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Applied Biochemistry > Osteoclasts, Osteoblasts & Fracture Healing (Exam V) > Flashcards

Osteoclasts, Osteoblasts & Fracture Healing (Exam V) Flashcards

1
Q

What is the origin & lineage of osteoclasts?

A

Hematopoietic origin- macrophage/monocyte lineage

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2
Q

In bone remodeling, this is a process by which mature/damaged bone is removed by osteoclasts & replaced with new one- there is no:

A

Net gain

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3
Q

The process by which bone size/shape is changed by independent action osteoblasts & osteoclasts (adding new bone without prior resorption or removing bone without replacing it)

A

Bone modeling

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4
Q

Bone modeling can occur in response to (2)

A

Longitudinal growth
Response to increase in mechanical loading of the bone

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5
Q

Bone modeling can lead to:

A

Net gain or loss of bone

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6
Q

Disease of impaired osteoclast function that leads to bones that are abnormally dense but brittle & prone to fracture

A

Osteopetrosis

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7
Q

Osteopetrosis leads to bones that are abnormally:

A

Dense but brittle & prone to fracture

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8
Q

Osteopetrosis is caused by mutations in genes important for:

A

Osteoclast resorption

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9
Q

A disease of low bone mass that occurs due to the inability of bone formation to keep up with bone resorption

A

Osteoporosis

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10
Q

Osteoporosis is usually seen in:

A

Post-menopausal women & elderly

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11
Q

Drug that inhibits bone resorption

A

Anti-resorption agent

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12
Q

Drug that stimulates bone formation

A

Bone anabolic agent

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13
Q

A fancy word for bone that is dead & does not have any viable osteocytes

A

Osteonecrotic bone

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14
Q

A complication of bone fracture n which the bone does not heal

A

Non-union

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15
Q

A disorganized network of cartilage/woven bone formed between the ends of the broken bone & extending beyond the original contour

A

Fracture callus

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16
Q

In a fracture callus, the callus is ultimately replaced by ____ following ____

A

Lamellar bone
Remodeling

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17
Q

A fancy word for blood clot

A

Hematoma

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18
Q

A tissue containing newly formed vascular tissue & fibrous extracellular matrix usually formed in healing wounds

A

Granulation tissue

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19
Q

A cell that is present in the wall of capillaries & has mesenchymal subcell properties since it can differentiate into other cell types such as muscle, fibroblasts & osteocytes

A

Pericyte

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20
Q

Pericytes can differentiate into:

A

Muscle, fibroblasts & osteoblast

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21
Q

Small cells found in the mature muscle that have stem cell-like properties & provide a source of progenitors for formation of muscle cells, especially in situations of muscle injury/repair

A

Muscle satellite cell

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22
Q

Muscle satellite cells may be able to differentiate into:

A

Osteoblasts

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23
Q

The ability to form cartilage

A

Chondrogenic

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24
Q

The ability to form bone

A

Osteogenic

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25
Q

The formation of new blood vessels from the outgrowth of pre-existing blood vessels

A

Angiogenesis

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26
Q

When new blood vessels form de novo

A

Vasculogenesis

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27
Q

A superfamily of structurally & evolutionarily relate proteins that include the transforming growth factor betas (TGFB), the bone morphogenic proteins (BMPs), activism, inhibins, & growth & differentiation factors (GDFs)

A

Transforming growth family beta superfamily

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28
Q

Transforming beta growth factor superfamily are structurally & evolutionarily related proteins that include (4):

A

1- TGF betas
2- BMPs
3- Activins/Inhibins
4- Growth/Differentiation factors

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29
Q

Osteoclasts express ____ for removing ____

A

Proteases
ECM proteins

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30
Q

Osteoclasts express proteins that act as ______ to generate ______ to (reduce the pH to dissolve minerals)

A

Proton pumps
H+ ions

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31
Q

Active osteoclasts have specialized ______ to increase surfaces area in the resorption compartment

A

Ruffled border

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32
Q

Life’s span of osteoclasts

A

Short (days)

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33
Q

Osteoclasts are bone resorbing cells responsible for:

  1. Bone resorption during _____ & _____
  2. Removal of _____ during tooth eruption
  3. Resorption of ____ of _____ teeth
  4. Removal of ____ during ____ movement
  5. Bone loss in _____
A
  1. Normal bone growth & remodeling
  2. Alveolar bone
  3. Tooth roots; primary teeth
  4. Alveolar bone; orthodontic tooth
  5. Pathological conditions
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34
Q

Must occur to maintain bone shape:

A

Modeling

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35
Q

Osteoclasts originally come from:

A

Hematopoietic stem cell (HSC)

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36
Q

During osteoclast differentiation- the hematopoietic stem cell (HSC) will differentiate into:

A

CFU-M

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37
Q

During osteoblast differentiation:

HSC —-> CFU-M —> _______

A

Monocyte

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38
Q

During osteoblast differentiation:

HSC —-> CFU-M —> Monocyte —> ______

A

Mononucleated osteoclast (pre-fusion)

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39
Q

During osteoblast differentiation:

HSC —-> CFU-M —> monocyte —> mononucleated osteoclast —-> _____

A

Multinucleated osteoclast

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40
Q

During osteoblast differentiation:

HSC —-> CFU-M —> monocyte —> multinucleated osteoclast —-> ____

A

Resorbing osteoclast

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41
Q

What is the master transcription factor of osteoclast formation?

A

NFATc1

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42
Q

Osteoclast marker genes are associated with the functions of the cell which include (4):

A
  1. Fusion
  2. Adherence to bone surface
  3. Acid production
  4. Protease production
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43
Q

Which transcription factors are downstream of NFATc1:

A

C-fos & NFKB

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44
Q

There are two factors produced by osteoblasts/osteocytes that are essential for:

A

Osteoclast differentiation

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45
Q

The two factors produced by osteoblasts/osteocytes that are essential for OCL differentiation include:

A

1- RANKL
2. M-CSF (also known as CSF-1)

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46
Q

RANKL is a receptor activator of:

A

NFKB ligand

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47
Q

M-CSF (aka CSF-1) is a _____ stimulating factor

A

Macrophage colony

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48
Q

Promotes proliferation/survival of osteoclast precursors:

A

M-CSF

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49
Q

Member of the TNF superfamily- required for osteoclast fusion & differentiation

A

RANKL

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50
Q

Natural inhibitor of RANK; a decoy receptor

A

OPG

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51
Q

Master transcription factor that controls osteoclast differentiation

A

NFATc1

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52
Q

The following osteoclast marker proteins falls under what category:

NFATc1
C-fos
NFkB

A

Transcription factors

53
Q

The following osteoclast marker proteins falls under what category:

Tartrate resistant acid phosphatase (TRAP)

54
Q

The following osteoclast marker proteins falls under what category:

RANK
C-f s
Calcitonin receptor
Integrin- aVB3

55
Q

The receptor for

RANKL=
C-fms=

A

RANKL
M-CSF

56
Q

The following osteoclast marker proteins falls under what category:

Carbons anhydrase II
Vascular-type ATPase

A

Generates protons/ proton pump

57
Q

The following osteoclast marker proteins falls under what category:

Cathespsin k
MMP9, MMP13

58
Q

Osteoclast attach via ______ to form a sealed zone

A

Alpha-v-beta-3 integrins

59
Q

In a mature resorbing osteoclast, carbonic anhydrase II (CAII) functions to:

A

Generate protons

60
Q

Vacuolar-type H+ ATPase pumps protons into _____ which creates acid to ____

A

Resorption lacuna
Dissolve mineral

61
Q

____ & ____ are exchangers o9n basolateral surface to remove excess bicarb

62
Q

In the mature resorbing osteoclast _____ maintains the charge neutrality

A

Chloride channel

63
Q

______ is release into the resorption lacuna to digest matrix proteins

A

Cathepsin K

64
Q

Impaired osteoclast function leases to:

A

Osteopetrosis

65
Q

Osteopetrosis can be due to failure in osteoclast ____ or osteoclast form normally but have impaired:

A

Formation
Resorptive function

66
Q

The two major clinical forms of Osteopetrosis include:

A

Autosomal dominant
Autosomal recessive

67
Q

Describe the autosomal dominant form of Osteopetrosis:

A

Adult benign type- relatively few symptoms

68
Q

Describe the autosomal recessive form of Osteopetrosis

A

Infantile malignant type- typically fatal (if untreated) in early childhood

69
Q

In patients with Osteopetrosis, their bone are:

A

Abnormally dense & prone to fracture

70
Q

Failed osteoclastic resorption affects (3):

A

Bone growth
Remodeling
Tooth eruption

71
Q

Osteopetrosis can be accompanied by (8):

A
  1. Scoliosis
  2. Nerve compression in head/face (hearing loss/blindness)
  3. Impaired marrow function (anemia)
  4. Enlarged liver or spleen
  5. Dental abnormalities
  6. Short stature
  7. Slow growth
  8. Recurrent infections
72
Q

In Osteopetrosis there are more than 60 mutations identified in gene TCIRG1 encoding _____ of vaculolar _____

This accounts for about 50% of _____ Osteopetrosis in humans

A

Alpha-3 subunit ; H+ ATPase
Autosomal recessive

73
Q

Mutations that account for about 75% of the AD forms of Osteopetrosis in humans are caused by mutations in the gene ClC7 which is associated with the:

A

Chloride channel

74
Q

Pycnodysostosis is a specific from of Osteopetrosis caused by mutations in:

A

Cathepsin K

75
Q

What are the three genes that if mutated result in a form of Osteopetrosis:

A

TCIRG1
CLCN7
Cathepsin K

76
Q

The TCIRG1 gene that gives rise to AR Osteopetrosis is associated with:

The CLCN7 gene that gives rise to AD Osteopetrosis is associated with:

A

Vacuolar ATPase alpha subunit

Chloride channel

77
Q

What factors can contribute to osteoporosis (3):

A

Aging population
Diet
Environmental factors

78
Q

Osteoporosis is defined by a patient with a BMF of greater than ____ standard deviations below average for a healthy young person

79
Q

Worldwide 1 in ___ women & 1 in ____ men over the age of 50 will experience osteoporotic factors

80
Q

Hip fractures associated with osteoporosis are associated with mortality rates of up to _____ in the first year after fracture & a greater risk of dying may persist for atleast ____

A

20-24%
5 years

81
Q

Treatments of osteoporosis can be directed at reducing _____, simulating ____ or both

A

Bone resorption
Bone formation

82
Q

Treatments for osteoporosis:

Preferentially bind to hydroxyapatite. Inhibit osteoclast activity by inhibiting mevolonate pathway that is important in prenylation of GTPases

A

Amino bisphosphonates

83
Q

Treatments for osteoporosis:

Restores hormone levels following menopause

A

Hormone replacement therapy (estrogen/progesterone)

84
Q

Osteoporosis treatment that is an antibody of RANKL - Inhibits osteoclast formation

85
Q

Osteoporosis mediation that is currently in clinical trial - functions by inhibiting bone degreding rnzyne Cathepsin K

A

Cathepsin K inhibitors

86
Q

Osteoporosis patients may also be treated with anabolic agents:

What anabolic agent is administered intermittently to stimulate bone formation, partly through the inhibition of sclerostin?

