Tissue Osteoblasts Osteocytes Osteoclasts Flashcards
(129 cards)
1
Q
three main bone cell types
A
osteoclasts
osteoblasts
osteocytes
2
Q
To Repair Damage Bone is Continually Being
Removed by — and Rebuilt by — (Bone Remodeling)
A
Osteoclasts
Osteoblasts
3
Q
Osteoblasts, chondrocytes, myoblasts and adipocytes differentiate from a common — precursor
A
mesenchymal
4
Q
osteoblasts are derived from
A
mesenchymal
stem cells
5
Q
shape of osteoblasts
A
Plump, cuboidal cells located on
bone forming surfaces
6
Q
osteoblasts produce large amounts of
extracellular matrix proteins
(esp. collagen type I) =
A
osteoid, which then mineralizes
7
Q
lifespan of osteoblasts
A
weeks
8
Q
osteoblasts marker proteins: transcription factors (2)
A
- Runx2
* Osterix
9
Q
osteoblasts marker proteins: enzymes (1)
A
Alkaline phosphatase
10
Q
osteoblasts marker proteins: ECM proteins (4)
A
- Type I collagen
- Osteopontin
- Osteocalcin
- Bone sialoprotein (BSP)
11
Q
Runx2 is a — for Bone
A
Master Transcription
Factor
12
Q
runx2 is essential for
A
bone and tooth development
13
Q
Mice lacking RUNX2 form a
cartilaginous skeleton that
A
fails to
mineralize
14
Q
Heterozygous mutation of RUNX2 in
humans results in
A
Cleidocranial Dysplasia (CCD)
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
16
Q
key characteristic of CCD
A
abnormal shoulder mobility due to hypoplastic/aplastic clavicles
17
Q
— is a Key Transcription Factor for
Osteoblast Differentiation that is
Downstream of Runx2
A
Osterix
18
Q
Runx2 induces another transcription
factor, —
A
Osterix
19
Q
Osterix is also critical for
A
osteoblast differentiation
20
Q
Mice lacking osterix (gene name SP7)
have
A
impaired osteoblast formation
21
Q
Osterix controls expression of osteoblast genes: (3)
A
Type I collagen
Osteocalcin
Osteopontin
22
Q
Human Mutations in SP7 (Osterix) - associated with
A
Osteogenesis Imperfecta type XII
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
24
Q
BMPs –
A
Bone Morphogenetic Proteins
25
TGFβs –
Transforming Growth Factor Beta
26
PTH and PTHrP –
Parathyroid hormone and parathyroid
| hormone-related peptide
27
FGFs –
Fibroblast growth factors
28
Notch Pathway –
Notch receptors and ligands (Delta, Serrate,
| Lag2)
29
BMPs - originally purified from bone extracts that induce
bone formation when implanted in muscle (ectopic bone assay)
30
BMPs are required for --- --- of adult bone
| homeostasis
skeletal development/maintenance
31
BMPs promote differentiation from early --- cells
osteoprogenitor
32
BMPs are important in
fracture healing
33
knockout of specific BMPs in bone leads to
skeletal defects
34
naturally occurring mutations in BMPs or their receptors result in
inherited skeletal disorders in humans
35
FOP –
Fibrodysplasia Ossificans Progressiva
36
Heterotopic bone formation
bone forming
| in soft tissues
37
(3) of bone in extra-
| skeletal sites - fuses joints, ribs, etc.
Ribbons, sheets, plates
38
Bone forms in response to --- ---
| exacerbated by surgical intervention
tissue trauma
39
Mutations in BMP --- --- --- (ACVR1
| gene) - single a.a. substitution R206H
type I receptor
40
Mutation causes mild ---
activation (i.e. in absence of ligand) and
--- with BMP ligand binding.
