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BIOM30002 - M2M > Lecture 27 - Rheumatoid Arthritis - Bone > Flashcards

Lecture 27 - Rheumatoid Arthritis - Bone Flashcards

1
Q

Describe the structure of bone

A

Cortical bone
• Outermost
• Dense

Cancellous / Trabecular
• Reinforces, with a cross network of struts
• Less dense

Bone marrow
• In the medullary cavity
• Production of haematopoietic cells

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2
Q

What is the main protein in bone?

A

Collagen

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3
Q

What is the composition of bone?

A
  1. Organic matrix - 10% adult bone mass
    • 90% collagen (90% of organic matrix)
    • Other proteins that help bind the minerals
2. Mineral component - 65% A.B.M.
 • Hydroxyapatite
 • Na
 • Mg
 • Bicarbonate
  1. Water - 25% A.B.M.
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4
Q

Is bone permanent?

A

No

5-10% of skeleton replaced each year

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5
Q

Where does bone remodelling occur?

Characterise the initiation

A

Occurs at 1-2 million microscopic foci

Initiation is asynchronous

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6
Q

Why is bone remodelled?

A

• Maintenance of metal ion homeostasis

• Adapt shape and structural organisation to alterations in biomechanics forces
- ‘Mechanostat’

• Maintain structural integrity
- repair of microdamage

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7
Q

Describe the role of bone in mineral ion homeostasis

A
  1. Decreased Ca in blood
  2. Bone ‘resorbed’, releasing Ca into blood
    and vice versa
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8
Q

Describe the BMU

A

“Basic multicellular unit” in bone

Osteocytes
• Embedded within the bone matrix, in lacunae
• “Mechanosensors”
• Control the osteoblasts and -clasts

Osteoblasts
• Form bone
• Cuboidal

Osteoclasts
• Resorb bone
• Multi-nucleated
• Large

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9
Q

Describe the process of bone remodelling

A
  1. Osteoclasts present on bone surface
  2. Resorption of a packet of bone, leaving ‘lacunae’
  3. Osteoblasts come in and release collagen
  4. Unmineralised bone matrix now formed: “Osteoid”
  5. Minerals bind the osteoid to form bone
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10
Q

What are lacunae?

A

Resorption cavities
After osteoclasts have resorbed a packet of bone, there are cavities left over in the bone

Osteocytes reside in here

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11
Q

What is Osteoid?

A 
Unmineralised bone matrix laid down initially by the osteoblasts
Composition:
 • Collagen
 • Bone sialoprotein
 • Osteocalcin
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12
Q

What is needed to maintain healthy bone mass?

A

Balance between bone resorption and bone formation

i.e. between Osteoblast and Osteoclast activity

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13
Q

How long does it take for a packet of bone to be:
• Resorbed
• Formed
What is the implication of this?

A

Resorption: 3 weeks

Formation: 3-4 months

Implication:
If there is much resorption occurring, it is very difficult to make up for this loss, even if there are many osteoblasts present

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14
Q

What is the function of osteocytes?

Where are they located?

What do they differentiate from?

What is their lifespan?

A

Embedded within the bone matrix, within Lacunae

Function:
• “Mechanosensors”
• Control the osteoblasts and -clasts

Differentiate from osteoblasts

Lifespan: 20-25 years

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15
Q

What is the clinical symptom of increased osteoclast activity?

A

Osteoporosis

  • Weakened bones
  • Thinner trabeculae
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16
Q

What is the clinical symptom of increased osteoblast activity?

A

Osteosclerosis
Osteopetrosis

  • High bone mass
  • More opaque bones on the X ray
  • Bone is much heavier
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17
Q

Describe the cellular features of osteoclasts

A

Multinucleated

Many mitochondria
• High energy needs required for bone resorption

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18
Q

Describe bone resorption by osteoclasts

A
  1. Formation of ‘sealing zone’
  2. Acidification
    • Forms the Ruffled border
    • Dissolves the mineral component
  3. Release of collagenases
    • Degrades the organic component
  4. Degradation products taken up by the osteoclasts
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19
Q

How do osteoclasts attach to the surface of bone?

