Fracture Healing Flashcards
a multipotent stem cell that has the capacity to differentiate into a variety of cell types, including fibroblasts, osteoblasts, muscle cells, adipocytes, chondrocytes.
Mesenchymal Stem Cell (MSC)
condensation of mesenchymal stem cells into a more dense mass of cells to initiate the formation of a bone rudiment
Mesenchymal Condensation
a process for formation of bone in which a cartilage template is made first, which is then replaced by bone.
Endochondral Bone Formation
cartilage in which the chondrocytes have undergone hypertrophy. This includes swelling of the cell volume, mineralization of the surrounding matrix, expression of marker genes of hypertrophy (see class on chondrocytes). In the final stages, the hypertrophic chondrocytes will undergo apoptosis.
Hypertrophic Cartilage
a process for formation of bone in which there is direct transformation of the mesenchymal precursor cells into bone forming osteoblasts without a cartilage intermediate.
Intramembranous Bone Formation
the type of bone that is laid down initially during endochondral or intramembranous bone formation and in situations such as fracture healing where there is a need for rapid deposition of bone. The collagen fibers are more randomly oriented and the tissue is much less organized than lamellar bone.
Woven Bone (Primary Bone)
bone that is formed after the woven (primary) bone is resorbed by osteoclasts (bone remodeling). The structure consists of concentric lamellae of bone surrounding a “Haversian canal” which contains a blood vessel and nerves. Collagen is more organized (often fibers run parallel to the long axis of the bone) and osteocytes are organized in concentric rings around the Haversian canal.
Lamellar Bone (Secondary Bone/Haversian Bone)
a complication of bone fracture in which the bone does not heal.
Non-union
the process by which bone is removed by osteoclasts and replaced with new bone
Bone remodeling
a disorganized network of cartilage/woven bone formed between the ends of the broken bone and extending beyond the original contour of the bone. The callus is ultimately replaced by lamellar bone following remodeling
Fracture Callus
a fancy word for a blood clot
Hematoma
a tissue containing newly formed vascular tissue and fibrous extracellular matrix, usually formed in healing wounds
Granulation Tissue
a cell that is present in the wall of capillaries and has mesenchymal stem cell properties since it can differentiate into other cell types such as muscle, fibroblasts, osteoblasts, etc.
Pericyte
these are small cells found in mature muscle that have stem cell-like properties and provide a source of progenitors for formation of muscle cells, especially in situations of muscle injury/repair. They may also be able to differentiate into osteoblasts.
Muscle Satellite Cell
the ability to form cartilage
Chondrogenic
the ability to form bone
Osteogenic
a condition in which a region of the body is deprived of an adequate oxygen supply.
Hypoxia
the formation of new blood vessels (from outgrowth of pre-existing vessels). This is different from vasculogenesis in which new blood vessels form de novo.
Angiogenesis
the directional movement of cells towards certain chemicals
Chemotaxis
a superfamily of structurally and evolutionarily related proteins that includes the transforming growth factor betas (TGFβs), the bone morphogenetic proteins (BMPs), activins, inhibins and growth and differentiation factors (GDFs)
Transforming Growth Factor Beta Superfamily
- Migration of preskeletal cells to sites of future
skeletogenesis - Interaction of these cells with epithelial cells
- Interaction leads to mesenchymal condensation
- Followed by differentiation to chondroblasts or
osteoblasts
Four Phases of Skeletal Development
- 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
Endochondral Bone formation
• 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
Intramembranous Bone Formation
Growth plate fusion occurs around age __-__ in humans depending on the specific bone and the gender of the individual
14-20
________ ossification center appears around the time of birth
Secondary
Which Bone formation process excludes a cartilage model proceding the bone formation.
Intramembraneous
First type of bone produced developmentally
woven Bone
Which type of bone is produced rapidly in development and in fracture healing?
Woven Bone
What are the two types of Lamellar Bones??
- Compact:
(Cortical/ Haversian) - cancellous:
(Spongy/ trabecular).
The inflammatory (reactive) phase peaks by __ hours and is deminished by __ week (s).