Also acquired responsiveness to activin A.
constitutive
| overactivation
41
Most cases due to
spontaneous mutation
in gametes/early embryo (most FOP
patients can’t have children)
42
potential treatments for FOP (2)
```
Palovaratene and antibodies against
activin A being investigated as potential
treatments as well as kinase inhibitors
selective for mutant receptor (based on
animal studies)
```
43
High Bone Mass Phenotype Due to Mutations
| in
LRP5 (affects Wnt/β-catenin signaling)
44
Wnt-β-catenin signaling pathway
| important in determining
bone
| mass
45
Activating mutations of Lrp5 lead
| to --- in humans
high bone mass
46
Inactivating mutations of Lrp5
| lead to
low bone mass
47
Alkaline Phosphatase is an enzyme highly expressed in
osteoblasts/
| odontoblasts
48
alkaline phosphatase hydrolyzes pyrophosphate (PPi), a natural inhibitor of mineralization,
thereby increasing local phosphate
concentration which promotes
mineralization
49
Mice lacking alkaline phosphatase gene
| (TNAP ) have
impaired mineralization
50
In humans - mutations in alkaline
phosphatase gene (TNSALP) associated
with ---
hypophosphatasia
51
Hypophosphatasia (HPP)
Rare heritable Rickets/Osteomalacia (~350
| cases reported)
52
>289 mutations identified in --- (~80% =
| missense mutations)
```
human alkaline
phosphatase gene (TNSALP)
```
53
HPP has reduced activity of
alkaline phosphatase
54
symptoms of HPP
Impaired mineralization of skeleton/dentition,
leg bowing, rachitic rosary, early tooth loss,
waddling gait, muscle weakness, seizures
55
HPP has varying severity from
perinatal lethal to adult onset or mild forms only affecting dentition
(dependent on degree of loss of function of
alkaline phosphatase)
56
Expert dental care is important – (2) may be necessary
soft
| foods/dentures
57
treatment for HPP
previously no established treatment
58
Infusion of --- enzyme ineffective for HPP treatment
alkaline phosphatase
59
--- --- successful in two severely affected infants
--- improved HPP in an adult patient (Whyte
Marrow transplantation
| Teriparatide (PTH 1-34)
60
NEW TREATMENT RECENTLY APPROVED for HPP:
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
osteocytes are terminally differentiated
osteoblasts
62
osteocytes are embedded in
bone matrix
63
osteocytes make up over --% of bone cells
90%
64
osteocytes have long
dendritic processes
65
osteocytes were previously thought to be
quiescent cells
66
osteocytes are now known to be an active cell type with key functions in
bone
67
is there a master transcriptional gene identified yet?
no
68
lifespan of osteocytes
decades
69
osteocyte marker proteins: transcription factor (1)
Mef2c
70
osteocyte marker proteins: early osteocyte markers (4)
```
• E11/gp38/podoplanin
• Dentin matrix protein-1 (DMP1)
• Matrix extracellular phosphoglycoprotein
(MEPE)
• Phosphate regulating endopeptidase
homolog, X-Linked (PHEX)
```
71
osteocyte marker proteins: later osteocyte marker (1)
Sclerostin (SOST)
72
Potential Functions of Osteocytes (4)
• 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
Sclerostin is highly expressed in
mature
osteocytes, cementocytes,
odontoblasts
74
Sclerostin is a negative regulator of
bone formation - antagonizes Wnt/beta-catenin signaling pathway
75
sclerotin is through to act as a --- to limit bone formation
brake
76
Sclerostin null mice show ---
| bone mass phenotype
high
(increased
bone formation)
77
Sclerostin gain of function mouse
models show --- bone mass
phenotype (decreased bone
formation)
low
(decreased bone
formation)
78
Deletion or mutation of SOST gene
| results in
Sclerosteosis or Van Buchem’s
| disease in humans
79
Increased bone mass, especially
| obvious in
craniofacial skeleton
80
Antibodies to sclerostin – in preclinical/
clinical trials as an anabolic treatment
for
osteoporosis
81
sclerotin establishes the osteocyte as a key target cell for development of
new treatments for diseases of bone loss and overgrowth
