Lecture 44: Osteoclasts Osteoporosis and Fracture Healing Flashcards
(80 cards)
1
Q
what are osteoclasts derived from
A
same precursors as macrophages- hematopoietic lineage
2
Q
what is a characteristic of mature osteoclasts
A
mutlinucleateed
3
Q
what are proteases in osteoclasts used for
A
removing ECM proteins
4
Q
what do proteins that acts as proton pumps in osteoclasts do
A
generate H+ iions to reduce pH to dissolve mineral
5
Q
where is the ruffled border and what does it do
A
in active osteoclasts to increase surface area in resorption compartment
6
Q
what is the lifespan of osteoclasts
A
days (short)
7
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
8
Q
where does bone growth occur
A
at the epiphyseal plate
9
Q
what are the main factors in regulating osteoclast differentiation
A
M-CSF, RANKL,OPG,
10
Q
what is the master transcription factor in the regulation of osteoclast formation/function
A
NFATc1 and C-fod and NFkB downstream
11
Q
what are the factors produced by osteoblasts/osteocytes that are essential for osteoclast differentiation
A
RANKL and M-CSF
12
Q
what does M-CSF do
A
promotes proliferation/survival of osteoclast precursors
13
Q
what does RANKL do
A
required for osteoclast fusion and differentiation
14
Q
what does OPG do
A
natural inhibitor of RANKL
15
Q
what does an osteoclast need to do
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
16
Q
what are the transcription factors for osteoclasts
A
NFATc1, C-fos, NFkB
17
Q
what enzyme is important in osteoclasts
A
TRAP
18
Q
what are the receptors associated with osteoclast formation/function
A
- RANK: receptor for RANKL
-C-fms: receptor for M-CSF
-calcitonin receptor
-integrin avB3
19
Q
what generates protons/proton pump in osteoclasts
A
carbonic anhydrase 2 and vacuolar type ATPase
20
Q
what proteases are involved with osteoclasts
A
Cathepsin K, MMP9 and MMP13
21
Q
what do osteoclasts attach to to form the sealed zone
A
avB3 integrins
22
Q
what generates protons in osteoclast
A
carbonic anhydrase 2
23
Q
what do vaculoar type H+ ATPase pumps do
A
pumps protons into resorption lacuna to create an acidic pH
24
Q
what do Cl- and HCO3- exchanger do and where is it located in osteoclasts
A
on basolateral surface removes excess bicarbonate
25
what does the chloride channel in osteoclasts do
maintain charge neutrality
26
what does cathepsin K in osteoclasts do
released into resorption lacuna to digest matrix proteins
27
what does impaired osteoclast function lead to
osteopetrosis
28
what can osteopetrosis be caused by
failure in osteoclast formation or osteoclasts form normally but have impaired resorptive function
29
what are the major clinical forms of osteopetrosis
- autosomal dominant adult type-few symptoms
- autosomal recessive infantile type - typically fatal in early childhood
30
describe the characteristics of bone in osteopetrosis
bones are abnormally dense and prone to fracture
31
what does failed osteoclastic resorption affect
bone growth, remodeling, tooth eruption
32
what can osteopetrosis be accompanies by
scoliosis, 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
33
what gene mutations are associated with osteopetrosis
TCIRG1, CLCN7, cathepsin K mutations
34
what mutation accounts for 50% of AR osteopetrosis
TCIRG1
35
what mutation accounts for 75% of AD forms of osteopetrosis
CLCN7
36
what are mutations in cathepsin K associated with
pycnodysostosis
37
what is the definition of osteoporosis
a patient with a BMD greater than 2.5 standard deviations below average for a healthy young female or male
38
how do bisphosphonates work
bind to hydroxyapatite, inhibit activity of osteoclasts by inhibiting mevalonate pathway important for prenylation of GTPases important for vesicular trafficking
39
how does hormone replacement therapy work in osteoporosis
restores hormone levels following menopause
40
how do SERMs work
work as partial agonist of estrogen receptor
41
what are bisphosphonates used for
osteoporosis and treatment of myeloma/bone metastatic cancers particularly if patients have high serum calcium
42
in which case is the dose of bisphosphonates are higher: cancer or osteoporosis
cancer
43
what is a bisphosphonate
non-hydrolyzable analog of pyrophosphate
44
what do bisphosphonates have a high affinity for
hydroxyapatite
45
what is the major side effect of bisphosphonates
osteonecrosis of the jaw (mandible or maxilla)
46
what is BONJ defined by
-current or previous treatment with a bisphosphonate
- exposed necrotic bone in the maxillofacial region that has been present for at least 8 weeks
- no history of radiation therapy to the jaws
47
what is the pathogenesis of BONJ
attributed mainly to suppression of bone turnover due to BP inhibition of osteoclast activity
48
how do bisphosphonates affect orthodontic tooth movement
they inhibit it
49
what is skeletal healing important for
- resolution of orthopedic trauma that has caused fractures
- healing of corrective surgeries where bony injuries are created intentionally to correct bone deformities
-bone regeneration in oral surgical procedures/tooth extractions
50
what can failed/delayed skeletal healing result from
