Lecture 26 - Healthy Bone Flashcards Preview

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Flashcards in Lecture 26 - Healthy Bone Deck (58):
1

Composition of healthy bone
1)
2)
3)

1) Organic matrix
2) Mineral
3) Water

2

Organic matrix of healthy bone composition
1)
2)

1) 90% collagen (collagen makes up ~10% healthy bone mass)
2) Other proteins that help bind mineral

3

Mineral composition of healthy bone
1)
2)

1) 65% adult bone mass is hypoxyapatite
2) Smal amounts of calcium, magnesium, bicarbonate

4

How much of adult bone mass is water?

25%

5

Hypoxyapatite

Insoluble salt of calcium and phosphorus
~65% healthy adult bone mass

6

How much adult bone is replaced each year?

5-10%

7

Number of microscopic bone remodelling foci

1-2 million

8

How is bone remodelling carried out?

Asynchronously.
At sites that are geographically and temporally separate

9

Reasons for bone remodelling
1)
2)
3)

1) Maintain ion concentration in the body (EG: Ca2+)
2) Adapt shape and structural organisation to alterations in biomechanical forces (mechanostat)
3) Maintain structural integrity, repair microdamage

10

Proportion of body's calcium in bone

99%

11

Proportion of body's phosphorus in bone

85%

12

Basic multicellular unit of bone
1)
2)
3)

1) Osteocytes
2) Osteoblasts
3) Osteoclasts

13

Name of cavity formed by osteoclast

Resorption cavity
Lacuna

14

Time taken for bone resorption

3 weeks

15

Time taken for bone formation

3-4 months

16

Disease where bone density is too low

Osteoporosis

17

Disease of net bone gain
1)
2)

Osteopetrosis
Osteosclerosis

18

Osteoclast phenotype
1)
2)

1) Large, multinucleated cells (4-20 nuclei)
2) Rich in mitochondria

19

Process by which osteoclasts resorb bone
1)
2)
3)
4)

1) Form a sealing zone (integrin-mediated)
2) Release H+, acidify lacuna, degrade mineral component
3) Release of collagenases, other enzymes to degrade organic component
4) Bone degradation products are taken up by osteoclast, released

20

What do osteoblasts differentiate from?

Mesenchymal stem cells

21

Other cells which differentiate from mesemchymal stem cells
1)
2)
3)

1) Muscle
2) Chondrocytes
3) Adipocytes

22

Three fates of osteoblasts
1)
2)
3)

1) Osteocyte (encased in bone)
2) Lining cell (sits on surface of bone)
3) Apoptosis

23

Bone formation of osteoblasts
1)
2)
3)

1) Secretion of ECM proteins (osteoid) including collagen, bone sialoprotein, osteocalcin
2) Expression of alkaline phosphatase
3) Mineral deposition

24

ECM proteins secreted by osteoblast during bone formation
1)
2)
3)

1) Collagen
2) Bone sialoprotein
3) Osteocalcin

25

Function of alkaline phosphatase

Renders the osteoid competent for mineral deposition

26

Osteoid

Unmineralised bone

27

What is unmineralised bone called?

Osteoid

28

RANKL
1)
2)
3)
4)
5)

1) Receptor activator of NF-kB ligand
2) Key differentiation factor in osteoclast development
3) Binds to osteoclast precursor
4) Member of TNF superfamily
5) Mostly membrane-bound, but can be cleaved to soluble form

29

Osteoclast differentiation
1)
2)
3)
4)

1) Haematopoietic stem cell
2) Myeloid progenitor develops into osteoclast progenitor by binding M-CSF released by osteoblast-lineage cells
3) Osteoclast progenitor expresses RANKL receptor, RANK-L receptor binds RANKL released by osteoblast lineage cells
4) Cell binds to bone, becomes osteoclast

30

Factor released by osteoblast-lineage cells that causes myeloid progenitor to differentiate into osteoclast progenitor

M-CSF (macrophage colony stimulating factor)

31

Effect of absent RANKL/RANK

RANKL-/- mice develop severe osteopetrosis

32

RANK
1)
2)
3)

1) Receptor for RANKL/ODF
2) Member of TNF receptor family
3) Expressed on osteoclasts and osteoclast progenitors

