Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Biochem > Lecture 44: Osteoclasts Osteoporosis and Fracture Healing > Flashcards

Lecture 44: Osteoclasts Osteoporosis and Fracture Healing Flashcards

1
Q

what are osteoclasts derived from

A

same precursors as macrophages- hematopoietic lineage

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

what is a characteristic of mature osteoclasts

A

mutlinucleateed

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

what are proteases in osteoclasts used for

A

removing ECM proteins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

what do proteins that acts as proton pumps in osteoclasts do

A

generate H+ iions to reduce pH to dissolve mineral

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

where is the ruffled border and what does it do

A

in active osteoclasts to increase surface area in resorption compartment

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

what is the lifespan of osteoclasts

A

days (short)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

where does bone growth occur

A

at the epiphyseal plate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

what are the main factors in regulating osteoclast differentiation

A

M-CSF, RANKL,OPG,

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

what is the master transcription factor in the regulation of osteoclast formation/function

A

NFATc1 and C-fod and NFkB downstream

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

what are the factors produced by osteoblasts/osteocytes that are essential for osteoclast differentiation

A

RANKL and M-CSF

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

what does M-CSF do

A

promotes proliferation/survival of osteoclast precursors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

what does RANKL do

A

required for osteoclast fusion and differentiation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

what does OPG do

A

natural inhibitor of RANKL

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

what are the transcription factors for osteoclasts

A

NFATc1, C-fos, NFkB

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

what enzyme is important in osteoclasts

A

TRAP

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

what are the receptors associated with osteoclast formation/function

A
  • RANK: receptor for RANKL
    -C-fms: receptor for M-CSF
    -calcitonin receptor
    -integrin avB3
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

what generates protons/proton pump in osteoclasts

A

carbonic anhydrase 2 and vacuolar type ATPase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

what proteases are involved with osteoclasts

A

Cathepsin K, MMP9 and MMP13

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

what do osteoclasts attach to to form the sealed zone

A

avB3 integrins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

what generates protons in osteoclast

A

carbonic anhydrase 2

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

what do vaculoar type H+ ATPase pumps do

A

pumps protons into resorption lacuna to create an acidic pH

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

what do Cl- and HCO3- exchanger do and where is it located in osteoclasts

A

on basolateral surface removes excess bicarbonate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

what does the chloride channel in osteoclasts do

A

maintain charge neutrality

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

what does cathepsin K in osteoclasts do

A

released into resorption lacuna to digest matrix proteins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

what does impaired osteoclast function lead to

A

osteopetrosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

what can osteopetrosis be caused by

A

failure in osteoclast formation or osteoclasts form normally but have impaired resorptive function

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

what are the major clinical forms of osteopetrosis

A
  • autosomal dominant adult type-few symptoms
  • autosomal recessive infantile type - typically fatal in early childhood
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

describe the characteristics of bone in osteopetrosis

A

bones are abnormally dense and prone to fracture

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

what does failed osteoclastic resorption affect

A

bone growth, remodeling, tooth eruption

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

what can osteopetrosis be accompanies by

A

scoliosis, nerve compression in head and face (hearing loss, blindness), impaired marrow function (anemia), enlarged liver or spleen, dental abnormalities, short stature, slow growth, recurrent infections

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

what gene mutations are associated with osteopetrosis

A

TCIRG1, CLCN7, cathepsin K mutations

34
Q

what mutation accounts for 50% of AR osteopetrosis

A

TCIRG1

35
Q

what mutation accounts for 75% of AD forms of osteopetrosis

A

CLCN7

36
Q

what are mutations in cathepsin K associated with

A

pycnodysostosis

37
Q

what is the definition of osteoporosis

A

a patient with a BMD greater than 2.5 standard deviations below average for a healthy young female or male

38
Q

how do bisphosphonates work

A

bind to hydroxyapatite, inhibit activity of osteoclasts by inhibiting mevalonate pathway important for prenylation of GTPases important for vesicular trafficking

39
Q

how does hormone replacement therapy work in osteoporosis

A

restores hormone levels following menopause

40
Q

how do SERMs work

A

work as partial agonist of estrogen receptor

41
Q

what are bisphosphonates used for

A

osteoporosis and treatment of myeloma/bone metastatic cancers particularly if patients have high serum calcium

42
Q

in which case is the dose of bisphosphonates are higher: cancer or osteoporosis

A

cancer

43
Q

what is a bisphosphonate

A

non-hydrolyzable analog of pyrophosphate

44
Q

what do bisphosphonates have a high affinity for

A

hydroxyapatite

45
Q

what is the major side effect of bisphosphonates

A

osteonecrosis of the jaw (mandible or maxilla)

46
Q

what is BONJ defined by

A

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

47
Q

what is the pathogenesis of BONJ

A

attributed mainly to suppression of bone turnover due to BP inhibition of osteoclast activity

48
Q

how do bisphosphonates affect orthodontic tooth movement

A

they inhibit it

49
Q

what is skeletal healing important for

A
  • resolution of orthopedic trauma that has caused fractures
  • healing of corrective surgeries where bony injuries are created intentionally to correct bone deformities
    -bone regeneration in oral surgical procedures/tooth extractions
50
Q

what can failed/delayed skeletal healing result from

A

inadequate fixation, infection, tumor, hypoxia/poor blood supply, metabolic dysfunction, chronic/inherited diseases

