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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
Q

What are the two major clinical forms of impaired osteoclast function?

A

autosomal dominant
-adult, few symptoms
autosomal recessive
-infantile, typically fatal

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26
Q

What do bones look like if there are impaired osteoclasts ?

A

abnormally dense and prone to fracture

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27
Q

What are some accompanying symptoms of impaired osteoclast function?

A

-scoliosis
-nerve compression in head and face
-impair marrow function (anemia)
-enlarged liver or spleen
-dental abnormalities
-short stature
-slow growth
-recurrent infection

28
Q

What type of mutations account for 50% of autosomal recessive osteopetrosis?

A

mutations in the alpha 3 subunit of vacuolar H+ ATPase

29
Q

What type of mutations account for 75% of autosomal dominant osteopetrosis?

A

mutations in genes encoding for the ClC7 chloride channels

30
Q

What are mutations in Cathepsin K associated with?

A

pycnodysostosis

31
Q

What is the definition of osteoporosis?

A

a patient with a BMD >2.5 SD below average for a healthy young male or female

32
Q

What is a widely used type of treatment for osteoporosis?

A

bisphosphonates

33
Q

What are bisphosphonates?

A

non-hydrolyzable analogs of pyrophosphate

34
Q

What is BONJ?

A

bisphosphonate associated osteonecrosis of the jaw

35
Q

What is the definition of BONJ?

A

-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
Q

What is the importance of skeletal healing?

A

-resolution of orthopedic trauma
-healing of corrective surgeries where bony injuries are created
-bone regeneration in oral surgical procedures

37
Q

What are the cell types that are required for fracture healing?

A

-inflammatory cells
-chondroprogenitor/chondrocytes
-osteoprogenitor/osteoblasts
-osteoclasts
-vascular cells

38
Q

What are the phases of fracture healing?

A

-inflammatory phase
-reparative phase
-remodeling phase

39
Q

When does the inflammatory phase of fracture healing happen?

A

peaks by 48 hours and is diminished by 1 weeks

40
Q

When does the reparative phase of fracture healing happen?

A

activated within a few days and persists up to 2-3 months

41
Q

When does the remodeling phase of fracture healing happen?

A

can continue for several years

42
Q

What occurs during the inflammatory/reactive phase of fracture repair?

A

formation of vascular hemotoma

43
Q

What occurs during the reparative phase of fracture repair?

A

-formation of fibrocartilage callus
-tissue metaplasia-callus replaced by mineralized bone

44
Q

What occurs during the remodeling phase of fracture repair?

A

bone remodeling and turnover

45
Q

What are the hemotoma associated cytokines released during the inflammatory/reactive phase?

A

TNF alpha
IL-1,6,11,and 18

46
Q

What do cytokines lead to?

A

recruitment/infiltration of inflammatory cells

47
Q

What do inflammatory cels do?

A

release more inflammatory cytokines and recruit mesenchymal stem cells to fracture site

48
Q

What lays down the connective tissue matrix to form the fibrocartilage callus?

A

fibroblasts

49
Q

What does the hypoxic region of MSC cause?

A

differentiation into chondrocytes
-initiate endochondral bone formation

50
Q

Where does intramembranous bone form?

A

subperiosteral sites where vascular supply is intact
-form a hard external callus

51
Q

When is the fracture considered healed?

A

when bone stability restored by bone tissue, completely bridging the original fracture

52
Q

What is the initial type of bone formed ?

A

woven bone

53
Q

What occurs during the remodeling phase of bone healing?

A

osteoclasts resorb woven bone in fracture callous then osteoblasts lay down new lamellar bone
-marrow cavity restored
-original bone contours restored
-biomechanically stable

54
Q

3 main categories of signalling molecules important in fracture healing?

A

-pro-inflammatory cytokines
-TGF-beta superfamily
-angiogenic factors

55
Q

What are the pro-inflammatory cytokines involved in fracture healing?

A

-TNF-alpha
-IL-1,-6,-11, and -18

56
Q

What do the pro-inflammatory cytokines do?

A

-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
Q

What secretes the pro-inflammatory cytokines ?

A

macrophages, mesenchymal cells, and inflammatory cells

58
Q

What are the members of the TGF-beta superfamily involved in fracture healing?

A

-TGF-B
-BMP2, 5, and 6
-GDF-8

59
Q

What do the members of the TGF-beta superfamily do in fracture healing?

A

-promote ECM synthesis and assembly/initation of callus formation
-promote osteogenic differentiation
-GDF-8 has a role in cell proliferation

60
Q

What are the angiogenic factors involved in fracture repair?

A

VEGF
PDGF
ANGPT

61
Q

What do the angiogenic factors do in fracture repair?

A

promote vascular ingrowth from vessels in periosteum

62
Q

What does VEGF do?

A

-promote chemotaxis of osteoprogenitors
-upregulated in regions of hypoxia

63
Q

What could bone repair be enhanced by?

A

-improving vascularization
-attracting progenitor cells
-accelerating bone formation
-accelerating remodeling

64
Q

What are BMPs being studied for?

A

appear to be effective alternative to autologous bone graft for repair of fracture

65
Q

What are some things being studied for increased fracture repair?

A

-BMPs
-platelet rich plasma
-FGFs
-PDGF
-Cell based therapies (autologous bone marrow)
-anti-resorptives
-bone anabolic agents

66
Q

What is sclerostin

A

inhibitor of Wnt/Beta-catenin signaling

67
Q

What are anti-sclerostin antibodies being studied for?

A

anabolic treatment for osteoporosis
-possibly enhancing bone regeneration

Biochem Exam 5 (12 decks)

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