Biology of Fracture Healing

Question 1

What are the four phases of skeletal development?

Answer 1

1. Migration
2. Epithelial-Mesenchymal Interaction
3. Condensation
4. Differentiation

Question 2

What interaction leads to the formation of condensed mesenchymal cells in skeletal development?

Answer 2

the interaction of epithelial and mesenchymal cells

Question 3

The interaction of epithelial cells and mesenchymal cells leads to what phase in skeletal development?

Answer 3

mesenchymal condensation

Question 4

What is the “indirect” way of forming bone?

Answer 4

through endochondral bone formation

Question 5

What is the “direct” way of forming bone?

Answer 5

through intramembranous bone formation

Question 6

Which type of bone formation forms a cartilage template first and then is later replaced by bone?

Answer 6

endochondral bone formation

Question 7

What type of bone formation directly transforms mesenchymal cells into osteblasts?

Answer 7

intramembranous bone formation

Question 8

What type of bone formation occurs in most types of bone, especially those that bear weight or have joints?

Answer 8

endochondral bone formation

Question 9

Which type of bone formation contributes to fracture repair?

Answer 9

BOTH

Question 10

The formation of what structure allows the hypertrophy of chondrocytes to occur?

Answer 10

sleeve of bone

Question 11

What type of chondrocytes release VEGF?

Answer 11

hypertrophic chondrocytes

Question 12

When do secondary ossification centers appear?

Answer 12

around the time of birth

Question 13

What bones undergo intramembranous bone formation?

Answer 13

flat bones of the skull; mandible

Question 14

____ are directly differentiated from mesenchymal cells in intramembranous bone formation, and begin to deposit ____ bone matrix.

Answer 14

Osteoblasts; osteoid

Question 15

What type of bone is the first type of bone produced developmentally?

Answer 15

woven bone

Question 16

What type of bone is woven bone?

Answer 16

immature bone

Question 17

What type of bone is produced when osteoblasts need to produce bone rapidly, like in embryonic development, fracture healing, or disease states such as Paget’s?

Answer 17

woven bone

Question 18

What type of mature bone is produced from remodeled bone?

Answer 18

lamellar bone

Question 19

What are the characteristics of woven bone?

Answer 19

• disorganized
• collagen fibrils in random orientation
• increased cell density
• reduced mineral content
• lower bifringence

Question 20

What are the characteristics of lamellar bone?

Answer 20

• highly organized
• bone lamellae concentrically arranged
• have Haversian canals
• collagen in parallel
• mechanically stronger
• more bifringence

Question 21

Secondary or lamellar bone can be further classified into ___ bone and ___ bone.

Answer 21

compact (cortical); spongy (cancellous)

Question 22

An ____ contains Haversian canals, osteocytes, osteocyte lacunae, and canaliculi.

Answer 22

osteon

Question 23

What is skeletal healing essential for in the medical field?

Answer 23

• resolution of orthopedic trauma
• healing of corrective surgeries of bony deformities
• bone regeneration in oral surgeries

Question 24

What cells and their coordinated activity are required in fracture healing?

Answer 24

inflammatory cells
chondroprogenitors
chondrocytes
osteoprogenitors
osteocytes
osteoclasts
vascular cells

Question 25

What are the phases/stages of fracture healing?

Answer 25

1. Inflammatory Phase 2. Reparative Phase 3. Remodeling Phase

Question 26

When does the inflammatory phase peak and diminish?

Answer 26

peaks by 48H; diminished by 1 week

Question 27

When does the reparative phase activate and eventually diminish?

Answer 27

activated within a few days; persists for 2-3 months

Question 28

In what phase does the formation of a vascular hematoma and inflammation occur?

Answer 28

Reactive Phase

Question 29

In what phase does the formation of a fibrocartilage callous occur, as well as tissue metaplasia with bone mineralization?

Answer 29

Reparative Phase

Question 30

In what phase does bony remodeling and turnover occur?

Answer 30

Remodeling Phase

Question 31

What cytokines does the hematoma release after a traumatic event?

Answer 31

TNF-alpha | Interleukins (IL-1, -6, -11, -18)

Question 32

What does the infiltration of cytokines lead to the recruitment of?

Answer 32

inflammatory cells

Question 33

What do the recruited inflammatory cells recruit to the fracture site?

Answer 33

- more inflammatory cytokines - mesenchymal stem cells - osteogenic precursors

Question 34

The degeneration of what allows the fibrous connective tissue matrix to form?

Answer 34

hematoma

Question 35

What is the fibrous connective tissue matrix laid down by? What type of tissue does this form?

Answer 35

fibroblasts; granulation tissue

Question 36

What are the broken ends of the bones where blood supply was disrupted afflicted by?

Answer 36

hypoxia and tissue necrosis

Question 37

In hypoxic regions of the bone after a fracture, what do the mesenchymal stem cells differentiate into?

Answer 37

chondrocytes

Question 38

What type of bone formation occurs in hypoxic regions of a broken bone?

Answer 38

endochondral bone formation

Question 39

Where might intramembranous bone form after a fracture?

Answer 39

in the periosteal sites (where vascular supply is still *intact* (callous area))

Question 40

Where do osteogenic precursors (mesenchymal stem cells, pericytes, and muscle satellite cells) come from?

Answer 40

- periosteum/bone marrow - circulation - muscle

Question 41

What are the basic steps to endochondral ossification?