A

Integrins

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20
Q

Describe the differentiation into osteoblasts

A
  1. Mesenchymal stem cell origin
  2. Differentiation down the osteoblast lineage
  3. Preosteoblast
  4. Mature osteoblast

3 fates:
• Osteocytes: embedded in the bone
• Lining cell (Fx unknown)
• Apoptosis

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21
Q

What do mesenchymal stem cells give rise to?

A
  • Osteoblasts
  • Chondrocytes
  • Muscle cells
  • Adipose cells
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22
Q

What are the functions of osteoblasts?

A
  • Bone formation

* Support of osteoclasts

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23
Q

Describe how osteoblasts promote and inhibit osteoclasts

A

Promotion: RANKL
• From the early-mid stage osteoblasts

Inhibition: OPG production
• From the mid-stage-mature osteoblasts

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24
Q

Describe the process of osteoblast bone formation

A

Secretion of EXM proteins:
• Collagen
• Bone sialoprotein
• Osteocalcin

Expression of alkaline phosphatase
• Renders the bone competent for mineralisation

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25
Q

Expession of which molecule is vital for rendering bone competent for mineralisation?

A

Alkaline phosphatase

26
Q

Describe differentiation into osteoclasts

A
  1. Haematopoietic stem cell
  2. Myeloid precursor

– M-CSF signalling –
• Myeloid precursor proliferation

  1. Osteoclast precursor
    • expressing RANK

– RANKL expression from osteoblasts –
• Binds to RANK on osteoclast precursor

  1. Mono-nucleated precursors

– fusion –

  1. Bone-resorbing osteoclast
    • Multinucleated
    • Attached to bone surface
27
Q

What are the progenitor cells for the following:
• Osteoblasts
• Osteoclasts
• Osteocytes

A

Osteoblasts:
• Mesenchymal stem cell

Osteoclasts:
• Haematopoietic stem cell
• Myeloid lineage

Osteocytes:
• Mesenchymal stem cell (differentiate from osteoblasts)

28
Q

What is another name for RANKL?

A

Receptor activator of NFκB-ligand

29
Q

An osteoclast is only an osteoclast when it is…

A

Sitting on the bone surface

30
Q

Describe the role of RANKL in osteoclast differentiation

A

RANKL expressed by osteoblasts

RANK expressed on surface of osteoclast precursors

RANKL signalling stimulates the differentiation into osteoclasts capable of resorbing bone

31
Q

Describe regulation of RANKL signalling in osteoclast differentiation

A

OPG: Osteoprotegerin

  • OPG inhibits RANKL
  • Soluble decoy receptor
  • Soaks up RANKL so that there is less differentiation into osteoclasts
  • Produced by early-mid stage osteoblasts
32
Q

What type of molecule is RANKL?

A

Member of TNF superfamily

33
Q

Describe the main features and functions of RANKL

What is seen in RANKL -/- mice?

A

Mostly membrane bound, but can be cleaved to a soluble form

Function:
• Induces osteoclast differentiation and activation

RANKL -/-:
• Severe osteopetrosis

34
Q

What is RANK also called?
Describe features
Where is it expressed?

What is seen in RANK -/- mice?

A

Receptor activator of NFκB

  • Member of TNF receptor superfamily
  • Expressed on osteoclasts and their precursors

RANK -/-:
• Severe osteopetrosis

35
Q

Why is RANKL ‘sufficient’?

A

It is the only factor required for osteoclast differentiation and function

36
Q

Describe the features and function of OGP

What is seen in OPG -/- mice?

A

“Osteoprotegerin”

• Soluble decoy receptor for RANKL
• Member of TNF receptor superfamily
(however structurally distinct form RANK)

• Blocks differentiation into Osteoclasts

OPG -/-:
• Osteoporosis

37
Q

What happens when there is an imbalance between RANKL and OPG?

