Lecture 42 Oral Tissues Osteoblasts Osteocytes Osteoclasts Flashcards
1
Q
To repair damage, bone is continually being removed by _______ and rebuilt by _______
A
- osteoclasts, osteoblasts
2
Q
Where do osteoblasts originate from?
A
- mesenchymal progenitors
3
Q
what types of cells can mesenchymal progenitors give off?
A
- myocytes
- adipocytes
- hypertrophic chondrocytes
- osteoblasts
4
Q
Osteoblasts, chondrocytes, myoblasts, and adipocytes differentiate from a common_________ precursor
A
- mesenchymal
5
Q
What do osteoblasts produce large amounts of?
A
- extracellular matrix proteins (esp. type I collagen) = osteoid which then mineralizes
6
Q
What is the lifespan of osteoblasts?
A
- weeks
7
Q
What are the transcription factors associated with osteoblasts?
A
- Runx2
- osterix
8
Q
What is the main enzyme associated with osteoblasts?
A
- alkaline phosphatase
9
Q
What are the extracellular proteins associated with osteoblasts?
A
- Type I collagen
- osteopontin
- osteocalcin
- Bone sialoprotein (BSP)
10
Q
what is runx2 roll in differentiating osteoblast?
A
- acts early (with B catenin) to form immature osteoblast from osteochondrogenic precursor
11
Q
When does osterix act (with b catenin) to form a mature osteoblast?
A
- late maturation
12
Q
What happens if b catenin is present in the proliferation phase of osteoblast differentiation?
A
- it inhibits the process
13
Q
What does b catenin accomplish in the terminal differentiation phase?
A
- turning mature osteoblast to osteocyte, lining cell, or apoptosis
14
Q
What happens if runx2 is present in late maturation phase of osteoblast differentiation?
A
- it inhibits the process (timing is everything)
15
Q
What can mature osteoblasts differentiate into?
A
- lining cell
- osteocyte
- apoptosis
16
Q
What is the master transcription factor for bone?
A
- Runx2
17
Q
What is runx 2 essential for?
A
- bone and tooth development
18
Q
What happens to mice lacking RUNX2?
A
- form a cartilaginous skeleton that fails to mineralize
19
Q
heterozygous mutation of RUNX2 in humans results in _____?
A
- Cleidocranial Dysplasia (CCD)
20
Q
What are the symptoms of cleidocranial dysplasia?
A
- autosomal dominant
- haploinsuffiency of RUNX2
- delayed ossification of midline structures of body (membranous bone)
- clavicles partly or completely missing
- late closing of fontanelle
- supernumerary teeth
- prognathic (protruding) mandible due to hypoplasia of maxilla
21
Q
What causes cleidocranial dylsplasia?
A
- inactivating mutation or deletion in one allele of RUNX2 which results in haploinsuffiency
22
Q
What transcription factor does RUNX2 induce downstream?
A
- osterix (also critical for osteoblast differentiation)
23
Q
What happens to mice lacking osterix (gene name SP7)
A
- have impaired osteoblast formation
24
Q
What osteoblast genes does osterix control the expression of?
A
- type I collagen
- osteocalcin
- osteopontin
25
What type of OI is associated with mutations in SP7 (osterix)?
- type XII
26
Where does BMP2,7 play a role in the osteoblast differentiation pathway?
- proliferation
27
What happens when you knockout specific BMPs in bone?
- leads to skeletal defects
28
______ are originally purified from bone extracts that induce bone formation when implanted in muscle (ectopic bone assay)
- BMPs
29
Bone morphogenetic proteins are required for?
- skeletal development/maintenance of adult bone homeostasis
30
Bone morphogenetic proteins do what in osteoblasts?
- promote differentiation form early osteoprogenitor cells
31
What is know as stone man syndrome?
