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Applied Biochemistry > Tissue Osteoblasts Osteocytes Osteoclasts > Flashcards

Tissue Osteoblasts Osteocytes Osteoclasts Flashcards

1
Q

three main bone cell types

A

osteoclasts
osteoblasts
osteocytes

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2
Q

To Repair Damage Bone is Continually Being

Removed by — and Rebuilt by — (Bone Remodeling)

A

Osteoclasts

Osteoblasts

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3
Q

Osteoblasts, chondrocytes, myoblasts and adipocytes differentiate from a common — precursor

A

mesenchymal

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4
Q

osteoblasts are derived from

A

mesenchymal

stem cells

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5
Q

shape of osteoblasts

A

Plump, cuboidal cells located on

bone forming surfaces

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6
Q

osteoblasts produce large amounts of
extracellular matrix proteins
(esp. collagen type I) =

A

osteoid, which then mineralizes

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7
Q

lifespan of osteoblasts

A

weeks

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8
Q

osteoblasts marker proteins: transcription factors (2)

A
  • Runx2

* Osterix

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9
Q

osteoblasts marker proteins: enzymes (1)

A

Alkaline phosphatase

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10
Q

osteoblasts marker proteins: ECM proteins (4)

A
  • Type I collagen
  • Osteopontin
  • Osteocalcin
  • Bone sialoprotein (BSP)
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11
Q

Runx2 is a — for Bone

A

Master Transcription

Factor

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12
Q

runx2 is essential for

A

bone and tooth development

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13
Q

Mice lacking RUNX2 form a

cartilaginous skeleton that

A

fails to

mineralize

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14
Q

Heterozygous mutation of RUNX2 in

humans results in

A 
Cleidocranial 
Dysplasia (CCD)
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15
Q 
Cleidocranial 
Dysplasia (CCD) symptoms
A

• Autosomal Dominant
• Haploinsuffiency of RUNX2 (due to
inactivating mutation/deletion in one allele)
• Delayed ossification of midline structures of
body (esp. 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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16
Q

key characteristic of CCD

A

abnormal shoulder mobility due to hypoplastic/aplastic clavicles

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17
Q

— is a Key Transcription Factor for
Osteoblast Differentiation that is
Downstream of Runx2

A

Osterix

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18
Q

Runx2 induces another transcription

factor, —

A

Osterix

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19
Q

Osterix is also critical for

A

osteoblast differentiation

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20
Q

Mice lacking osterix (gene name SP7)

have

A

impaired osteoblast formation

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21
Q

Osterix controls expression of osteoblast genes: (3)

A

Type I collagen
Osteocalcin
Osteopontin

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22
Q

Human Mutations in SP7 (Osterix) - associated with

A

Osteogenesis Imperfecta type XII

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23
Q

some key signaling pathways that regulate osteoblast differentiation (8)

A 
BMPs
TGFb
WNT/B catenin signaling pathway 
hedgehog proteins 
IGF-1 
PTH and PTHrP
FGFs
Notch pathway
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24
Q

BMPs –

A

Bone Morphogenetic Proteins

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25
Q

TGFβs –

A

Transforming Growth Factor Beta

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26
Q

PTH and PTHrP –

A

Parathyroid hormone and parathyroid

hormone-related peptide

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27
Q

FGFs –

A

Fibroblast growth factors

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28
Q

Notch Pathway –

A

Notch receptors and ligands (Delta, Serrate,

Lag2)

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29
Q

BMPs - originally purified from bone extracts that induce

A

bone formation when implanted in muscle (ectopic bone assay)

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30
Q

BMPs are required for — — of adult bone

homeostasis

A

skeletal development/maintenance

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31
Q

BMPs promote differentiation from early — cells

A

osteoprogenitor

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32
Q

BMPs are important in

A

fracture healing

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33
Q

knockout of specific BMPs in bone leads to

A

skeletal defects

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34
Q

naturally occurring mutations in BMPs or their receptors result in

A

inherited skeletal disorders in humans

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35
Q

FOP –

A

Fibrodysplasia Ossificans Progressiva

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36
Q

Heterotopic bone formation

A

bone forming

in soft tissues

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37
Q

(3) of bone in extra-

skeletal sites - fuses joints, ribs, etc.

A

Ribbons, sheets, plates

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38
Q

Bone forms in response to — —

exacerbated by surgical intervention

A

tissue trauma

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39
Q

Mutations in BMP — — — (ACVR1

gene) - single a.a. substitution R206H

A

type I receptor

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40
Q

Mutation causes mild —
activation (i.e. in absence of ligand) and
— with BMP ligand binding.
Also acquired responsiveness to activin A.

