Osteoclasts, Osteoblasts & Fracture Healing (Exam V) Flashcards
1
Q
What is the origin & lineage of osteoclasts?
A
Hematopoietic origin- macrophage/monocyte lineage
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
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
4
Q
Bone modeling can occur in response to (2)
A
Longitudinal growth
Response to increase in mechanical loading of the bone
5
Q
Bone modeling can lead to:
A
Net gain or loss of bone
6
Q
Disease of impaired osteoclast function that leads to bones that are abnormally dense but brittle & prone to fracture
A
Osteopetrosis
7
Q
Osteopetrosis leads to bones that are abnormally:
A
Dense but brittle & prone to fracture
8
Q
Osteopetrosis is caused by mutations in genes important for:
A
Osteoclast resorption
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
10
Q
Osteoporosis is usually seen in:
A
Post-menopausal women & elderly
11
Q
Drug that inhibits bone resorption
A
Anti-resorption agent
12
Q
Drug that stimulates bone formation
A
Bone anabolic agent
13
Q
A fancy word for bone that is dead & does not have any viable osteocytes
A
Osteonecrotic bone
14
Q
A complication of bone fracture n which the bone does not heal
A
Non-union
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
16
Q
In a fracture callus, the callus is ultimately replaced by ____ following ____
A
Lamellar bone
Remodeling
17
Q
A fancy word for blood clot
A
Hematoma
18
Q
A tissue containing newly formed vascular tissue & fibrous extracellular matrix usually formed in healing wounds
A
Granulation tissue
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
20
Q
Pericytes can differentiate into:
A
Muscle, fibroblasts & osteoblast
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
22
Q
Muscle satellite cells may be able to differentiate into:
A
Osteoblasts
23
Q
The ability to form cartilage
A
Chondrogenic
24
Q
The ability to form bone
A
Osteogenic
25
The formation of new blood vessels from the outgrowth of pre-existing blood vessels
Angiogenesis
26
When new blood vessels form de novo
Vasculogenesis
27
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)
Transforming growth family beta superfamily
28
Transforming beta growth factor superfamily are structurally & evolutionarily related proteins that include (4):
1- TGF betas
2- BMPs
3- Activins/Inhibins
4- Growth/Differentiation factors
29
Osteoclasts express ____ for removing ____
Proteases
ECM proteins
30
Osteoclasts express proteins that act as ______ to generate ______ to (reduce the pH to dissolve minerals)
Proton pumps
H+ ions
31
Active osteoclasts have specialized ______ to increase surfaces area in the resorption compartment
Ruffled border
32
Life’s span of osteoclasts
Short (days)
33
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 _____
1. Normal bone growth & remodeling
2. Alveolar bone
3. Tooth roots; primary teeth
4. Alveolar bone; orthodontic tooth
5. Pathological conditions
34
Must occur to maintain bone shape:
Modeling
35
Osteoclasts originally come from:
Hematopoietic stem cell (HSC)
36
During osteoclast differentiation- the hematopoietic stem cell (HSC) will differentiate into:
CFU-M
37
During osteoblast differentiation:
HSC —-> CFU-M —> _______
Monocyte
38
During osteoblast differentiation:
HSC —-> CFU-M —> Monocyte —> ______
Mononucleated osteoclast (pre-fusion)
39
During osteoblast differentiation:
HSC —-> CFU-M —> monocyte —> mononucleated osteoclast —-> _____
Multinucleated osteoclast
40
During osteoblast differentiation:
HSC —-> CFU-M —> monocyte —> multinucleated osteoclast —-> ____
Resorbing osteoclast
41
What is the master transcription factor of osteoclast formation?