- Fibrodysplasia ossificans progressiva
32
_______ is bone forming in soft tissues and is a symtom of FOP (fibrodyslplasia ossificans progressiva)
- Heterotropic bone formation
33
T/F In FOP bone forms in response to tissue trauma or surgery
- T
34
What causes FOP?
- mutations in BMP type I receptor (ACVR1 gene)
| - single a.a substitution R206H
35
With FOP can there be mild constitutive activation and overactivation with ligand binding?
- Yes
36
What are most of the cases of FOP due to?
- spontaneous mutation in gametes/early embryo (most FOP patients can't have children)
37
What is a a potential treatment for FOP?
- Palovaratene and antibodies against activin A as well as kinase inhibitors selective for mutant receptor
38
What happens to B-cat in the absence of Wnt?
- it binds to GSK-3B and it is degraded
39
What happens with the Wnt/B catenin signaling pathway?
- went binds to Lrp5/6 and frizzled
- wnt allows b-cat to get into nucleus and be transcriped
- gene transcription leads to bone formation
40
Activating mutations of Lrp5 lead to ____ bone mass in humans?
- high
41
Inactivating mutations of Lrp5 lead to?
- low bone mass in humans
42
What is Pryophosphate (PPI)
- a natural inhibitor of mineralization
43
What does alkaline phosphatase do?
- it inhibits PPI which promates mineralization by stopping PPI
44
Mice lacking alkaline phosphatase gene (______) have impaired mineralization
- TNAP
45
What is the alkaline phosphatase gene in humans?
- TNSALP
46
Mutations in alkaline phosphatase gene (TNSALP) is associated with?
- hypophasphatasia
47
80 % of the mutations assocaited with TNSALP/hypophosphatasia are?
- missense mutations
48
What are the symptoms of Hypophasphatasia (HPP)
- impaired mineralization of skeleton/dentition
- leg bowing, rachitic rosary, tooth loss, waddling gait
- muscle weakness, seizures
49
What are the outcomes of HPP
- varying severity from perinatal lethal to adult onset or mild forms only affecting dentition (dependent on degree of loss of function of akaline phosphatse)
50
What is the most promising new treatment for HPP?
- bone-targeted enzyme replacement therapy
| - TNSALP recombinant enzyme with a 10 amino acid bone targeting peptide sequence (deca-aspartate)
51
How long did the bone targeted enzyme replacement therapy take for the patient to grow finger bones and ribs?
- 24 weeks
52
What are some characteristics of osteocytes?
- terminally differentiated osteoblasts
- embedded in bone matrix
- make up 90% of all bone cells
- long dendritic processes
- previously thought to be "quiescent cells"
- now know to be an active cell type with key functions in bone
- no "master" trancriptional gene identified yet
- lifespan=decades
53
What is the transcription factor associated with osteocytes that is also found in muscles?
- Mef2c
54
What are the early osteocyte markers?
- E11/gp38/ podoplanin
- Dentin matrix protein - 1 (DMP1)
- Matrix extracellular phosphoglycoprotein
- phosphate regulating endopeptidase homolog x-linked (PHEX)
55
What is the late osteocyte marker protein?
- Sclerostin (SOST)
56
What are the potential functions of osteocytes?
- mechanosensors (control responses of bone cells to mechanical loading)
- control bone resporption and bone formation (by regulating osteoclast and osteoblast activity)
- regulate mineralization
- regulators of mineral homeostasis - both calcium and phosphorus
57
What is the SOST gene role?
- highly expressed in mature osteocytes
- negative regulator of bone formation (antagonizes Wnt/beta-catenin signaling pathway)
- thought to act as brake to limit bone formation
58
What happens when you dont have Sclerostin(sost)
- No sclerostin leads to high bone mass because there is no break
59
Deletion or mutation of the SOST gene leads to what disease?
- Sclerosteosis or Van Buchem's
| - (increased bone mass, especially obvious in craniofacial skeleton)
60
How is sclerostin being looked at in osteoporosis treatment?