33

OPG
1)
2)
3)
4)

1) Osteoprotegerin
2) Member of TNF receptor family
3) Binds RANKL as a decoy receptor
4) Blocks RANKL-induced osteoclast differentiation

34

Effect of absent osteoprotegerin

Osteoprotegerin-/- mice develop osteoporosis

35

Key regulator of osteoclast differentiation

Osteoprotegerin:RANKL ratio

36

M-CSF roles
1)
2)

1) Proliferation of myeloid precursors
2) Survival of osteoclast progenitors and mature osteoclasts

37

Producers of RANKL
1)
2)

1) Primary producers are early-mid stage osteoblasts
2) Can also be produced by osteocytes

38

Main producers of OPG

Mid- to late-stage osteoblasts

39

Promoters of osteoblast differentiation and function

Wnt ligands

40

Differentiation induced by wnt ligands

Osteoblastic progenitor to pre-osteoblast

41

Effect of wnt activation in osteoblasts
1)
2)

1) Promotes bone formation
2) Inhibits bone resorption

42

How do wnt ligands promote bone formation?
1)
2)
3)

1) Wnt ligand binds coreceptors frizzled or LRP5/6
2) Beta-catenin in cytoplasm is stabilised
3) Beta-catenin translocated to nucleus, acts as a transcription factor, induces genes that induce osteoblast differentiation, increase OPG expression

43

Factors that inhibit wnt signalling in osteoblasts
1)
2)
3)

1) Sclerostin binds LRP5/6
2) Dikkopf (DKK) binds LRP5/6
3) Secreted frizzled-related protein 1 (sFRP1) binds wnt ligands

44

Effect of increased sclerostin/DKK/secreted frizzled-related protein 1

Increased bone resorption by reducing osteoblast differentiation, increases osteoclast differentiation (increases RANKL:OPG ratio)

45

Cell that produces endogenous wnt antagonists

Osteoblast

46

Osteocyte

Terminally-differentiated osteoblast, encased in bone matrix

47

Osteocyte features
1)
2)
3)
4)

1) Longest-lived cell in the body (20-25 years)
2) Sit within bone matrix in lacunae
3) Dendrite-like cell processes (canaliculi) that sense mechanical loading, communicate between other osteocytes, cells on bone surface
4) Regulate osteoblasts and osteoclasts

48

How do osteocytes regulate osteoblasts and osteoclasts?

1) Regulate levels of DKK and sclerostin
2) Can release RANKL

49

What is sclerostosis?

Mutation in sclerostin, which inactivates it
Very thick bone, osteosclerotic condition

50

Effect of increased mechanical loading on osteocytes

Reduce expression of DKK, sclerostin
This increases bone formation, reduces resorption, because of activation of wnt signaling

51

Treatment strategies for osteoporosis
1) a,b
2) a

1) Target osteoclast
a) Inhibit osteoclast
b) Inhibit RANKL
2) Target osteoblast
a) Target osteoblast progenitor differentiation

52

Bisphosphonates
1)
2)
3)

1) Inhibit osteoclasts, lead to apoptosis
2) Used to treat osteoporosis
3) EG: Zoledronate

53

Denosumab
1)
2)

1) Anti-RANKL, fully-humanised MAb
2) Inhibits osteoclast differentiation and survival

54

Effect of bisphosphonates and anti-RANKL MAbs

1) Reduces number of fractures
2) Reduces bone loss
3) No increase in bone volume

55

Osteoporosis treatments that target osteoclasts
1)
2)

1) Bisphosphonates
2) Anti-RANKL MAbs

56

Osteoporosis treatment that targets ostoblasts

Recombinant parathyroid hormone, amino acids 1-34 (rhPTH,1-34, teriparatide)

57

Recombinant parathyroid hormone, amino acids 1-34
1)
2)
3)

1) Only approved anabolic therapy for osteoporosis
2) Given as an intermittent injection. Constant exposure doesn't lead to increased bone density
3) Induces mesenchymal stem cell differentiation into osteoblasts

58

Emergin osteoporosis therapy that promotes bone formation

Anti-sclerostin MAb
AMG785 or Romosozumab