82
Osteocytes as Regulators of ---
| Homeostasis
Phosphate
83
Osteocytes express several genes important in
| phosphate homeostasis: (3)
FGF23
DMP1
PHEX
84
FGF23
Fibroblast growth factor-23 (FGF23)
85
DMP1
Dentin matrix protein-1
86
PHEX
Phosphate regulating endopeptidase
| homolog, X-linked
87
osteocytes play an endocrine role in regulation of --- homeostasis
phosphate
88
osteoclasts are derived from same precursors as
macrophages (hematopoietic lineage)
89
Mature osteoclasts are
multinucleated
90
osteoclasts express --- for removing ECM proteins (e.g. collagen)
proteases
91
osteoclasts express proteins that act as
proton
pumps to generate H+ ions (reduces pH
to dissolve mineral)
92
Active osteoclasts have specialized
| “--- ---”, which increases
ruffled border
| surface area in resorption compartment
93
lifespan of osteoclasts
short (days)
94
osteoclasts are responsible for (5)
• 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
Osteoclastic Resorption is Important
| for
Normal Bone Growth
96
growth occurs at the
epiphyseal plate
97
---: must occur to
| maintain the bone shape
Modeling
98
Master transcription factor of osteoclast formation/function
NFATc1
99
(2) are downstream of NFATc 1 and also important
C-fos and NFƙB
100
2 factors produced by osteoblasts/osteocytes which are essential for OCL differentiation
– RANKL
| – M-CSF
101
RANKL
receptor activator of NFkB ligand
102
M-CSF (a.k.a CSF-1)
Macrophage colony stimulating factor)
103
M-CSF promotes
proliferation/ survival of osteoclast precursors
104
RANKL (member of TNF
| superfamily) is required for
osteoclast fusion and differentiation
105
OPG (osteoprotogerin)
natural inhibitor of RANKL decoy receptor
106
What Does an Osteoclast Need to Do? (5)
• 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
Osteoclast Marker Proteins: transcription factors (3)
* NFATc1
* C-fos
* NFkB
108
Osteoclast Marker Proteins: enzyme (1)
Tartrate resistant acid Phosphatase
| TRAP
109
Osteoclast Marker Proteins: receptor (4)
* RANK (receptor for RANKL)
* C-fms (receptor for M-CSF)
* Calcitonin receptor
* Integrin αvβ3
110
Osteoclast Marker Proteins: generates protons/proton pump (2)
* Carbonic anhydrase II
| * Vacuolar-type ATPase
111
Osteoclast Marker Proteins: proteases (2)
* Cathepsin K
| * MMP9, MMP13
112
Osteoclasts attach via --- --- to form sealed zone
αvβ3
| integrins
113
--- ---
| generates protons
Carbonic anhydrase II (CAII)
114
Vacuolar-type H+ ATPase pumps
protons into resorption lacuna –
creates
acid pH (dissolves mineral)
115
(2) exchanger on
basolateral surface removes excess
bicarbonate
Cl- and HCO3-
116
Chloride channel maintains
charge
| neutrality
117
--- (and other proteases)
also released into resorption
lacuna (digests matrix proteins)
Cathepsin K
118
Impaired Osteoclast Function
| Leads to
Osteopetrosis
119
Osteopetrosis can be due to
failure in osteoclast FORMATION or osteoclasts
| form normally but have impaired resorptive FUNCTION
120
two major clinical forms of osteopetrosis
autosomal dominant adult (benign) type
| autosomal recessive infantile (malignant) type
121
autosomal dominant adult (benign) type
relatively few
| symptoms
122
autosomal recessive infantile (malignant) type -
typically
| fatal (if untreated) in early childhood
123
Bones abnormally --- and prone to ---
dense
| fracture
124
Failed osteoclastic resorption affects bone (3)
growth, remodeling,
| tooth eruption, etc.
125
osteopetrosis can be accompanied by
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
-- mutations identified in gene
encoding α3 subunit of vacuolar
H+ ATPase (TCIRG1)
>60
127
Accounts for about --% of AR
| osteopetrosis in humans
50
128
Mutations also found in gene
encoding -– accounts for 75% of ADforms of osteopetrosis (OMIM#
166600)
ClC7 chloride channel
| CLCN7
129
Cathepsin K mutations associated
with --– a specific
form of osteopetrosis
pycnodysostosis