51
Q

what cell types are required in fracture healing

A

-inflammatory cells
-chondroprogenitors/chondrocytes
-osteoprogenitors/osteocytes
-osteoclasts
-vascular cells

52
Q

what is the timeline of fracture healing and how long does each phase occur

A

-inflammatory phase: peaks by 48h and lasts a week
-reparative phase: activated within a few days and persists for up to 2-3 months
- remodeling phase: can continue for several years

53
Q

what are the 4 stages of fracture repair and what phase do they occur in

A

-formation of vascular hematoma (reactive phase)
- formation of (fibrocartilage) callus (reparative)
- tissue metaplasia - callus replaced by mineralized bone (reparative)
- bone remodeling and turnover (remodeling)

54
Q

what happens in hematoma formation/inflammation

A

-formation of hematoma at injury site
- cytokines released: TNF alpha, IL-1, -6, -11, and -18
-cytokines lead to recruitment/infiltration of inflammatory cells
-inflammatory cells release more inflammatory cytokines and recruit mesenchymal stem cells/osteogenic precursors to fracture site

55
Q

what happens in the formation of fibrocartilage callus

A
  • MSC/connective tissue stem cells/blood vessels invade hematoma
    -hematoma degenerates/phagocytes clear debris
    -fibrous connective tissue matrix laid down by fibroblasts - granulation tissue
  • MSc differentiation towards chondrogenic/osteogenic lineages
  • hypoxia/tissue necrosis occurs at ends of bones
  • in hypoxic regions MSC differentiate into chondrocytes - initiates endochondral bone formation
    -intramembranous bone may form in subperiosteal sites where vascular supply is intact - hard callus
56
Q

how long does hematoma formation/inflammation last

A

0-2 days

57
Q

how long does formation of fibrocartilagenous callus last

A

about 1 week

58
Q

what are the cell sources of osteogenic precursors

A

-periosteum
-muscle
-bone marrow
-maybe circulating

59
Q

what are the cell types of osteogenic precursors

A

-mesenchymal stem cells (MSC)
- pericyte
- muscle satellite cell

60
Q

what happens in the formation of bony callus

A
  • intramembranous bone contributed to bony callus
  • cartilage undegoes endochondral ossification
  • fracture considered healed when bone stability restored by bone tissue completely bridging the original fracture
    -initial bone formed- woven bone
61
Q

how long does formation of bony callus take

A

several weeks up to 2-3 months

62
Q

what happens in remodeling

A
  • initial woven bone must be remodeled
  • osteoclasts resorb woven bone in fracture callous then osteoblasts lay down new lamellar bone (haversian)
    -restores marrow cavity
    -restores original contours of bone
  • biomechanical stability matches that of the original bone
63
Q

how long does remodeling last

A

several weeks/months/years

64
Q

what does fracture healing include

A

inflammation, endochondral bone formation, intramembranous bone formation, osteoclastic bone resorption

65
Q

what do the early phases of fracture healing include

A

-formation of hematoma
-recruitment of MSC
- cell proliferation
-initation of chondrogenesis/osteogenesis
-vascular ingrowth/angiogensis

66
Q

what are the 3 main categories of signaling molecules important in fracture healing

A

pro-inflammatory cytokines
-TGFbeta superfamily members
- angiogenic factors

67
Q

what do TNF alpha and interleukins 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

68
Q

what are pro-inflammatory cytokines secreted by

A

macrophages, mesenchymal cells, inflammatory cells

69
Q

what are the pro-inflammatory cytokines

A

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

70
Q

what are the TGF beta superfamily members

A

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

71
Q

what do TGF beta superfamily members do

A

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

72
Q

what are TGF beta superfamily members produced by

A

hematoma (platelets)/granulation tissue/differentiating MSC/periosteal callus

73
Q

what are the angiogenic factors

A

VEGF, PDGF, and ANGPT

74
Q

what do angiogenic factors do

A

promote vascular ingrowth from vessels in periosteum - brings pericytes

75
Q

what does VEGF do

A

-promotes chemotaxis of osteoprogenitors
-upregulated in regions of hypoxia (under control of HIF 1 alpha)

76
Q

what does vascularization do

A

-critical for fracture repair/bone formation
-brings in calcium and phosphate for mineralization

77
Q

what could bone repair by enhanced by

A

-improving vascularization
-attracting progenitor cells
-acclerating bone formation
- accelerating remodelin
- BMPs, FGFs, PDGF, platelet rich plasma

78
Q

what cell based therapies might enhance bone repair and formation

A

-autologous bone marrow collected from iliac crest and injected into non union site
-purified stem cell sources

79
Q

what other approaches may be taken to enhance bone formation and reapir

A

-anti resopritves, bone anabolic agnets, gene therapy

80
Q

what are antibodies to sclerostin being developed for

A

anabolic treatment for osteoporosis

Biochem (34 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions