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Biochemistry (Cole) > Lecture 44 Biology of Fracture Healing > Flashcards

Lecture 44 Biology of Fracture Healing Flashcards

1
Q

What are the four phases of skeletal development?

A
  • Migration (of preskeletal cells to sites of future skeltogenesis)
  • Epithelial- mesenchymal interaction
  • condensation (of mesenchymal cells)
  • Differentiation (into odontoblasts and chondrocytes)
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2
Q

What are the two types of bone formation?

A
  • Endochondral bone formation

- Intramembranous Bone Formation

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3
Q

What is endochondral bone formation?

A
  • Indirect (mesenchyme forms cartilage template first which is later replaced by bone)
  • occurs in most bones in the skeleton esp. bones that bear weight and have joints
  • also occurs during fracture repair
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4
Q

What is intramembranous bone formation?

A
  • direct transformation of mesenchymal cells to osteoblasts (no cartilage intermediate)
  • restricted to cranial vault, some facial bones, parts of the mandible and clavicle
  • contributes to fracture repair
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5
Q

When do secondary ossification centers appear?

A
  • around the time of birth
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6
Q

What produces VEGF and what does it do?

A
  • hypertrophic chondrocytes

- attracts blood vessels that invade the cartilage model

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7
Q

When does growth plate fusion occur?

A
  • around age 14-20 in humans
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8
Q

How do the flat bones of the skull form?

A
  • intramembranous bone formation
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9
Q

What is the process of intramembranous bone formation?

A
  • mesenchymal cells condense to produce osteoblasts which deposit osteoid (unmineralized) bone matrix
  • osteoid matrix calcifies/osteoblasts become arrangled along calcified region of the matrix
  • some osteoblasts trapped in bone matrix- become osteocytes
  • NO CARTILAGE MODEL PRECEDING THE BONE
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10
Q

What is the immature bone that is produced first?

A
  • woven bone aka primary bone (immature)
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11
Q

Woven bone is produced when osteoblasts need to form bone rapidly in situations like:

A
  • embryonic development
  • fracture healing
  • disease states (paget’s disease)
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12
Q

What is immature woven bone remodeled and replaced with?

A
  • Lamellar bone (aka secondary bone) (mature)
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13
Q

What are the features of woven bone?

A
  • disorganized structure
  • collagen fibrils in random orientation (lower birefringence w/polarized light)
  • increased cell density
  • reduced mineral content
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14
Q

What are the features of lamellar bone?

A
  • highly organized
  • bone lamellae concentrically arranged around central canal containing blood vessels and nerves
  • collagen fibrils in parallel orientation (more birefringence w/polarized light)
  • mechanically stronger
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15
Q

What can lamellar bone be further classified into?

A
  • Compact
    (cortical/haversian)
  • cancellous (spongy/trabecular)
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16
Q

What type of bone is the bone marrow located in?

A
  • cancellous bone
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17
Q

What is skeletal healing essential 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
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18
Q

Fracture healing requires coordinated activity of several cell types:

A
  • inflammatory cells
  • chondroprogenitors/chondrocytes
  • osteoprogenitors
  • osteoclasts
  • vascular cells
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19
Q

What is the timeline of the inflammatory phase?

A
  • peaks at 48 hrs and is diminished by 1 week
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20
Q

What is the timeline of the reparative phase?

A
  • activated within a few days and persists for up to 2-3 months
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21
Q

What is the timeline of the remodeling phase?

A
  • can continue for several years
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22
Q

John hunter (1935) described the 4 stages of fracture repair as what?

A
  1. Formation of vascular hematoma
  2. Formation of (fibrocartilage) callus
  3. Tissue metaplasia- callus replaced by mineralized bone
  4. Bone remodeling and turnover
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23
Q

What are the cytokines that the hematoma releases in the hematoma formation/inflammation phase?

A
  • Tumor necrosis factor a (TNF-a)

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

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24
Q

What do the cytokines do?

A
  • lead to recruitment/infiltration of inflammatory cells
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25
Q

What do the inflammatory cells do?

A
  • release more inflammatory cytokines and recruit mesenchymal stem cells (MSC)/osteogenic precursors to fracture site
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26
Q

What happens during formation of fibrocartilagenous 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)
  • some MSC differentiate towards chondrogenic/osteogenic lineages
  • at borken ends of bones where blood supply was disrupted hypoxia/tissue necrosis occurs
  • in hypoxic regions MSC differentiate into chondrocytes
  • intramembranous bone may form in subperiosteal sites where vascular supply is intact= hard (external) callus
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27
Q

What initiates endochondral bone formation?

A
  • MSC differentiating into chondrocytes
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28
Q

What are the cell sources of osteogenic precursors?

A
  • periosteum
  • muscle
  • bone marrow
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29
Q

What are the cell types of osteogenic precursors?

A
  • mesenchymal stem cell (MSC)
  • pericyte
  • muscle satellite cell
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30
Q

How does the bony callus form?

A
  • intramembranous bone (formed where vascular supply is intact) contributes to bony callus
  • ** cartilage under goes endochondral ossification
31
Q

What is endochrondral ossification?

A
  • hypertrophy –>calcification of cartilage –> removal by osteoclasts –> replacement with bone
32
Q

When is the fracture considered healed?

A
  • when bone stability is restored by bone tissue completely bridging the original fracture
    “clinical union”
33
Q

What is the timeline for formation of bony callus?

A
  • several weeks up to 2-3 months
34
Q

how long does formation of fibrocartilagenous callus take?

A
  • 1 week
35
Q

How quickly does the hematoma form at the fracture site?

A
  • 0-2 days
36
Q

T/F the remodeling phase of bone repair can last years

A
  • T
37
Q

What is the process of remodeling?

A
  • osteoclasts resorb woven bone in fracture callous then osteoblasts lay down new lamellar bone (haversian) which is mechanically stronger
38
Q

T/F same sequence of fracture healing events occurs for healing of alveolar bone in tooth socket after tooth extraction

A
  • T
39
Q

Early phase of fracture healing include?

A
  • Formation of hematoma
  • recruitment of MSC
  • cell proliferation
  • initiation of chondrogenesis/osteogenesis
  • vascular ingrowth/angiogenesis
40
Q

Signaling molecules important in the fracture healing?

A
  • pro- inflammatory cytokines
  • TGFB superfamily members
  • angiogenic factors
41
Q

Who secretes the pro-inflammatory cytokines?

A
  • macrophages, mesenchymal cells, inflammatory cells
42
Q

Mice null for TNFa receptor show?

A
  • impaired fracture healing
43
Q

What are the pro-inflammatory cytokines?

A
  • Tumor necrosis factor (TNFa)

- Interluekins

44
Q

What is the function of the pro-inflammatory cytokines?

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
45
Q

What is the TGFB superfamily members job in fracture healing?

A
  • promote ECM synthesis and assembly/initiation of callus formation
  • promote osteogenic differentiation
  • GDF-8 has a role in cell proliferation
46
Q

What are the TGFB superfamily members involved in fracture healing?

A
  • Transforming growth factor B (TGFB)
  • Bone morphogenetic protein-2 BMP2 (also 5,6)
  • Growth and differentiation factor (GDF-8)
47
Q

What produces the TGFB superfamily members?

A
  • produced by hematoma (platelets)/granulation tissue/differentiating MSC/periosteal callus
48
Q

What are the angiogenic factors?

A
  • VEGF- Vascular endothelial growth factor
  • PDGF - platelet derived growth factor
  • ANGPT- Angiopoietin
49
Q

What do the angiogenic factors do?

A
  • promote vascular ingrowth vessels in periostum (brings oxygen/osteogenic precursors [pericytes])
50
Q

VEGF:

A
  • promotes chemotaxis of osteoprogenitors
  • up regulated in regions of hypoxia (under control of transcription factor HIF1a)
  • HIF1a overexpressing mice show enhanced bone regeneration
51
Q

Why is vascularization important? (why are angiogenic factors important)

A
  • critical for fracture repair/bone formation

- brings in calcium and phosphate for mineralization

52
Q

What dictates why type of healing will occur?

A
  • fracture stability (mechanical environment)
53
Q

If strain <2% _______ bone healing will occur

A
  • intramembranous
54
Q

If strain is >2% <10% _________

A
  • endrochondral bone healing will occur
55
Q

High strain > 15% promotes

A
  • fibrous tissue
56
Q

Bone repair could be enhanced by:

A
  • improving vascularization
  • attracting progenitor cells
  • accelerating bone formation
  • accelerating remodeling
57
Q

How have BMPS been used to help grow bone?

A
  • appear to be effective alternative to autologous bone graft for repair of fracture non union/open tibial fractures
  • controversy about clinical use due to cost effectiveness and potential safety drawbacks
58
Q

Why have platelet rich plasma been tried for osteogenesis?

A
  • contains multiple growth factors
  • evaluated in preclinical and clinical trials
  • appears effective in promoting bone heling
59
Q

Why is FGFs being used for osteogenesis?

A
  • FGF signaling is important in skeletal healing
  • FGF2 shown to enhance fracture healing in various in vivo experiments dating back to 1990s
  • continued elevation of FGF2 may impair mineralization so timing of treatment needs to be optimized
60
Q

What are the cell based therapies for bone growth/healing?

A
  • autologous bone marrow - collected from iliac crest/injected into non-union site (increases # of progenitor cells)
  • purified stem cell sources (MSC- mesenchymal stem cells, EPC- endothelial progenitor cells)
61
Q

Other approaches to bone healing treatments?

A
  • anti resorptives (bisphosphonates, denosumab)
  • bone anabolic agents (sclerostinn abs, teriparitide)
  • gene therapy (still experimental)
62
Q

Sclerostin

A
  • inhibitor of Wnt/b catenin signaling

- anitbodies to sclerostin being developed as anabolic treatment for osteoporosis

63
Q

_____ showed sclerostin abs enhaced bone regeneration in rat model of periodontitis

A
  • Taut
64
Q

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

A
  • osteoporosis definition
65
Q

Is osteoporosis associated with menopause and or aging?

A
  • Yes
66
Q

Osteoporosis facts

A
  • causes > 8.9 million fractures annually
  • worldwide 1 in 3 women and 1 in 5 men over 50 will experience osteoporotic fractures
  • Hip fractures with mortality rates of up to 20-24% in first year after fracture. greater risk of dying may persist for at least 5 years
67
Q

What are the anti resorptive medecines? (prevent further bone degredation)

A
  • amino bishosphonates
  • hormone replacement therapy
  • selective estrogen receptor modulators (SERMS) e.g raloxifene
  • Denosumab
  • Cathepsin K inhibitors
68
Q

What are the anabolic agents?

A
  • PTH 1-84, Teriparitide (PTH 1-34)

- Anti sclerostin antibodies

69
Q

_____ preferentially bind to hydroxyapatite. Inhibit activity of osteoclasts by inhibiting mevalonate pathway important for prenylation of GTPases important for vesicular trafficking

A

-Amino bisphosphonates

70
Q

__________ restores hormone levels following menopause

A
  • Hormone replacement therapy
71
Q

Serms

A
  • work as a partial antagonists of estrogen receptor but mechanism of action not fullly understood
72
Q

Denosumab

A
  • antibody against Rankl (inhibits osteocalst formation)

- comparable efficacy as bishosphonates

73
Q

Cathepsin K inhibitors

A
  • currently in clinical trails (inhibit gone degrading enzyme Cathepsin K)
74
Q

PTH 1-84, Teriparitide (PTH 1-34)

A
  • intermitten administration of teriparatide stimulates bone formation, partly through inhibition of sclerostin

Biochemistry (Cole) (25 decks)

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