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Biochemistry (Cole) > Lecture 42 Oral Tissues Osteoblasts Osteocytes Osteoclasts > Flashcards

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
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2
Q

Where do osteoblasts originate from?

A
  • mesenchymal progenitors
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3
Q

what types of cells can mesenchymal progenitors give off?

A
  • myocytes
  • adipocytes
  • hypertrophic chondrocytes
  • osteoblasts
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4
Q

Osteoblasts, chondrocytes, myoblasts, and adipocytes differentiate from a common_________ precursor

A
  • mesenchymal
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5
Q

What do osteoblasts produce large amounts of?

A
  • extracellular matrix proteins (esp. type I collagen) = osteoid which then mineralizes
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6
Q

What is the lifespan of osteoblasts?

A
  • weeks
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7
Q

What are the transcription factors associated with osteoblasts?

A
  • Runx2

- osterix

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8
Q

What is the main enzyme associated with osteoblasts?

A
  • alkaline phosphatase
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9
Q

What are the extracellular proteins associated with osteoblasts?

A
  • Type I collagen
  • osteopontin
  • osteocalcin
  • Bone sialoprotein (BSP)
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10
Q

what is runx2 roll in differentiating osteoblast?

A
  • acts early (with B catenin) to form immature osteoblast from osteochondrogenic precursor
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11
Q

When does osterix act (with b catenin) to form a mature osteoblast?

A
  • late maturation
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12
Q

What happens if b catenin is present in the proliferation phase of osteoblast differentiation?

A
  • it inhibits the process
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13
Q

What does b catenin accomplish in the terminal differentiation phase?

A
  • turning mature osteoblast to osteocyte, lining cell, or apoptosis
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14
Q

What happens if runx2 is present in late maturation phase of osteoblast differentiation?

A
  • it inhibits the process (timing is everything)
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15
Q

What can mature osteoblasts differentiate into?

A
  • lining cell
  • osteocyte
  • apoptosis
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16
Q

What is the master transcription factor for bone?

A
  • Runx2
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17
Q

What is runx 2 essential for?

A
  • bone and tooth development
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18
Q

What happens to mice lacking RUNX2?

A
  • form a cartilaginous skeleton that fails to mineralize
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19
Q

heterozygous mutation of RUNX2 in humans results in _____?

A
  • Cleidocranial Dysplasia (CCD)
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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
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21
Q

What causes cleidocranial dylsplasia?

A
  • inactivating mutation or deletion in one allele of RUNX2 which results in haploinsuffiency
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22
Q

What transcription factor does RUNX2 induce downstream?

A
  • osterix (also critical for osteoblast differentiation)
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23
Q

What happens to mice lacking osterix (gene name SP7)

A
  • have impaired osteoblast formation
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24
Q

What osteoblast genes does osterix control the expression of?

A
  • type I collagen
  • osteocalcin
  • osteopontin
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25
Q

What type of OI is associated with mutations in SP7 (osterix)?

A
  • type XII
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26
Q

Where does BMP2,7 play a role in the osteoblast differentiation pathway?

A
  • proliferation
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27
Q

What happens when you knockout specific BMPs in bone?

A
  • leads to skeletal defects
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28
Q

______ are originally purified from bone extracts that induce bone formation when implanted in muscle (ectopic bone assay)

A
  • BMPs
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29
Q

Bone morphogenetic proteins are required for?

A
  • skeletal development/maintenance of adult bone homeostasis
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30
Q

Bone morphogenetic proteins do what in osteoblasts?

A
  • promote differentiation form early osteoprogenitor cells
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31
Q

What is know as stone man syndrome?

A
  • Fibrodysplasia ossificans progressiva
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32
Q

_______ is bone forming in soft tissues and is a symtom of FOP (fibrodyslplasia ossificans progressiva)

A
  • Heterotropic bone formation
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33
Q

T/F In FOP bone forms in response to tissue trauma or surgery

A
  • T
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34
Q

What causes FOP?

A
  • mutations in BMP type I receptor (ACVR1 gene)

- single a.a substitution R206H

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35
Q

With FOP can there be mild constitutive activation and overactivation with ligand binding?

A
  • Yes
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36
Q

What are most of the cases of FOP due to?

A
  • spontaneous mutation in gametes/early embryo (most FOP patients can’t have children)
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37
Q

What is a a potential treatment for FOP?

A
  • Palovaratene and antibodies against activin A as well as kinase inhibitors selective for mutant receptor
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38
Q

What happens to B-cat in the absence of Wnt?

A
  • it binds to GSK-3B and it is degraded
39
Q

What happens with the Wnt/B catenin signaling pathway?

A
  • 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
Q

Activating mutations of Lrp5 lead to ____ bone mass in humans?

A
  • high
41
Q

Inactivating mutations of Lrp5 lead to?

A
  • low bone mass in humans
42
Q

What is Pryophosphate (PPI)

A
  • a natural inhibitor of mineralization
43
Q

What does alkaline phosphatase do?

A
  • it inhibits PPI which promates mineralization by stopping PPI
44
Q

Mice lacking alkaline phosphatase gene (______) have impaired mineralization

A
  • TNAP
45
Q

What is the alkaline phosphatase gene in humans?

A
  • TNSALP
46
Q

Mutations in alkaline phosphatase gene (TNSALP) is associated with?

A
  • hypophasphatasia
47
Q

80 % of the mutations assocaited with TNSALP/hypophosphatasia are?