A

constitutive

overactivation

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41
Q

Most cases due to

A

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

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42
Q

potential treatments for FOP (2)

A 
Palovaratene and antibodies against
activin A being investigated as potential
treatments as well as kinase inhibitors
selective for mutant receptor (based on
animal studies)
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43
Q

High Bone Mass Phenotype Due to Mutations

in

A

LRP5 (affects Wnt/β-catenin signaling)

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44
Q

Wnt-β-catenin signaling pathway

important in determining

A

bone

mass

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45
Q

Activating mutations of Lrp5 lead

to — in humans

A

high bone mass

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46
Q

Inactivating mutations of Lrp5

lead to

A

low bone mass

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47
Q

Alkaline Phosphatase is an enzyme highly expressed in

A

osteoblasts/

odontoblasts

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48
Q

alkaline phosphatase hydrolyzes pyrophosphate (PPi), a natural inhibitor of mineralization,
thereby increasing local phosphate
concentration which promotes

A

mineralization

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49
Q

Mice lacking alkaline phosphatase gene

(TNAP ) have

A

impaired mineralization

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50
Q

In humans - mutations in alkaline
phosphatase gene (TNSALP) associated
with —

A

hypophosphatasia

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51
Q

Hypophosphatasia (HPP)

A

Rare heritable Rickets/Osteomalacia (~350

cases reported)

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52
Q

> 289 mutations identified in — (~80% =

missense mutations)

A 
human alkaline 
phosphatase gene (TNSALP)
53
Q

HPP has reduced activity of

A

alkaline phosphatase

54
Q

symptoms of HPP

A

Impaired mineralization of skeleton/dentition,
leg bowing, rachitic rosary, early tooth loss,
waddling gait, muscle weakness, seizures

55
Q

HPP has varying severity from

A

perinatal lethal to adult onset or mild forms only affecting dentition
(dependent on degree of loss of function of
alkaline phosphatase)

56
Q

Expert dental care is important – (2) may be necessary

A

soft

foods/dentures

57
Q

treatment for HPP

A

previously no established treatment

58
Q

Infusion of — enzyme ineffective for HPP treatment

A

alkaline phosphatase

59
Q

— — successful in two severely affected infants

— improved HPP in an adult patient (Whyte

A

Marrow transplantation

Teriparatide (PTH 1-34)

60
Q

NEW TREATMENT RECENTLY APPROVED for HPP:

A

bone-targeted enzyme replacement therapy - TNSALP recombinant enzyme with a 10 amino acid bone targeting peptide sequence (deca-aspartate) (Whyte et al 2012, N. Engl. J.
Medicine, 366:904) – performing very well so far in tests with infantile HPP

61
Q

osteocytes are terminally differentiated

A

osteoblasts

62
Q

osteocytes are embedded in

A

bone matrix

63
Q

osteocytes make up over –% of bone cells

A

90%

64
Q

osteocytes have long

A

dendritic processes

65
Q

osteocytes were previously thought to be

A

quiescent cells

66
Q

osteocytes are now known to be an active cell type with key functions in

A

bone

67
Q

is there a master transcriptional gene identified yet?

A

no

68
Q

lifespan of osteocytes

A

decades

69
Q

osteocyte marker proteins: transcription factor (1)

A

Mef2c

70
Q

osteocyte marker proteins: early osteocyte markers (4)

A 
• E11/gp38/podoplanin
• Dentin matrix protein-1 (DMP1)
• Matrix extracellular phosphoglycoprotein
(MEPE)
• Phosphate regulating endopeptidase 
homolog, X-Linked (PHEX)
71
Q

osteocyte marker proteins: later osteocyte marker (1)

A

Sclerostin (SOST)

72
Q

Potential Functions of Osteocytes (4)

A

• Mechanosensors (control responses of bone cells
to mechanical loading)
• Control bone resorption and bone formation (by
regulating osteoclast and osteoblast activity)
• Regulate mineralization
• Regulators of mineral homeostasis-both calcium
and phosphorus

73
Q

Sclerostin is highly expressed in

A

mature
osteocytes, cementocytes,
odontoblasts

74
Q

Sclerostin is a negative regulator of

A

bone formation - antagonizes Wnt/beta-catenin signaling pathway

75
Q

sclerotin is through to act as a — to limit bone formation

A

brake

76
Q

Sclerostin null mice show —

bone mass phenotype

A

high
(increased
bone formation)

77
Q

Sclerostin gain of function mouse
models show — bone mass
phenotype (decreased bone
formation)

A

low
(decreased bone
formation)

78
Q

Deletion or mutation of SOST gene

results in

A

Sclerosteosis or Van Buchem’s

disease in humans

79
Q

Increased bone mass, especially

obvious in

A

craniofacial skeleton

80
Q

Antibodies to sclerostin – in preclinical/
clinical trials as an anabolic treatment
for

A

osteoporosis

81
Q

sclerotin establishes the osteocyte as a key target cell for development of

A

new treatments for diseases of bone loss and overgrowth

82
Q

Osteocytes as Regulators of —

Homeostasis

A

Phosphate

83
Q

Osteocytes express several genes important in

phosphate homeostasis: (3)

