11/9: Osteoclasts/Osteoporosis and Fracture Healing Flashcards
1
Q
What are the 3 main bone cells?
A
Osteoclasts
Osteocytes
Osteoblasts
2
Q
To repair damaged bone, it is continually being removed by ______ and rebuilt by _______
A
Osteoclasts; osteoblasts
3
Q
What are osteoclasts derived from?
A
Same precursor as macrophages
4
Q
How many nuclei are in mature osteoclasts?
A
Multinucleated
5
Q
What do osteoclasts express to remove ECM proteins?
A
Proteases
6
Q
What do osteoclasts express to generate H+ ions?
A
Proteins that act as proton pumps
7
Q
What do active osteoclasts have that are specialized?
A
“ruffled border”
8
Q
What does ruffled border do?
A
Increase surface area in resorption compartment
9
Q
What is the lifespan of osteoclasts?
A
Short (days)
10
Q
What are osteoclasts responsible for?
A
- Bone resorption during normal bone growth and
remodeling - Removal of alveolar bone during tooth eruption
- Resorption of tooth roots of primary teeth
- Removal of alveolar bone during orthodontic tooth
movement - Bone loss in pathological conditions (osteoporosis,
tumor associated osteolysis, etc.)
11
Q
What is osteoclastic resorption important for?
A
Normal bone growth
12
Q
Where does growth occur?
A
At epiphyseal plate
13
Q
What does modeling occur to maintain?
A
Bone shape
14
Q
What are the main factors that regulate osteoclastic differentiation?
A
M-CSF
RANKL
15
Q
What inhibits M-CSF RANKL?
A
OPG
16
Q
What inhibits RANKL?
A
OPG
17
Q
What is an enzyme for mononucleated osteoclast?
A
NFATc1
C-fos
NFkB
18
Q
What stimulates monocytes?
A
M-CSF
19
Q
What stimulations mononucleated (prefusion) osteoclasts?
A
M-CSF RANKL
20
Q
What stimulates multinucleated osteoclasts and resorbing osteoclasts?
A
RANKL
21
Q
What is the master transcription factor?
A
NFATc1
22
Q
What are downstream of NFATc1?
A
C-fos and NFkB
23
Q
What are two factors produced by osteoblasts/osteoctes that are essential for OCL differentiation?
A
RANKL
M-CSF
24
Q
What is a receptor activator of NFkB ligand?
A
RANKL
25
What is a macrophage colony stimulating factor?
M-CSF (aka CSF-1)
26
What promotes
proliferation/ survival of
osteoclast precursors?
M-CSF
27
What (member of TNF
superfamily) – required for
osteoclast fusion and
differentiation?
RANKL
28
What (natural inhibitor of RANKL– decoy receptor)?
OPG (osteoprotogerin)
29
What does an osteoclast need to do?
* Differentiate/fuse
* Adhere to the bone surface
* Produce acid to dissolve mineral
* Produce proteases to breakdown extracellular matrix
components
* Respond to factors that regulate osteoclast survival/
activity
30
What are transcription factors for osteoclast marker proteins?
NFATc1
C-fos
NFkB
31
What are enzymes for osteoclast marker proteins?
Tartrate resistant acid phophatase (TRAP)
32
What are receptors for osteoclast marker proteins?
RANK
C-fms
Calcitonin receptor
Integrin alpha-v-beta-3
33
What generates protons/proton pump for osteoclast marker proteins?
Carbonic anhydrase II
Vacuolar-type ATPase
34
What are proteases for osteoclast marker proteins?
Cathepsin K
MMP9, MMP13
35
What do osteoclasts attach via to form a sealed zone?
Alphavbeta3
36
What generates protons?
Carbonic anhydrase II (CAII)
37
What pumps protons into resorption lacuna and what happens?
Vacuolar-type H+ ATPase; create acidic pH (Dissolves material)
38
What removes excess bicarbonate?
Cl- and HCO3- exchanger on
basolateral surface
39
What maintains charge
neutrality?
Chloride channel
40
What is released into resorption lacuna?
Cathepsin K (and other proteases)
41
What lead to osteopetrosis?
Impaired osteoclast function
42
What is osteopetrosis due to?
Failure in osteoclast FORMATION or osteoclasts
form normally but have impaired resorptive FUNCTION
43
What are two major clinical forms?
Autosomal dominant adult type - benign
Autosomal recessive child type - malignant
44
What genes are association with osteopetrosis?