A

PTH (1-84 & 1-34)

87
Q

Anabolic agent that is an exciting new therapeutic agent under clinical trials due to its dramatic bone formation- however a recent concern has arose for potential cardiovascular side effects

A

Anti-sclerostin antibodies

88
Q

Oral bisphosphonates are widely used for treatment of osteoporosis as they function as ______

A

Anti-resorptives

89
Q

Bisphosphonates can also be given in a stronger IV dose for treatments of ______ , particularly if patient have high serum calcium

A

Myeloma/bone metastatic cancers (breast, prostate, lung)

90
Q

Non-hydrolyzation analogs of Pyrophosphate

A

Bisphosphonates

91
Q

Bisphosphonates have a high affinity for:

A

Hydroxyapatite

92
Q

Condition that affects the maxilla or mandible-associated with use of high dose (likely for cancer treatment) bisphosphonates that affects the 2-3% in the cancer population on BPs

A

Osteonecrosis of the jaw

93
Q

BONJ is not fully understood but is attributed manly to:

A

Suppression of bone turnover due to BP inhibition of osteoclast activity

94
Q

Skeletal healing is important for:

  1. Resolution of _____ that has caused ____
  2. Healing of corrective surgery’s where _____are created intentially to correct bone deformities
  3. ______ in oral surgical procedures/tooth extractions etc.
A
  1. Orthopedic trauma; fractures
  2. Bone injuries
  3. Bone regeneration
95
Q

The bone formation process that occurs in a fracture callus recapitulates the process of:

A

Embryonic bone formation (endochondral & intramembranous)

96
Q

Fracture healing requires coordinated activities of what cells (5):

A
  1. Inflammatory cells
  2. Chondroprogenitors/chondrocytes
  3. Osteoprogenitors/osteoblasts
  4. Osteoclasts
  5. Vascular cells
97
Q

Timeline of fracture healing:

  1. Phase that peaks by 48 hours & is diminished by 1 week
A

Inflammatory

98
Q

Timeline of fracture healing:

Phase that is activated within a few days & persists for up to 2-3 months

A

Reparative phase

99
Q

Timeline of fracture healing:

Phase that can continue for several years

A

Remodeling

100
Q

List the phases of fracture healing in the right order

A

Inflammatory (Reactive) phase
Reparative phase
Remodeling phase

101
Q

What is the first step (reactive/inflammatory phase) in the fracture repair process?

A

1- Formation of a vascular hematoma

102
Q

What occurs in the first part of the reparative phase in fracture repair?

What occurs in the second part of the reparative phase?

A

2a. Formation of a fibrocartilage callus

2b. Tissue metaplasia- callus is replaced by mineralized bone

103
Q

What occurs in the remodeling phase of fracture repair?

A

Bone remodeling & turnover

104
Q

Fracture repair- hematoma formation/inflammation stage (0-2 days)

  1. Fracture trauma causes:
  2. ______ are realeased
  3. Cytokines lead tot he recruitment/infiltration of:
  4. Inflammatory cells release more inflammatory cytokines & recruit (2) to the fracture site
A
  1. Bleeding/formation of hematoma at injury site
  2. Hematoma-associated cytokines are released (Tumor necrosis factor alpha & interleukins (-1, -6, -11, 18)
  3. Inflammatory cells
  4. Mesenchymal stem cells/ osteogenic precursors
105
Q

Fracture repair- formation of Fibrocartilagenous callus

  1. _____ invade the hematoma
  2. Hematoma degenerates & ____ clear debris
  3. Fibrous connective tissue matrix called _____ is layed down by _____
    4.Some MSC differentiates towards ______ lineages
  4. At broken ends of bones where blood supply was disrupted _____/______ occurs
  5. In hypoxic regions ____ differentates to ____ & initates endochondral bone formation
A
  1. MSC/Connective tissue stem cells/blood vessels
  2. Phagocytes
  3. Granulation tissue ; fibroblast
  4. Chondrogenic/osteogenic
  5. Hypoxia/tissue necrosis
  6. MSC; Chondrocytes
106
Q

Cell sources osteogenic precursors (4):

Cell types of osteogenic precursors (3):

A

1- periosteum
2- muscle
3- bone marrow
4- circulate (?)