- antibodies being developed to target sclerostin so there will be no brake on bone formation in osteoporosis patients
61
What are the genes that osteocytes express that are important in phosphate homeostasis?
- FGF23- Fibroblast growth factor - 23
- DMP1 - dentin matrix protein-1
- PHEX
62
What is the precursor of osteoclasts?
- derived from same precursors as macrophages
| - (hematopoietic lineage)
63
T/F Mature osteoclasts have only one nucleus?
- false they are multinucleated
64
How long to osteoclasts live?
- days
65
How do osteoclasts work?
- express proteases for removing ECM proteins (collagen)
- express proteins that act as proton pumps to generate H+ ions (reduces pH to dissolve mineral)
- active osteoclasts have specialized "ruffled border" - increase surface area in resorption compartment
66
What are osteoclasts responsible for?
- 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.)
67
Why are osteoclasts important in normal bone growth?
- they reshape the bone/model it to maintain shape
68
What is the master transcription factor of osteoclasts?
- NFATc1
69
What are the two growth factors associated with osteoclast differentiation?
- M-CSF
| - RANK
70
What inhibits osteoclast differentiation?
- OPG
71
What are the down stream transcription factors involved with osteoclast formation/function?
- C-fos and NFkb
72
____ promotes proliferation/survival of osteoclasts precursors?
- M-CSF
73
_______ member of TNF superfamily that is required for osteoclast fusion and differentiation
- RANKL
74
_____ is a natural inhibitor of RANKL (decoy receptor)
- OPG osteoprotogerin
75
What produces rankl and opg?
- osteoblasts/osteocytes
76
What are the 5 things osteoclasts need to do?
1. Differentiate/fuse
2. Adhere to bone surface
3. Produce acid to dissolve mineral
4. Produce proteases to breakdown extracellular matrix components
5. Respond to factors that regulate osteoclast survival/activity
(most osteoclast enriched marker genes will reflect one of these five things)
77
What are the osteoclast transcription factors?
- NFATc1 (master regulator)
- C-fos
- NFkB`
78
What is the enzyme that is an osteoclast marker protein?
- Tartate resistant acid phosphatase
79
What receptors are used to mark osteoclasts?
- RANK (receptor for RANKL)
- C-fms (receptor for M-CSF)
- calcitonin receptor
- Integrin avB3
80
What are the proton pumps that mark osteoclasts?
- carbonic anhydrase II
| - vacular type ATPase
81
What are the proteases that mark osteoclast activity?
- cathepsin k
| - MMP9, MMP13
82
Osteoclasts attach via ______ integrins to form sealed zone?
- avB3
83
What generates the protons in osteoclasts?
- carbonic anhydrase II (CAII)
84
What do osteoclasts use to create an acid PH in resorption lacuna?
- vacuolar-type H+ ATPase that pumps protons
85
What does the osteoclast release to digest matrix proteins?
- cathepsin K and other proteases
86
What removes excess bicarbonate in the osteoclast?
- Cl- and HCO3- exchanger on basolateral surface
87
What are the two ways you can have impaired osteoclast function?
- failure in osteoclast formation
| - impaired osteoclast resorptive function
88
Is the autosomal dominant form of osteopetrosis bad?
- no there relatively few symptoms
89
Is the autosomal recessive form of osteopetrosis severe?
- yes typically fatal if untreated in early childhood
90
What are the symptoms of osteopetrosis?
- bone abnormally dense and prone to fracture
- affects bone growth, remodeling and tooth eruption
- lots of other complications
91
What mutation accounts for 50% of the AR cases of osteopetrosis?
- TCIRG1
| - a3 subunit of vacuolar H+ ATPase
92
What mutation accounts of 75% of the AD forms of osteopetrosis?
- mutation in gene encoding CIC7 (chloride channel)
| - CLCN7
93
What are cathepsin K mutations associated with?
- pycnodysostosis ( as specific form of osteopetrosis)