48; 1
he reparative phase lasts up to _ - _ months
2-3 months
What are the four phases of fracture repair:
- -Reactive–
1) Formation of vascular hematoma. - -Reparative–
2) Formation of (fibrocartilage) callus
3) Tissue metaplasia – callus replaced by mineralized bone - -Remodeling–
4) Bone remodeling and turnover
What cytokines are released in association to the hematoma?
Tumor necrosis factor-α (TNF-α )
Interleukins (IL-1,-6, -11 and -18)
______ lead to recruitment/infiltration of inflammatory cells.; These inflammatory cells will release more of these which will lead to the recruitment of mesenchymal stem cells. (MSC)
cytokines
What are key events of the formation of the fibrocartilagenous callous?
- MSC/ connective tissues stem cells/ and blodd vessels invade the hematoma.
- hematoma degenerates.
- granulation tissues is laid by fibroblasts.
- where the bone was broken become hypoxic and here the MSC differentiate into chondrocytes (endochondral bone formation).
- Periosteum
- Muscle
- Bone Marrow
- Circulating
four sources for osteogenic precursors
- Mesenchymal Stem Cell (MSC)
- Pericyte
- Muscle satellite cell
Types of osteogenic precursors.
Fracture considered healed when bone
stability restored by bone tissue completely bridging the original fracture
clinical union
• Initial woven bone must be remodeled
• Osteoclasts resorb woven bone in
fracture callous then osteoblasts lay down new lamellar bone (Haversian) = mechanically stronger
• Restores marrow cavity
• Restores original contours of bone
• Biomechanical stability matches that of
the original bone
Remodeling
Types of genes expressed for Inflammation/ MSC recruitment
TGFβ superfamily members
Pro-inflammatory cytokines
Types of genes expressed for Mesenchymal Condensation/early cartilage formation
Early chondrogenic markers
Types of genes expressed for Chondrocyte differentiation/hypertrophy
Late (prehypertrophic and hypertrophic) chondrocyte markers
Types of genes expressed for Angiogenesis/vascularization
Angiogenic factors
Types of genes expressed for Recruitment of osteoclasts to remodel hypertrophic cartilage
Osteoclastogenic factors
Types of genes expressed for Osteogenic markers and angiogenic factors
Osteogenic markers and angiogenic factors
What are the three main categories of Signaling Molecules Important in Fracture Healing
pro-inflammatory cytokines
TGFB superfamily members
angiogenic factors
What are the two types of Pro-Inflammatory Cytokines
Tumor necrosis factor-α (TNF-α)
Interleukins (IL-1,-6, -11 and -18)
What are the functions of Tumor necrosis factor-α (TNF-α) and Interleukins (IL-1,-6, -11 and -18)
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
What secrete pro-inflammatory cytokines?
macrophages
mesenchymal cells and inflammatory cells.
Transforming growth factor-β (TGFβ) Bone morphogenetic protein-2 BMP2 (also 5,6) Growth and differentiation factor-8 (GDF-8)
TGFβ Superfamily Members
Functions of ______ include:
− Promote osteogenic differentiation
− GDF-8 – role in cell proliferation
− Promote ECM synthesis & assembly/initiation of callus formation
What are the major functions of TGFβ Superfamily Members?
What cells produce TGFβ Superfamily Members?
Produced by hematoma (platelets)/ granulation tissue/differentiating
MSC/periosteal callus
VEGF - Vascular endothelial growth factor PDGF - Platelet derived growth factor ANGPT - Angiopoietin
Angiogenic Factors
− promotes chemotaxis of osteoprogenitors
-upregulated in regions of hypoxia
VEGF
₋ If strain <2%_________ bone healing will occur
intramembranous
₋ If strain is >2% <10%_________ bone healing will occur
endochondral
• Appear to be effective alternative to autologous bone graft for repair of fracture non union/open tibial fractures.
BMPs
Bone Morphogenic Protein
______ _____ ____ _ is shown to enhance fracture healing. However, if exposed for too long it can impair mineralization, so timing is key.
Fibroblast Growth Factor 2
Autologous bone marrow collected from iliac
crest/injected into non-union site (increases #
of progenitor cells)
Cell-Based Therapies
Inhibitor of Wnt/β-catenin signaling (important pathway for bone formation)
Sclerostin
T/ F: Anti-Sclerostin Antibodies Promote Bone Healing
True