Answer 41

1. hypertrophy 2. calcification of cartilage 3. removal by osteoclasts 4. replacement with bone

Question 42

When is a fracture considered "healed?"

Answer 42

when "clinical union" is observed, when bone tissue completely bridges the original fracture

Question 43

Does the same sequence of bony formation events take place in the healing of alveolar bone in the tooth socket?

Answer 43

YES

Question 44

______ includes inflammation, endochondral bone formation, intramembranous bone formation, and osteoclastic bone resorption.

Answer 44

Fracture healing

Question 45

What genes are expressed in the inflammation and mesenchymal stem cell recruitment stages of fracture healing?

Answer 45

``` TNF-alpha IL-1, 6, 11, 18 TGF-beta BMP2 GDF-8 ```

Question 46

What genes are expressed in the mesenchymal condensation and early cartilage formation stages of fracture healing?

Answer 46

SOX9 type II collagen PTHrP

Question 47

What genes are expressed in the chondrocyte differentiation and hypertrophy stages of fracture healing?

Answer 47

type X collagen MMP9, 13 alkaline phosphatase IHH

Question 48

What genes are expressed in the angiogenesis and vascularization stages of fracture healing?

Answer 48

HIF1a | VEGF

Question 49

What genes are expressed in the recruitment of osteoclasts to remodel hypertrophic cartilage in fracture healing?

Answer 49

RANKL decreased OPG M-CSF

Question 50

What genes are expressed in bone formation, both intramembranous and endochondral?

Answer 50

``` RUNX2 Osterix (OSX) type I collagen osteocalcin VEGF alkaline phosphastase ```

Question 51

Formation of a hematoma, recruitment of mesenchymal stem cells, cell proliferation, chondrogenesis/osteogenesis and vascular angiogenesis are all ____ phases of fracture healing.

Answer 51

early

Question 52

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

Answer 52

pro-inflammatory cytokines TGF-beta superfamily angiogenic factors

Question 53

____ cytokines recruit other inflammatory cells and promote mesenchymal stem cells in bone formation.

Answer 53

Pro-inflammatory; TNF-alpha and IL-1

Question 54

Which types of cytokines induce apoptosis of hypertrophic chondrocytes and promote osteoclast formation?

Answer 54

pro-inflammatory cytokines (TNF-a, IL-1)

Question 55

Which cytokines recruit fibrogenic cells and promote formation of granulation tissue?

Answer 55

pro-inflammatory cytokines (TNF-a, IL-1)

Question 56

Pro-inflammatory cytokines are secreted by ____, ____, and ____.

Answer 56

macrophages; mesenchymal cells; inflammatory cells

Question 57

Which cytokine family promotes extracellular matrix synthesis and assembly/initiation of the callous formation?

Answer 57

TBF-beta superfamily

Question 58

What genes promote osteogenic differentiation?

Answer 58

TGF-beta BMP2 GDF-8

Question 59

____ promotes osteogenic differentiation and has a role is cell proliferation.

Answer 59

GDF-8

Question 60

What are the TGF-beta superfamily members produced by?

Answer 60

hematoma (platelets) granulation tissue differentiating MSC periosteal callous

Question 61

____ promotes vascularization of the periostem, bringing oxygen and osteogenic precursors, like pericytes, to the site.

Answer 61

VEGF

Question 62

Where is HIF1a most greatly expressed in?

Answer 62

hypoxic regions

Question 63

What is VEGF under the control of?

Answer 63

HIF1a

Question 64

What dictates the type of bone healing that will occur?

Answer 64

the fracture stability or mechanical environment

Question 65

What type of bone healing will occur if strain is less than 2%?

Answer 65

intramembranous bone healing

Question 66

What type of bone healing will occur if strain is 2% to 10%?

Answer 66

endochondral bone healing

Question 67

What kind of bone healing will occur if there is high strain, or movement in the fracture area?

Answer 67

fibrous tissue formation (non-union)

Question 68

Can bone healing occur as a combination between intramembranous, endochondral, and fibrous bone healing?

Answer 68

YES

Question 69

Does zero mechanical loading of the bone promote or delay bone healing?

Answer 69

DELAY - so, some mechanical loading is needed to promote healing

Question 70

Are BMPs important in promoting osteogenesis?

Answer 70

YES

Question 71

What agents are being shown to be effective in bone healing in clinical use?

Answer 71

- recombinant BMPs - platelet rich plasma - FGFs - PDGF - cell-based therapies - anti-resorptives - bone anabolic agents

Question 72

An ____ bone graft is when a bone is taken from a region of your body and placed into the non-union area.

Answer 72

autologous

Question 73

What agent is attempting to replace autologous bone grafts?

Answer 73

recombinant BMPs

Question 74

What is FGF signaling important in?

Answer 74

skeletal development and fracture healing

Question 75

Where is autologous bone marrow collected from?

Answer 75

the iliac crest

Question 76

What does autologous bone marrow collection increase at the site of non-union?

Answer 76

increases the number of progenitor cells

Question 77

Sclerostin is an inhibitor of the _____ signaling pathway important for bone formation.

Answer 77

Wnt/B-catenin

Question 78

Antibodies to sclerostin would be important in what type of clinical syndrome as a treatment?

Answer 78

osteoporosis (inhibiting sclerostin would allow the Wnt/B-catenin pathway to transcribe genes to increase bone density/formation)