons into resorption lacuna
-create acidicpH

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22
Q

What removes excess bicarbonate from the osteoclasts?

A

Cl- and HCO3- exchangers on basolateral surface

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23
Q

What maintains the charge neutrality of osteoclasts ?

A

chloride channels

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24
Q

Where is Cathepsin K released into?

A

the resorption lacuna

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25
What are the two major clinical forms of impaired osteoclast function?
autosomal dominant -adult, few symptoms autosomal recessive -infantile, typically fatal
26
What do bones look like if there are impaired osteoclasts ?
abnormally dense and prone to fracture
27
What are some accompanying symptoms of impaired osteoclast function?
-scoliosis -nerve compression in head and face -impair marrow function (anemia) -enlarged liver or spleen -dental abnormalities -short stature -slow growth -recurrent infection
28
What type of mutations account for 50% of autosomal recessive osteopetrosis?
mutations in the alpha 3 subunit of vacuolar H+ ATPase
29
What type of mutations account for 75% of autosomal dominant osteopetrosis?
mutations in genes encoding for the ClC7 chloride channels
30
What are mutations in Cathepsin K associated with?
pycnodysostosis
31
What is the definition of osteoporosis?
a patient with a BMD >2.5 SD below average for a healthy young male or female
32
What is a widely used type of treatment for osteoporosis?
bisphosphonates
33
What are bisphosphonates?
non-hydrolyzable analogs of pyrophosphate
34
What is BONJ?
bisphosphonate associated osteonecrosis of the jaw
35
What is the definition of BONJ?
-current or past treatment of bisphosphonates -exposed, necrotic bone in the maxillofacial region present for at least 8 weeks -no history of radiation therapy to the jaw
36
What is the importance of skeletal healing?
-resolution of orthopedic trauma -healing of corrective surgeries where bony injuries are created -bone regeneration in oral surgical procedures
37
What are the cell types that are required for fracture healing?
-inflammatory cells -chondroprogenitor/chondrocytes -osteoprogenitor/osteoblasts -osteoclasts -vascular cells
38
What are the phases of fracture healing?
-inflammatory phase -reparative phase -remodeling phase
39
When does the inflammatory phase of fracture healing happen?
peaks by 48 hours and is diminished by 1 weeks
40
When does the reparative phase of fracture healing happen?
activated within a few days and persists up to 2-3 months
41
When does the remodeling phase of fracture healing happen?
can continue for several years
42
What occurs during the inflammatory/reactive phase of fracture repair?
formation of vascular hemotoma
43
What occurs during the reparative phase of fracture repair?
-formation of fibrocartilage callus -tissue metaplasia-callus replaced by mineralized bone
44
What occurs during the remodeling phase of fracture repair?
bone remodeling and turnover
45
What are the hemotoma associated cytokines released during the inflammatory/reactive phase?
TNF alpha IL-1,6,11,and 18
46
What do cytokines lead to?
recruitment/infiltration of inflammatory cells
47
What do inflammatory cels do?
release more inflammatory cytokines and recruit mesenchymal stem cells to fracture site
48
What lays down the connective tissue matrix to form the fibrocartilage callus?
fibroblasts
49
What does the hypoxic region of MSC cause?
differentiation into chondrocytes -initiate endochondral bone formation
50
Where does intramembranous bone form?
subperiosteral sites where vascular supply is intact -form a hard external callus
51
When is the fracture considered healed?
when bone stability restored by bone tissue, completely bridging the original fracture
52
What is the initial type of bone formed ?
woven bone
53
What occurs during the remodeling phase of bone healing?
osteoclasts resorb woven bone in fracture callous then osteoblasts lay down new lamellar bone -marrow cavity restored -original bone contours restored -biomechanically stable
54
3 main categories of signalling molecules important in fracture healing?
-pro-inflammatory cytokines -TGF-beta superfamily -angiogenic factors
55
What are the pro-inflammatory cytokines involved in fracture healing?
-TNF-alpha -IL-1,-6,-11, and -18
56
What do the pro-inflammatory cytokines do?
-recruit other inflammatory cells/promote MSC recruitment -induce apoptosis of hypertrophic chondrocytes -recruit fibrogenic cells/promote formation of granulation tissue/ECM formation -can promote osteoclast formation
57
What secretes the pro-inflammatory cytokines ?
macrophages, mesenchymal cells, and inflammatory cells
58
What are the members of the TGF-beta superfamily involved in fracture healing?
-TGF-B -BMP2, 5, and 6 -GDF-8
59
What do the members of the TGF-beta superfamily do in fracture healing?
-promote ECM synthesis and assembly/initation of callus formation -promote osteogenic differentiation -GDF-8 has a role in cell proliferation
60
What are the angiogenic factors involved in fracture repair?
VEGF PDGF ANGPT
61
What do the angiogenic factors do in fracture repair?
promote vascular ingrowth from vessels in periosteum
62
What does VEGF do?
-promote chemotaxis of osteoprogenitors -upregulated in regions of hypoxia
63
What could bone repair be enhanced by?
-improving vascularization -attracting progenitor cells -accelerating bone formation -accelerating remodeling
64
What are BMPs being studied for?
appear to be effective alternative to autologous bone graft for repair of fracture
65
What are some things being studied for increased fracture repair?
-BMPs -platelet rich plasma -FGFs -PDGF -Cell based therapies (autologous bone marrow) -anti-resorptives -bone anabolic agents
66
What is sclerostin
inhibitor of Wnt/Beta-catenin signaling
67
What are anti-sclerostin antibodies being studied for?
anabolic treatment for osteoporosis -possibly enhancing bone regeneration

Biochem Exam 5 (12 decks)

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