inadequate fixation, infection, tumor, hypoxia/poor blood supply, metabolic dysfunction, chronic/inherited diseases
51
what cell types are required in fracture healing
-inflammatory cells
-chondroprogenitors/chondrocytes
-osteoprogenitors/osteocytes
-osteoclasts
-vascular cells
52
what is the timeline of fracture healing and how long does each phase occur
-inflammatory phase: peaks by 48h and lasts a week
-reparative phase: activated within a few days and persists for up to 2-3 months
- remodeling phase: can continue for several years
53
what are the 4 stages of fracture repair and what phase do they occur in
-formation of vascular hematoma (reactive phase)
- formation of (fibrocartilage) callus (reparative)
- tissue metaplasia - callus replaced by mineralized bone (reparative)
- bone remodeling and turnover (remodeling)
54
what happens in hematoma formation/inflammation
-formation of hematoma at injury site
- cytokines released: TNF alpha, IL-1, -6, -11, and -18
-cytokines lead to recruitment/infiltration of inflammatory cells
-inflammatory cells release more inflammatory cytokines and recruit mesenchymal stem cells/osteogenic precursors to fracture site
55
what happens in the formation of fibrocartilage callus
- MSC/connective tissue stem cells/blood vessels invade hematoma
-hematoma degenerates/phagocytes clear debris
-fibrous connective tissue matrix laid down by fibroblasts - granulation tissue
- MSc differentiation towards chondrogenic/osteogenic lineages
- hypoxia/tissue necrosis occurs at ends of bones
- in hypoxic regions MSC differentiate into chondrocytes - initiates endochondral bone formation
-intramembranous bone may form in subperiosteal sites where vascular supply is intact - hard callus
56
how long does hematoma formation/inflammation last
0-2 days
57
how long does formation of fibrocartilagenous callus last
about 1 week
58
what are the cell sources of osteogenic precursors
-periosteum
-muscle
-bone marrow
-maybe circulating
59
what are the cell types of osteogenic precursors
-mesenchymal stem cells (MSC)
- pericyte
- muscle satellite cell
60
what happens in the formation of bony callus
- intramembranous bone contributed to bony callus
- cartilage undegoes endochondral ossification
- fracture considered healed when bone stability restored by bone tissue completely bridging the original fracture
-initial bone formed- woven bone
61
how long does formation of bony callus take
several weeks up to 2-3 months
62
what happens in remodeling
- initial woven bone must be remodeled
- osteoclasts resorb woven bone in fracture callous then osteoblasts lay down new lamellar bone (haversian)
-restores marrow cavity
-restores original contours of bone
- biomechanical stability matches that of the original bone
63
how long does remodeling last
several weeks/months/years
64
what does fracture healing include
inflammation, endochondral bone formation, intramembranous bone formation, osteoclastic bone resorption
65
what do the early phases of fracture healing include
-formation of hematoma
-recruitment of MSC
- cell proliferation
-initation of chondrogenesis/osteogenesis
-vascular ingrowth/angiogensis
66
what are the 3 main categories of signaling molecules important in fracture healing
pro-inflammatory cytokines
-TGFbeta superfamily members
- angiogenic factors
67
what do TNF alpha and interleukins do
-recruit other inflammatory cells/promote MSc recruitment
-induce apoptosis of hypertrophic chondrocytes
recruit fibrogenic cells/promote formation of granulation tissue/ECM formation
- can promote osteoclast formation
68
what are pro-inflammatory cytokines secreted by
macrophages, mesenchymal cells, inflammatory cells
69
what are the pro-inflammatory cytokines
TNF alpha dn IL-1, -6, -11, -18
70
what are the TGF beta superfamily members
-TGF beta
-BMP2, 5 and 6
- GDF-8
71
what do TGF beta superfamily members do
-promote ECM synthesis and assembly/initiation of callus formation
- promote osteogenic differentiation
-GDF-8 role in cell proliferation
72
what are TGF beta superfamily members produced by
hematoma (platelets)/granulation tissue/differentiating MSC/periosteal callus
73
what are the angiogenic factors
VEGF, PDGF, and ANGPT
74
what do angiogenic factors do
promote vascular ingrowth from vessels in periosteum - brings pericytes
75
what does VEGF do
-promotes chemotaxis of osteoprogenitors
-upregulated in regions of hypoxia (under control of HIF 1 alpha)
76
what does vascularization do
-critical for fracture repair/bone formation
-brings in calcium and phosphate for mineralization
77
what could bone repair by enhanced by
-improving vascularization
-attracting progenitor cells
-acclerating bone formation
- accelerating remodelin
- BMPs, FGFs, PDGF, platelet rich plasma
78
what cell based therapies might enhance bone repair and formation
-autologous bone marrow collected from iliac crest and injected into non union site
-purified stem cell sources
79
what other approaches may be taken to enhance bone formation and reapir
-anti resopritves, bone anabolic agnets, gene therapy
80
what are antibodies to sclerostin being developed for
anabolic treatment for osteoporosis