A

FGF23
DMP1
PHEX

84
Q

FGF23

A

Fibroblast growth factor-23 (FGF23)

85
Q

DMP1

A

Dentin matrix protein-1

86
Q

PHEX

A

Phosphate regulating endopeptidase

homolog, X-linked

87
Q

osteocytes play an endocrine role in regulation of — homeostasis

A

phosphate

88
Q

osteoclasts are derived from same precursors as

A

macrophages (hematopoietic lineage)

89
Q

Mature osteoclasts are

A

multinucleated

90
Q

osteoclasts express — for removing ECM proteins (e.g. collagen)

A

proteases

91
Q

osteoclasts express proteins that act as

A

proton
pumps to generate H+ ions (reduces pH
to dissolve mineral)

92
Q

Active osteoclasts have specialized

“— —”, which increases

A

ruffled border

surface area in resorption compartment

93
Q

lifespan of osteoclasts

A

short (days)

94
Q

osteoclasts are responsible for (5)

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.)

95
Q

Osteoclastic Resorption is Important

for

A

Normal Bone Growth

96
Q

growth occurs at the

A

epiphyseal plate

97
Q

—: must occur to

maintain the bone shape

A

Modeling

98
Q

Master transcription factor of osteoclast formation/function

A

NFATc1

99
Q

(2) are downstream of NFATc 1 and also important

A

C-fos and NFƙB

100
Q

2 factors produced by osteoblasts/osteocytes which are essential for OCL differentiation

A

– RANKL

– M-CSF

101
Q

RANKL

A

receptor activator of NFkB ligand

102
Q

M-CSF (a.k.a CSF-1)

A

Macrophage colony stimulating factor)

103
Q

M-CSF promotes

A

proliferation/ survival of osteoclast precursors

104
Q

RANKL (member of TNF

superfamily) is required for

A

osteoclast fusion and differentiation

105
Q

OPG (osteoprotogerin)

A

natural inhibitor of RANKL decoy receptor

106
Q

What Does an Osteoclast Need to Do? (5)

A

• 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

107
Q

Osteoclast Marker Proteins: transcription factors (3)

A
  • NFATc1
  • C-fos
  • NFkB
108
Q

Osteoclast Marker Proteins: enzyme (1)

A

Tartrate resistant acid Phosphatase

TRAP

109
Q

Osteoclast Marker Proteins: receptor (4)

A
  • RANK (receptor for RANKL)
  • C-fms (receptor for M-CSF)
  • Calcitonin receptor
  • Integrin αvβ3
110
Q

Osteoclast Marker Proteins: generates protons/proton pump (2)

A
  • Carbonic anhydrase II

* Vacuolar-type ATPase

111
Q

Osteoclast Marker Proteins: proteases (2)

A
  • Cathepsin K

* MMP9, MMP13

112
Q

Osteoclasts attach via — — to form sealed zone

A

αvβ3

integrins

113
Q

generates protons

A

Carbonic anhydrase II (CAII)

114
Q

Vacuolar-type H+ ATPase pumps
protons into resorption lacuna –
creates

A

acid pH (dissolves mineral)

115
Q

(2) exchanger on
basolateral surface removes excess
bicarbonate

A

Cl- and HCO3-

116
Q

Chloride channel maintains

A

charge

neutrality

117
Q

— (and other proteases)
also released into resorption
lacuna (digests matrix proteins)

A

Cathepsin K

118
Q

Impaired Osteoclast Function

Leads to

A

Osteopetrosis

119
Q

Osteopetrosis can be due to

A

failure in osteoclast FORMATION or osteoclasts

form normally but have impaired resorptive FUNCTION

120
Q

two major clinical forms of osteopetrosis

A

autosomal dominant adult (benign) type

autosomal recessive infantile (malignant) type

121
Q

autosomal dominant adult (benign) type

A

relatively few

symptoms

122
Q

autosomal recessive infantile (malignant) type -

A

typically

fatal (if untreated) in early childhood

123
Q

Bones abnormally — and prone to —

A

dense

fracture

124
Q

Failed osteoclastic resorption affects bone (3)

A

growth, remodeling,

tooth eruption, etc.

125
Q

osteopetrosis can be accompanied by

A

scoliosis (spinal curvature), nerve
compression in head and face (hearing loss, blindness), impaired
marrow function (anemia), enlarged liver or spleen, dental
abnormalities, short stature, slow growth, recurrent infections,
etc

126
Q

– mutations identified in gene
encoding α3 subunit of vacuolar
H+ ATPase (TCIRG1)

A

> 60

127
Q

Accounts for about –% of AR

osteopetrosis in humans

A

50

128
Q

Mutations also found in gene
encoding -– accounts for 75% of ADforms of osteopetrosis (OMIM#
166600)

A

ClC7 chloride channel

CLCN7

129
Q

Cathepsin K mutations associated
with –– a specific
form of osteopetrosis

A

pycnodysostosis

Applied Biochemistry (52 decks)

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