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Molecule to Malady > Lecture 26 - Healthy Bone > Flashcards

Lecture 26 - Healthy Bone Flashcards

1
Q

Composition of healthy bone
1)
2)
3)

A

1) Organic matrix
2) Mineral
3) Water

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2
Q

Organic matrix of healthy bone composition
1)
2)

A

1) 90% collagen (collagen makes up ~10% healthy bone mass)

2) Other proteins that help bind mineral

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3
Q

Mineral composition of healthy bone
1)
2)

A

1) 65% adult bone mass is hypoxyapatite

2) Smal amounts of calcium, magnesium, bicarbonate

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4
Q

How much of adult bone mass is water?

A

25%

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5
Q

Hypoxyapatite

A

Insoluble salt of calcium and phosphorus

~65% healthy adult bone mass

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6
Q

How much adult bone is replaced each year?

A

5-10%

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7
Q

Number of microscopic bone remodelling foci

A

1-2 million

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8
Q

How is bone remodelling carried out?

A

Asynchronously.

At sites that are geographically and temporally separate

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9
Q

Reasons for bone remodelling
1)
2)
3)

A

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

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10
Q

Proportion of body’s calcium in bone

A

99%

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11
Q

Proportion of body’s phosphorus in bone

A

85%

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12
Q

Basic multicellular unit of bone
1)
2)
3)

A

1) Osteocytes
2) Osteoblasts
3) Osteoclasts

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13
Q

Name of cavity formed by osteoclast

A

Resorption cavity

Lacuna

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14
Q

Time taken for bone resorption

A

3 weeks

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15
Q

Time taken for bone formation

A

3-4 months

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16
Q

Disease where bone density is too low

A

Osteoporosis

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17
Q

Disease of net bone gain
1)
2)

A

Osteopetrosis

Osteosclerosis

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18
Q

Osteoclast phenotype
1)
2)

A

1) Large, multinucleated cells (4-20 nuclei)

2) Rich in mitochondria

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19
Q 
Process by which osteoclasts resorb bone
1)
2)
3)
4)
A

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

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20
Q

What do osteoblasts differentiate from?

A

Mesenchymal stem cells

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21
Q

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

A

1) Muscle
2) Chondrocytes
3) Adipocytes

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22
Q

Three fates of osteoblasts
1)
2)
3)

A

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

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23
Q

Bone formation of osteoblasts
1)
2)
3)

A

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

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24
Q

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

A

1) Collagen
2) Bone sialoprotein
3) Osteocalcin

25
Q

Function of alkaline phosphatase

A

Renders the osteoid competent for mineral deposition

26
Q

Osteoid

A

Unmineralised bone

27
Q

What is unmineralised bone called?

A

Osteoid

28
Q 
RANKL
1)
2)
3)
4)
5)
A

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
Q 
Osteoclast differentiation
1)
2)
3)
4)
A

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
Q

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

A

M-CSF (macrophage colony stimulating factor)

31
Q

Effect of absent RANKL/RANK

A

RANKL-/- mice develop severe osteopetrosis

32
Q

RANK
1)
2)
3)

A

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

33
Q 
OPG
1)
2)
3)
4)
A

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

34
Q

Effect of absent osteoprotegerin

A

Osteoprotegerin-/- mice develop osteoporosis

35
Q

Key regulator of osteoclast differentiation

A

Osteoprotegerin:RANKL ratio

36
Q

M-CSF roles
1)
2)

A

1) Proliferation of myeloid precursors

2) Survival of osteoclast progenitors and mature osteoclasts

37
Q

Producers of RANKL
1)
2)

A

1) Primary producers are early-mid stage osteoblasts

2) Can also be produced by osteocytes

38
Q

Main producers of OPG

A

Mid- to late-stage osteoblasts

39
Q

Promoters of osteoblast differentiation and function

A

Wnt ligands

40
Q

Differentiation induced by wnt ligands

A

Osteoblastic progenitor to pre-osteoblast

41
Q

Effect of wnt activation in osteoblasts
1)
2)

A

1) Promotes bone formation

2) Inhibits bone resorption

42
Q

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

A

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
Q

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

A

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

44
Q

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

A

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

45
Q

Cell that produces endogenous wnt antagonists

A

Osteoblast

46
Q

Osteocyte

A

Terminally-differentiated osteoblast, encased in bone matrix

47
Q 
Osteocyte features
1)
2)
3)
4)
A

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
Q

How do osteocytes regulate osteoblasts and osteoclasts?

A

1) Regulate levels of DKK and sclerostin

2) Can release RANKL

49
Q

What is sclerostosis?

A

Mutation in sclerostin, which inactivates it

Very thick bone, osteosclerotic condition

50
Q

Effect of increased mechanical loading on osteocytes

A

Reduce expression of DKK, sclerostin

This increases bone formation, reduces resorption, because of activation of wnt signaling

51
Q

Treatment strategies for osteoporosis

1) a,b
2) a

A

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

52
Q

Bisphosphonates
1)
2)
3)

A

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

53
Q

Denosumab
1)
2)

A

1) Anti-RANKL, fully-humanised MAb

2) Inhibits osteoclast differentiation and survival

54
Q

Effect of bisphosphonates and anti-RANKL MAbs

A

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

55
Q

Osteoporosis treatments that target osteoclasts
1)
2)

A

1) Bisphosphonates

2) Anti-RANKL MAbs

56
Q

Osteoporosis treatment that targets ostoblasts

A

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

57
Q

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

A

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
Q

Emergin osteoporosis therapy that promotes bone formation

A

Anti-sclerostin MAb

AMG785 or Romosozumab

Molecule to Malady (35 decks)

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