A
  • missense mutations
48
Q

What are the symptoms of Hypophasphatasia (HPP)

A
  • impaired mineralization of skeleton/dentition
  • leg bowing, rachitic rosary, tooth loss, waddling gait
  • muscle weakness, seizures
49
Q

What are the outcomes of HPP

A
  • 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
Q

What is the most promising new treatment for HPP?

A
  • bone-targeted enzyme replacement therapy

- TNSALP recombinant enzyme with a 10 amino acid bone targeting peptide sequence (deca-aspartate)

51
Q

How long did the bone targeted enzyme replacement therapy take for the patient to grow finger bones and ribs?

A
  • 24 weeks
52
Q

What are some characteristics of osteocytes?

A
  • 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
Q

What is the transcription factor associated with osteocytes that is also found in muscles?

A
  • Mef2c
54
Q

What are the early osteocyte markers?

A
  • E11/gp38/ podoplanin
  • Dentin matrix protein - 1 (DMP1)
  • Matrix extracellular phosphoglycoprotein
  • phosphate regulating endopeptidase homolog x-linked (PHEX)
55
Q

What is the late osteocyte marker protein?

A
  • Sclerostin (SOST)
56
Q

What are the potential functions of osteocytes?

A
  • 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
Q

What is the SOST gene role?

A
  • 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
Q

What happens when you dont have Sclerostin(sost)

A
  • No sclerostin leads to high bone mass because there is no break
59
Q

Deletion or mutation of the SOST gene leads to what disease?

A
  • Sclerosteosis or Van Buchem’s

- (increased bone mass, especially obvious in craniofacial skeleton)

60
Q

How is sclerostin being looked at in osteoporosis treatment?

A
  • antibodies being developed to target sclerostin so there will be no brake on bone formation in osteoporosis patients
61
Q

What are the genes that osteocytes express that are important in phosphate homeostasis?

A
  • FGF23- Fibroblast growth factor - 23
  • DMP1 - dentin matrix protein-1
  • PHEX
62
Q

What is the precursor of osteoclasts?

A
  • derived from same precursors as macrophages

- (hematopoietic lineage)

63
Q

T/F Mature osteoclasts have only one nucleus?

A
  • false they are multinucleated
64
Q

How long to osteoclasts live?

A
  • days
65
Q

How do osteoclasts work?

A
  • 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
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.)
67
Q

Why are osteoclasts important in normal bone growth?

A
  • they reshape the bone/model it to maintain shape
68
Q

What is the master transcription factor of osteoclasts?

A
  • NFATc1
69
Q

What are the two growth factors associated with osteoclast differentiation?

A
  • M-CSF

- RANK

70
Q

What inhibits osteoclast differentiation?

A
  • OPG
71
Q

What are the down stream transcription factors involved with osteoclast formation/function?

A
  • C-fos and NFkb
72
Q

____ promotes proliferation/survival of osteoclasts precursors?

A
  • M-CSF
73
Q

_______ member of TNF superfamily that is required for osteoclast fusion and differentiation

A
  • RANKL
74
Q

_____ is a natural inhibitor of RANKL (decoy receptor)

A
  • OPG osteoprotogerin
75
Q

What produces rankl and opg?

A
  • osteoblasts/osteocytes
76
Q

What are the 5 things osteoclasts need to do?

A
  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
Q

What are the osteoclast transcription factors?

A
  • NFATc1 (master regulator)
  • C-fos
  • NFkB`
78
Q

What is the enzyme that is an osteoclast marker protein?

A
  • Tartate resistant acid phosphatase
79
Q

What receptors are used to mark osteoclasts?

A
  • RANK (receptor for RANKL)
  • C-fms (receptor for M-CSF)
  • calcitonin receptor
  • Integrin avB3
80
Q

What are the proton pumps that mark osteoclasts?

A
  • carbonic anhydrase II

- vacular type ATPase

81
Q

What are the proteases that mark osteoclast activity?

A
  • cathepsin k

- MMP9, MMP13

82
Q

Osteoclasts attach via ______ integrins to form sealed zone?

A
  • avB3
83
Q

What generates the protons in osteoclasts?

A
  • carbonic anhydrase II (CAII)
84
Q

What do osteoclasts use to create an acid PH in resorption lacuna?

A
  • vacuolar-type H+ ATPase that pumps protons
85
Q

What does the osteoclast release to digest matrix proteins?

A
  • cathepsin K and other proteases
86
Q

What removes excess bicarbonate in the osteoclast?

A
  • Cl- and HCO3- exchanger on basolateral surface
87
Q

What are the two ways you can have impaired osteoclast function?

A
  • failure in osteoclast formation

- impaired osteoclast resorptive function

88
Q

Is the autosomal dominant form of osteopetrosis bad?

A
  • no there relatively few symptoms
89
Q

Is the autosomal recessive form of osteopetrosis severe?

A
  • yes typically fatal if untreated in early childhood
90
Q

What are the symptoms of osteopetrosis?

A
  • bone abnormally dense and prone to fracture
  • affects bone growth, remodeling and tooth eruption
  • lots of other complications
91
Q

What mutation accounts for 50% of the AR cases of osteopetrosis?

A
  • TCIRG1

- a3 subunit of vacuolar H+ ATPase

92
Q

What mutation accounts of 75% of the AD forms of osteopetrosis?

A
  • mutation in gene encoding CIC7 (chloride channel)

- CLCN7

93
Q

What are cathepsin K mutations associated with?

A
  • pycnodysostosis ( as specific form of osteopetrosis)

Biochemistry (Cole) (25 decks)

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