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Applied Biochemistry > Biology of Fracture Healing > Flashcards

Biology of Fracture Healing Flashcards

1
Q

osteoporosis

A

loss of bone bass, often associated with menopause and/or aging

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2
Q

who does osteoporosis affect

A

women and men

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3
Q

osteoporosis is a major medical problem due to (3)

A

aging population, diet, environmental factors

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4
Q

Osteoporosis definition -

A

a patient with a BMD
>2.5 standard deviations below average for a
healthy young female or male.

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5
Q

those with osteoporosis have an increased susceptibility to

A

fracture

causes ?8.9 million fractures annually

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6
Q

Worldwide, — women and — men over 50

will experience osteoporotic fractures

A

1 in 3

1 in 5

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7
Q

Hip fractures associated with mortality rates of up

to

A

20-24% in first year after fracture. Greater risk

of dying may persist for at least 5 years

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8
Q

In Osteoporosis Bone Formation Can’t Keep up

With

A

Bone Destruction and we Lose Bone (Remo

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9
Q

Oral bisphosphonates widely used for treatment of

A

osteoporosis

anti-resorptives

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10
Q

I.V. bisphosphonates used for treatment of

particularly if…

A

myeloma/ bone metastatic cancers (e.g. breast, prostate, lung),
particularly if patients have high serum calcium

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11
Q

Doses used for — treatment often much higher than those used for —

A

cancer

osteoporosis

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12
Q

Bisphosphonates =

A

non-hydrolyzable analogs of

pyrophosphate (PPi) – inhibit mineralization similarly to PPi

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13
Q

bisphosphinates have a high affinity for

A

hydroxyapatite

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14
Q

BONJ

A

Bisphosphonate Associated Osteonecrosis of the Jaw

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15
Q

Vast majority in patients with myeloma/bone metastatic cancers on

A

i.v. bisphosphonates (esp. zoledronate and other N-containing BP’s)

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16
Q

Prevalence = –% in cancer population on BPs

A

2-3

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17
Q

Prevalence in oral BP (osteoporosis patients) = –%

A

0.1-0.5

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18
Q

BONJ affects the (2)

A

maxilla or mandible

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19
Q

BONJ definition (American Association of Oral and Maxillofacial Surgeons [AAOMS]): (3)

A

(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

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20
Q

BONJ Pathogenesis

A

Not fully understood, but attributed mainly to suppression

of bone turnover due to BP inhibition of osteoclast activity

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21
Q

With osteoclast inhibition, bone may be unable to

A

repair in response to trauma

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22
Q

BPs may also have — effects on epithelia

A

inhibitory

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23
Q

Bisphosphonates may also have an inhibitory effect on

A

orthodontic tooth movement

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24
Q

Bone formation during fracture healing recapitulates processes of

A

embryonic bone formation

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25
Q

Four Phases of Skeletal Development

A
  1. Migration of preskeletal cells to sites of future
    skeletogenesis
  2. Interaction of these cells with epithelial cells
  3. Interaction leads to mesenchymal condensation
  4. Followed by differentiation to chondroblasts or
    osteoblasts
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26
Q

Endochondral Bone Formation is —

A

indirect

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27
Q

Indirect in endochondral bone formation because

A

mesenchyme forms cartilage template first, which is later replaced by bone

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28
Q

where does endochondral bone formation occur?

A

in most bones in the skeleton

esp bones that ear weight and have joints

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29
Q

endochondral bone formation also occurs during

A

fracture repair

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30
Q

Intramembranous Bone Formation is —

A

direct

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31
Q

intramembranous bone formation is direct because it involves

A

transformation of mesenchymal cells to osteoblasts (no cartilage intermediate)

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32
Q

where does intramembranous bone formation occur? (3)

A

restricted to cranial vault, some facial bones, parts of the mandible and clavicle

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33
Q

intramembranous bone formation contributes to

A

fracture repair

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34
Q

in endochondral bone formation (typically long bone)
Growth plate fusion occurs around age —
in humans depending on the (2)

A

14-20

specific bone and the gender of the individual

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35
Q

in endochondral bone formation (typically long bone)

Vascular endothelial growth factor (VEGF) produced by hypertrophic chondrocytes attracts

A

blood vessels that invade the cartilage model

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36
Q

in endochondral bone formation (typically long bone)

Secondary ossification center appears around the time of —

A

birth

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37
Q

in intramembranous bone formation, mesenchymal cells condense to produce —, which

A 
osteoblasts
deposit osteoid (unmineralized) bone matrix
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38
Q

in intramembranous bone formation, osteoid matrix calcifies/osteoblasts become arranged along
calcified region of the

A

matrix

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39
Q

some osteoblasts trapped in bone matrix, which become

A

osteocytes

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40
Q

First type of bone produced developmentally =

A

Woven Bone (a.k.a. Primary Bone) (immature)

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41
Q

when is woven bone produced?

A

when osteoblasts need to form bone rapidly

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42
Q

examples of when woven bone is formed (3)

A

embryonic development
fracture healing
disease states (ex pagets disease)

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43
Q

Immature woven bone then remodeled and replaced with

A

Lamellar Bone (a.k.a. Secondary Bone) (mature)

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44
Q

woven bone (4)

A 
•Disorganized structure
•Collagen fibrils in random 
orientation  (lower 
birefringence w/ polarized 
light)
•Increased cell density
•Reduced mineral content
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45
Q

lamellar bone (4)

A 
•Highly organized 
•Bone lamellae concentrically 
arranged around central canal 
(Haversian canal) containing 
blood vessels, nerves.
•Collagen fibrils in parallel 
orientation  (more birefringence 
w/ polarized light)
•Mechanically stronger
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46
Q

Secondary bone = further classified into (2)

A

Compact (cortical) Bone and Cancellous (trabecular/spongy) Bone

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47
Q

Compact

A

cortical/

Haversian

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48
Q

Cancellous

A

spongy/

trabecular

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49
Q

Skeletal healing essential for: (3)

A

•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.

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50
Q 
Development of new treatments to promote
healing of (3)
A

fibrous non-unions,
critically sized defects,
conditions of impaired healing.

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51
Q

Failed/delayed healing affects up to –% of

fracture patients seen clinically

A

10

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52
Q

Can result from inadequate (6)

A 
fixation, 
infection, 
tumor, 
hypoxia/poor blood supply, 
metabolic dysfunction, 
chronic diseases/inherited diseases
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53
Q

Fracture Healing Requires Coordinated

Activity of Several Cell Types: (5)

A
  • Inflammatory Cells
  • Chondroprogenitors/chondrocytes
  • Osteoprogenitors/osteoblasts
  • Osteoclasts
  • Vascular cells
54
Q

Inflammatory (Reactive) phase:

A

peaks by 48h and is

diminished by 1 week

55
Q

Reparative phase:

A

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

56
Q

Remodeling phase:

A

can continue for

several years

57
Q 
John Hunter (1935) - Described 4 stages of 
fracture repair:
A

reactive: 1) Formation of vascular hematoma
reparative: 2) Formation of (fibrocartilage)
callus
repairative: 3) Tissue metaplasia – callus
replaced by mineralized bone
remodeling: 4) Bone remodeling and turnover

58
Q

Fracture trauma causes

A

bleeding/formation of hematoma at injury site

59
Q

Hematoma-associated cytokines

released: (2)

A

Tumor necrosis factor-α (TNF-α )

Interleukins (IL-1,-6, -11 and -18)

60
Q

Cytokines lead to recruitment/infiltration

of

A

inflammatory cells

61
Q

Inflammatory cells release more — and recruit — to fracture site

A

inflammatory cytokines

mesenchymal stem cells (MSC)/osteogenic precursors

62
Q

Hematoma Formation/Inflammation occurs within

A

0-2 days

63
Q

MSC/connective tissue stem cells/blood

vessels invade —

A

hematoma

64
Q

Hematoma —/Phagocytes

clear —

A

degenerates

debris

65
Q

Fibrous connective tissue matrix laid

down by

A

fibroblasts (granulation tissue)

66
Q

Some MSC differentiate toward — lineages

A

chondrogenic/osteogenic

67
Q

At broken ends of bones where blood

supply was disrupted — occurs

A

hypoxia/ tissue necrosis

68
Q

In hypoxic regions MSC differentiate into

— which initiates —

A

chondrocytes

endochondral bone formation

69
Q

Intramembranous bone may form in
subperiosteal sites where vascular supply
is intact =

A

hard (external) callus

70
Q

formation of fibrocartilagenous callus takes

A

~1 week

71
Q

Cell sources (4)

A
  • Periosteum
  • Muscle
  • Bone Marrow
  • Circulating?
72
Q

Cell types (3)

A
  • Mesenchymal Stem Cell (MSC)
  • Pericyte
  • Muscle satellite cell
73
Q 
Intramembranous bone (formed where 
vascular supply intact) contributes to
A

bony

callus

74
Q

Cartilage undergoes — —

A

endochondral

ossification

75
Q

endochondral

ossification

A

hypertrophy>calcification of
cartilage>removal by osteoclasts>
replacement with bone

76
Q

Fracture considered healed when

A

bone stability restored by bone tissue
completely bridging the original fracture
(“clinical union”)

77
Q

Initial bone formed =

A

woven bone

78
Q

Formation of Bony Callus takes

A

~several weeks up to 2-3 months

79
Q

Initial woven bone must be —

A

remodeled

80
Q

Osteoclasts resorb woven bone in
fracture callous then osteoblasts lay
down new lamellar bone (Haversian) =

A

mechanically stronger

81
Q

remodeling restores

A

marrow cavity

82
Q

remodeling resortes

A

original contours of bone

83
Q

Biomechanical stability matches that of

the — bone

A

original

84
Q

Same sequence of fracture healing events

occurs for

A

healing of alveolar bone in

tooth socket after tooth extraction

85
Q

remodeling takes

A

~several weeks/months/years

86
Q

Gene expression profiles/signaling molecules important during

A

fracture healing

87
Q

Fracture healing includes (4)

A

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

88
Q

Gene expression profile =
— dependent
reflective of these —

A

stage dependent

and reflective of these processes

89
Q

Early Phases of Fracure Healing Include: (5)

A
  • Formation of hematoma
  • Recruitment of MSC
  • Cell proliferation
  • Initiation of chondrogenesis/osteogenesis
  • Vascular ingrowth/angiogenesis
90
Q

Signaling Molecules Important in
Fracture Healing:
3 Main categories:

A
  • Pro-inflammatory cytokines
  • TGFβ superfamily members
  • Angiogenic factors
91
Q

pro-inflammatory cytokines (4)

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

92
Q

pro inflammatory cytokines are secreted by (3)

A

macrophages,
mesenchymal cells,
inflammatory cells

93
Q

Mice null for TNF-α receptor show impaired

A

fracture healing

94
Q

Pro-Inflammatory Cytokines (2)

A

Tumor necrosis factor-α (TNF-α)

Interleukins (IL-1,-6, -11 and -18)

95
Q

TGFβ Superfamily Members (3)

A

Transforming growth factor-β (TGFβ)
Bone morphogenetic protein-2 BMP2 (also 5,6)
Growth and differentiation factor-8 (GDF-8)

96
Q

TGFβ Superfamily Members promote (3)

A

− Promote ECM synthesis & assembly/initiation of callus formation
− Promote osteogenic differentiation
− GDF-8 – role in cell proliferation

97
Q

TGFβ Superfamily Members produced by (4)

A

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

98
Q

angiogenic factors (3)

A

VEGF - Vascular endothelial growth factor
PDGF - Platelet derived growth factor
ANGPT - Angiopoietin

99
Q

Promote vascular ingrowth from vessels in

A

periosteum (brings oxygen/osteogenic precursors [pericytes])

100
Q

VEGF:
−promotes — of osteoprogenitors
−upregulated in regions of — (under control of
transcription factor HIF1α)
−— overexpressing mice show enhanced bone
regeneration (Wan et al 2008: PNAS 105:686-91)

A

chemotaxis
hypoxia
HIF1α

101
Q

Vascularization is critical for

A

fracture repair/bone formation

102
Q

vascularization brings in (2) for mineralization

A

calcium and phosphate

103
Q

Factors regulating other aspects of fracture

healing: (3)

A
  • Osteoblastic bone formation
  • Osteoclastic bone resorption
  • Cartilage formation
104
Q

Fracture stability (mechanical environment) dictates the type of — that will occur

A

healing

105
Q

— — determines mechanical strain in fracture site

A

Mechanical stability

106
Q

If strain <2% — — — will occur

A

intramembranous bone healing

107
Q

If strain is >2% <10% — — — will occur

A

endochondral bone healing

108
Q

High strain >15% promotes — —

A

fibrous tissue

109
Q

Healing may occur as combination of the above processes depending on

A

stability throughout the fracture healing process

110
Q

Important to stabilize fracture, but still have some strain on the bone, as zero mechanical loading can

A

delay healing

111
Q

Bone Repair Could be Enhanced by: (4)

A
  • Improving vascularization
  • Attracting progenitor cells
  • Accelerating bone formation
  • Accelerating remodeling
112
Q

BMPs (recombinant) are evaluated in

A

preclinical and clinical trials

113
Q

BMPs appear to be an effective alternative to

A

autologous bone graft for repair of fracture non union/open tibial fractures

114
Q

Controversy about clinical use of BMPs due to (2)

A

cost

effectiveness and potential safety drawbacks

115
Q

Platelet Rich Plasma contains

A

multiple growth factors

116
Q

Platelet Rich Plasma is evaluated in

A

preclinical and clinical trials

117
Q

Platelet Rich Plasma also appears to be effective in

A

promoting bone healing

118
Q

FGF signaling also important in (2)

A

skeletal development/fracture healing

119
Q

— – shown to enhance
fracture healing in various in vivo experiments
dating back to 1990s

A

FGF2 (a.k.a. basic FGF)

120
Q

But – continued elevation of FGF2 may impair
mineralization, so — of treatment needs to be
optimized

A

timing

121
Q

— is also promising in preclinical studies

A

PDGF

123
Q

cell based therapies (2)

A

Autologous bone marrow
Purified stem cell sources (MSC-mesenchymal
stem cells, EPC - endothelial progenitor cells)

124
Q

Combining these growth factors with — — — may lead to further improvements

A

tissue engineering techniques

124
Q

cell based therapies (2)

A

Autologous bone marrow
Purified stem cell sources (MSC-mesenchymal
stem cells, EPC - endothelial progenitor cells)

125
Q

Autologous bone marrow – collected from

A

iliac crest/injected into non-union site (increases #

of progenitor cells)

126
Q

cell based therapies (2)

A

Autologous bone marrow
Purified stem cell sources (MSC-mesenchymal
stem cells, EPC - endothelial progenitor cells)

127
Q

other approaches (3)

A
  • Anti-resorptives (bisphosphonates, denosumab)
  • Bone anabolic agents (sclerostin Abs, teriparitide)
  • (Gene therapy) – [still experimental]
128
Q

Sclerostin =

A

inhibitor of Wnt/β-catenin signaling

important pathway for bone formation

129
Q

Antibodies to sclerostin being developed as

A

anabolic treatment for osteoporosis (in clinical

trials)

130
Q

sclerotin is also evaluated in

A

fracture healing preclinical models – results very promising

131
Q

sclerostin Abs enhanced bone regeneration in rat model of —

A

periodontitis

Applied Biochemistry (52 decks)

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