NFATc1
42
Osteoclast marker genes are associated with the functions of the cell which include (4):
1. Fusion
2. Adherence to bone surface
3. Acid production
4. Protease production
43
Which transcription factors are downstream of NFATc1:
C-fos & NFKB
44
There are two factors produced by osteoblasts/osteocytes that are essential for:
Osteoclast differentiation
45
The two factors produced by osteoblasts/osteocytes that are essential for OCL differentiation include:
1- RANKL
2. M-CSF (also known as CSF-1)
46
RANKL is a receptor activator of:
NFKB ligand
47
M-CSF (aka CSF-1) is a _____ stimulating factor
Macrophage colony
48
Promotes proliferation/survival of osteoclast precursors:
M-CSF
49
Member of the TNF superfamily- required for osteoclast fusion & differentiation
RANKL
50
Natural inhibitor of RANK; a decoy receptor
OPG
51
Master transcription factor that controls osteoclast differentiation
NFATc1
52
The following osteoclast marker proteins falls under what category:
NFATc1
C-fos
NFkB
Transcription factors
53
The following osteoclast marker proteins falls under what category:
Tartrate resistant acid phosphatase (TRAP)
Enzyme
54
The following osteoclast marker proteins falls under what category:
RANK
C-f s
Calcitonin receptor
Integrin- aVB3
Receptors
55
The receptor for
RANKL=
C-fms=
RANKL
M-CSF
56
The following osteoclast marker proteins falls under what category:
Carbons anhydrase II
Vascular-type ATPase
Generates protons/ proton pump
57
The following osteoclast marker proteins falls under what category:
Cathespsin k
MMP9, MMP13
Proteases
58
Osteoclast attach via ______ to form a sealed zone
Alpha-v-beta-3 integrins
59
In a mature resorbing osteoclast, carbonic anhydrase II (CAII) functions to:
Generate protons
60
Vacuolar-type H+ ATPase pumps protons into _____ which creates acid to ____
Resorption lacuna
Dissolve mineral
61
____ & ____ are exchangers o9n basolateral surface to remove excess bicarb
Cl-
HCO3-
62
In the mature resorbing osteoclast _____ maintains the charge neutrality
Chloride channel
63
______ is release into the resorption lacuna to digest matrix proteins
Cathepsin K
64
Impaired osteoclast function leases to:
Osteopetrosis
65
Osteopetrosis can be due to failure in osteoclast ____ or osteoclast form normally but have impaired:
Formation
Resorptive function
66
The two major clinical forms of Osteopetrosis include:
Autosomal dominant
Autosomal recessive
67
Describe the autosomal dominant form of Osteopetrosis:
Adult benign type- relatively few symptoms
68
Describe the autosomal recessive form of Osteopetrosis
Infantile malignant type- typically fatal (if untreated) in early childhood
69
In patients with Osteopetrosis, their bone are:
Abnormally dense & prone to fracture
70
Failed osteoclastic resorption affects (3):
Bone growth
Remodeling
Tooth eruption
71
Osteopetrosis can be accompanied by (8):
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
In Osteopetrosis there are more than 60 mutations identified in gene TCIRG1 encoding _____ of vaculolar _____
This accounts for about 50% of _____ Osteopetrosis in humans
Alpha-3 subunit ; H+ ATPase
Autosomal recessive
73
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:
Chloride channel
74
Pycnodysostosis is a specific from of Osteopetrosis caused by mutations in:
Cathepsin K
75
What are the three genes that if mutated result in a form of Osteopetrosis:
TCIRG1
CLCN7
Cathepsin K
76
The TCIRG1 gene that gives rise to AR Osteopetrosis is associated with:
The CLCN7 gene that gives rise to AD Osteopetrosis is associated with:
Vacuolar ATPase alpha subunit
Chloride channel
77
What factors can contribute to osteoporosis (3):
Aging population
Diet
Environmental factors
78
Osteoporosis is defined by a patient with a BMF of greater than ____ standard deviations below average for a healthy young person
2.5
79
Worldwide 1 in ___ women & 1 in ____ men over the age of 50 will experience osteoporotic factors
3
5
80
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 ____
20-24%
5 years
81
Treatments of osteoporosis can be directed at reducing _____, simulating ____ or both
Bone resorption
Bone formation
82
Treatments for osteoporosis:
Preferentially bind to hydroxyapatite. Inhibit osteoclast activity by inhibiting mevolonate pathway that is important in prenylation of GTPases
Amino bisphosphonates
83
Treatments for osteoporosis:
Restores hormone levels following menopause
Hormone replacement therapy (estrogen/progesterone)
84
Osteoporosis treatment that is an antibody of RANKL - Inhibits osteoclast formation
Denosumab
85
Osteoporosis mediation that is currently in clinical trial - functions by inhibiting bone degreding rnzyne Cathepsin K
Cathepsin K inhibitors
86
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?
PTH (1-84 & 1-34)
87
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
Anti-sclerostin antibodies
88
Oral bisphosphonates are widely used for treatment of osteoporosis as they function as ______
Anti-resorptives
89
Bisphosphonates can also be given in a stronger IV dose for treatments of ______ , particularly if patient have high serum calcium
Myeloma/bone metastatic cancers (breast, prostate, lung)
90
Non-hydrolyzation analogs of Pyrophosphate
Bisphosphonates
91
Bisphosphonates have a high affinity for:
Hydroxyapatite
92
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
Osteonecrosis of the jaw
93
BONJ is not fully understood but is attributed manly to:
Suppression of bone turnover due to BP inhibition of osteoclast activity
94
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.