1- mesenchymal stem cell
2- pericyte
3- muscle satellite cell

107
Q

Fracture repair- formation of bony callus

______ Bone formation is initiated mainly in areas that are more _______ & _______ bone formation occurs in regions where the vascular supply is _______

The fracture is considered to be healed when:

A

Endochondral
Hypoxia
Intramembranous
Better preserved

Bone stability is restored with complete bridging of original fracture

108
Q

Fracture repair- Remodeling- several weeks/months/years

  1. Initial ______ bone must be remodeled
  2. Osteoclasts ______ in the fracture callous
  3. Osteoblast lay down new ____ bone that is mechanically _____
  4. Restores _______ & original _____ of bone
  5. _____ matches that of the original bone
A
  1. Woven
  2. Resorb; lamellar; stronger
  3. Marrow cavity; contours
  4. Biomechanical stability
109
Q

The same sequence of fracture healing events occurs for healing of:

A

Alveolar bone in tooth socket after fracture

110
Q

Fracture healing includes (4):

A

1- inflammation
2- endochondral bone formation
3- intramembranous bone formation
4- Osteoclastic bone resorption

111
Q

During fracture healing what is stage dependent & reflective of the fracture healing processes

A

Gene expression profile

112
Q

Key signaling molecules that regulate fracture healing include (general sense):

A

1- inflammatory cytokines
2- TGFbeta supferfamily members
3. Mediators of angiogenesis

113
Q

What specific inflammatory cytokines act as key signaling molecules during fracture repair?

A

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

114
Q

Which members of the TBF-beta superfamily act as key signaling molecules during fracture repair?

A

TGF-beta
BMPs
GDF-8

115
Q

What mediators of angiogenesis act as key signaling molecules during fracture repair?

A

VEGF
PDGF
Angiopoietin

116
Q
  • recruit inflammatory cells, promote MSC recruitment
  • induce apoptosis of hypertrophic chondrocytes
  • recruit fibrogenic cells/promotes formation of granular tissue/ECM formation
  • can promote osteoclast formation

These are all indicative of what:

A

Pro-inflammatory cytokines

117
Q

The pro-inflammatory cytokines in fracture repair are secreted by:

A

Macrophages
Mesenchymal cells
Inflammatory cells

118
Q
  • Promote ECM synthesis & assembly/intiation of callus formation
  • Promote osteogenic differentiation
  • GDF-8 role in cell proliferation

These are indicative of:

A

TGF-beta superfamily

119
Q

The TGF beta superfamily members involved in fracture repair are produced by:

A

Hematoma (platelets)
Granulation tissue
Differentiating MSC
Periosteal callus

120
Q
  • promote vascular ingrowth from vessels in periosteum (brings oxygen/osteogenic precursors [pericytes])

This is a function of:

A

Angiogenic factors

121
Q

What is critical for bone repair/formation & brings in calcium & phosphate for mineralization

A

Vascularization

122
Q

VEGF
1. promotes _______ of osteoprogenitors
2. ______ in regions of hypoxia

A
  1. Chemotaxis
  2. Unregulated
123
Q

Bone respair could be enhanced by (4):

This is an active area of research

A
  1. Improving vascularization
  2. Attracting progenitor cells
  3. Accelerating bone formation
  4. Accelerating remodeling
124
Q

Potential enhancer in bone repair:

Evaluated in clinical trials, appear to be affective alternative to autologous bone graft repair of fracture nonunion/open tibial fractures but controversial as far as clinical use due to cost & safety drawbacks

A

Recombinant BMPs

125
Q

Potential enhancer in bone repair:

Contains multiple growth factors, & appears to be effective in promoting bone healing

A

Platelet rich plasma

126
Q

Potential enhancer in bone repair:

Important in aspects of signaling in skeletal development/fracture healing, but continued elevation of this may impair mineralization so timing would need to be optimized

127
Q

What cell-based therapies could potentially enhance bone repair:

A
  1. Autologous bone marrow
  2. Purified stem cell sources
128
Q

Because sclerostin is an inhibitor of Wnt/Beta-catenin signaling- which is an important pathway for bone formation, _________ are being developed as anabolic treatments for osteoporosis with promising results

A

Anti-sclerostin antibodies

Applied Biochemistry (18 decks)

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