ATPase
Chloride Channel
Cathepsin K
45
What gene mutations is associated with pycnodysostosis?
Cathepsin K
46
What BMD does an osteoporosis patient have?
BMD >2.5 standard deviations below average
47
What are anti-resorptives as treatment for osteoporosis?
Amino bisphosphonates
Hormone replacement therapy
Selective estrogen receptor modulators
Denosumab
Cathepsin K inhibitors
48
What are anabolic agents for osteoporosis?
PTH 1-84, Teriparitide
Anti-sclerostin antibodies
49
What is widely used for treatment of osteoporosis?
Oral bisphosphonates
50
What are used for treatment of myeloma/bone metastatic cancers?
I.V. bisphosphonates
51
What are non-hydrolyzable analogs of pyrophosphate (PPi) – inhibit mineralization similarly to PPi?
Bisphosphonates
52
What are nitrogen containing bisphosphonates?
Alendronate
Risedronate
Pamidronate
Zoledronate
Ibandronate
53
What is the definition for Bisphosphonate associated osteonecrosis of the jaw (BONJ)?
(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
54
What is the pathogenesis of BONJ?
Not fully understood - attributed mainly to suppression of bone turnover due to BP inhibition of osteoclast activity
55
What is skeletal healing essential for?
* 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
56
Fracture healing requires coordinated activity of severall cell types:
* Inflammatory Cells
* Chondroprogenitors/chondrocytes
* Osteoprogenitors/osteoblasts
* Osteoclasts
* Vascular cells
57
What are the three phases of fracture healing?
Inflammatory (reactive) phase
1. days to weeks
reparative phase
1. weeks to months
remodeling phase
1. months to years
58
What is the process of reactive fracture repair?
1) formation of vascular hematoma
59
What is the process of reparative fracture repair?
2) Formation of (fibrocartilage)
callus
3) Tissue metaplasia – callus
replaced by mineralized bone
60
What is the process of remodeling fracture repair?
4) Bone remodeling and turnover
61
Hematoma-associated cytokines
released:
Tumor necrosis factor-α (TNF-α )
Interleukins (IL-1,-6, -11 and -18)
62
Cytokines lead to recruitment/infiltration
of
inflammatory cells
63
What do inflammatory cells release?
more inflammatory cytokines and recruit mesenchymal stem cells (MSC)/osteogenic precursors to fracture site
64
During the formation of fibrocartilagenous callus, what invades the hematoma?
MSC/connective tissue stem cells/blood vessels which degenerates/phagocytes clear debris
65
What lays down a connective issue matrix?
Fibroblasts (granulation tissue)
66
What do some MSC differentiate towards?
Chondrogenic/osteogenic lineages
67
What happens at broken ends of bones where blood supply is disrupted?
Hypoxia/tissue necrosis occurs
68
In hypoxic regions MSC differentiate into, which initiates?
chondrocytes – initiates endochondral bone formation
69
What are cell sources of osteogenic precursors?
- Periosteum
- Muscle
- Bone Marrow
- Circulating?
70
What are cell types of osteogenic precursors?
- Mesenchymal Stem Cell (MSC)
- Pericyte
- Muscle satellite cell
71
What contributes to a bony callus?
Intramembranous bone (formed where vascular supply intact)
72
What does cartilage undergo
endochondral ossification (hypertrophy>calcification of
cartilage>removal by osteoclasts>
replacement with bone)
73
When is the fracture considered healed?
when bone stability restored by bone tissue completely bridging the original fracture (“clinical union”)
74
When is initial bone formed called?
Woven bone
75
What is the function of osteoclasts/blasts in woven bone during remodeling?
Osteoclasts resorb woven bone in
fracture callous then osteoblasts lay down new lamellar bone (Haversian) = mechanically stronger
76
Are genes expressed during fracture healing?
Yes
77
What are the 3 main signaling molecules that are important in fracture healing?
1. Pro-inflammatory cytokines
2. TGF beta
3. Angiogenic factors
78
When TNF and Interleukins get released, what does their release cause?
1. Recruitment of other inflammatory cells and mesenchymal stem cells differentiation
2. Apoptosis of hypertrophic chondrocytes
3. Osteoclast formation
79
What does TGF, BMP, and GDF proteins do?
1. Promote ECM synthesis and assembly
2. Promote osteogenic differentiation
3. Cell proliferation
80
What angiogenic factors are released during fracture repair?
VEGF
PDGF
Angiopoietin
81
What do these angiogenic factors do?
Cause the promotion of vascular ingrowth