1. Orthopedic trauma; fractures
2. Bone injuries
3. Bone regeneration
95
The bone formation process that occurs in a fracture callus recapitulates the process of:
Embryonic bone formation (endochondral & intramembranous)
96
Fracture healing requires coordinated activities of what cells (5):
1. Inflammatory cells
2. Chondroprogenitors/chondrocytes
3. Osteoprogenitors/osteoblasts
4. Osteoclasts
5. Vascular cells
97
Timeline of fracture healing:
1. Phase that peaks by 48 hours & is diminished by 1 week
Inflammatory
98
Timeline of fracture healing:
Phase that is activated within a few days & persists for up to 2-3 months
Reparative phase
99
Timeline of fracture healing:
Phase that can continue for several years
Remodeling
100
List the phases of fracture healing in the right order
Inflammatory (Reactive) phase
Reparative phase
Remodeling phase
101
What is the first step (reactive/inflammatory phase) in the fracture repair process?
1- Formation of a vascular hematoma
102
What occurs in the first part of the reparative phase in fracture repair?
What occurs in the second part of the reparative phase?
2a. Formation of a fibrocartilage callus
2b. Tissue metaplasia- callus is replaced by mineralized bone
103
What occurs in the remodeling phase of fracture repair?
Bone remodeling & turnover
104
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
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
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
5. At broken ends of bones where blood supply was disrupted _____/______ occurs
6. In hypoxic regions ____ differentates to ____ & initates endochondral bone formation
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
Cell sources osteogenic precursors (4):
Cell types of osteogenic precursors (3):
1- periosteum
2- muscle
3- bone marrow
4- circulate (?)
1- mesenchymal stem cell
2- pericyte
3- muscle satellite cell
107
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:
Endochondral
Hypoxia
Intramembranous
Better preserved
Bone stability is restored with complete bridging of original fracture
108
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
1. Woven
2. Resorb; lamellar; stronger
3. Marrow cavity; contours
4. Biomechanical stability
109
The same sequence of fracture healing events occurs for healing of:
Alveolar bone in tooth socket after fracture
110
Fracture healing includes (4):
1- inflammation
2- endochondral bone formation
3- intramembranous bone formation
4- Osteoclastic bone resorption
111
During fracture healing what is stage dependent & reflective of the fracture healing processes
Gene expression profile
112
Key signaling molecules that regulate fracture healing include (general sense):
1- inflammatory cytokines
2- TGFbeta supferfamily members
3. Mediators of angiogenesis
113
What specific inflammatory cytokines act as key signaling molecules during fracture repair?
TNF-alpha
IL-1, 6, 11, 18
114
Which members of the TBF-beta superfamily act as key signaling molecules during fracture repair?
TGF-beta
BMPs
GDF-8
115
What mediators of angiogenesis act as key signaling molecules during fracture repair?
VEGF
PDGF
Angiopoietin
116
- 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:
Pro-inflammatory cytokines
117
The pro-inflammatory cytokines in fracture repair are secreted by:
Macrophages
Mesenchymal cells
Inflammatory cells
118
- Promote ECM synthesis & assembly/intiation of callus formation
- Promote osteogenic differentiation
- GDF-8 role in cell proliferation
These are indicative of:
TGF-beta superfamily
119
The TGF beta superfamily members involved in fracture repair are produced by:
Hematoma (platelets)
Granulation tissue
Differentiating MSC
Periosteal callus
120
- promote vascular ingrowth from vessels in periosteum (brings oxygen/osteogenic precursors [pericytes])
This is a function of:
Angiogenic factors
121
What is critical for bone repair/formation & brings in calcium & phosphate for mineralization
Vascularization
122
VEGF
1. promotes _______ of osteoprogenitors
2. ______ in regions of hypoxia
1. Chemotaxis
2. Unregulated
123
Bone respair could be enhanced by (4):
This is an active area of research
1. Improving vascularization
2. Attracting progenitor cells
3. Accelerating bone formation
4. Accelerating remodeling
124
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
Recombinant BMPs
125
Potential enhancer in bone repair:
Contains multiple growth factors, & appears to be effective in promoting bone healing
Platelet rich plasma
126
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
FGFs
127
What cell-based therapies could potentially enhance bone repair:
1. Autologous bone marrow
2. Purified stem cell sources
128
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
Anti-sclerostin antibodies