A

Increased RANKL:
• Net bone loss

Increased OPG:
• Net bone gain

38
Q

Which molecules are important for:
• Proliferation of myeloid precursors into osteoclasts
• Osteoclast differentiation and function?

A

Proliferation of myeloid cells into osteoclasts: M-CSF

Osteoclast differentiation and Fx: RANKL

39
Q

Which molecules are important for differentiation into osteoblasts?

A

Wnt ligands

among others

40
Q

Describe Wnt signalling

A
  1. Wnt ligand binds Frizzled receptor
    Associated with LRP5/6
  2. Stabilisation of β-catenin
  3. β-catenin translocates into nucleus and turns on gene transcription

→→→

  1. Increase in osteoblast activity:
    • Increased OPG production
    (→ decrease in osteoclast activity)
41
Q

What two processes does Wnt signalling bring about?

How does it do this?

A
  1. Increased osteoblast activity
  2. Decreased osteoclast activity
    • Expression of osteoprotegerin
42
Q

Describe regulation of Wnt signalling

A
  1. Antagonists of LRP5/6
    • DKK1
    • Sclerostin
  2. Soluble decoy receptors for Wnt ligands
    • sFRP-1
    • Binds Wnt ligand, preventing it from binding the co-receptor

→ Destabilisation of β-catenin

→ Effects:
1. Decreased osteoblast activity

  1. Increased osteoclast activity
    • loss of OPG expression
43
Q

What is sFRP-1?

A

Secreted frizzled related proteins

Soluble decoy receptor for Wnt ligands
Prevent Wnt from signalling
→ decreased osteoblast activity

44
Q

What is the most abundant bone cell?

A

Osteocytes

45
Q

Describe intercellular communication in osteocytes

A

Canaliculi:
• Dendrite-like cell processes

Enable intercellular communication with:
• Other osteocytes
• Osteoblasts
• Osteoclasts (at the bone surface)

46
Q

Which cells are the ‘mechanostat’?

A

Osteocytes

47
Q 
Are the following inhibitors or promoters of bone formation:
 • DKK-1
 • OPG
 • RANKL
 • Sclerostin
 • Wnt ligands
A 
DKK-1: inhibitor
OPG: promoter
RANKL: inhibitor
Sclerostin: inhibitor
Wnt ligands: promoter
48
Q

Describe how osteocytes regulate bone formation

A

Express DKK-1 and sclerostin

These molecules inhibit Wnt signalling → decreased osteoblast activity → inhibition of bone formation

49
Q

What is sclerostosis?

Describe the disease pathogenesis

A 
Mutation in sclerostin
→ Increased Wnt signalling
→ Over-expression of OPG
→ Under-active osteoclasts
→ Increased bone mass

→ Osteosclerosis

50
Q

Describe mechanosensation in osteocytes

A

→ Increased mechanical load
• Reduced expression of DKK-1 and sclerostin →
a. Increased osteoblastic bone formation
b. Decreased osteoclastic bone resorption (increased OPG)

51
Q

Do osteocytes produce RANKL?

A

Still controversial:
• Some say yes, and some no

The key source of RANKL is osteoblasts

52
Q

What is seen in bones in people with RA?

A

Osteoporosis

53
Q

What are some approved therapeutics for Osteoporosis?

A

– Targeting osteoclasts –

  1. Bisphosphonates
    • Inhibit osteoclast activity
    • may lead to osteoclast apoptosis
    • First port of call
  2. Anti-RANKL antibody
    • Injected every 6 months
    • Blocks action of RANKL
    • Expensive, not as widely used as bisphonates

– Targeting osteoblasts –

  1. Teriparatide
    • Recombinant parathyroid hormone - rhPTH
    • Increase in bone mass
    • Only approved anabolic therapy
4. Anti-sclerostin mAb
 • "Romosozumab"
 • Phase II trial
 • Increased in bone mineral density
 • Better results than rhPTH
54
Q

What is the effect of Bisphosphonates and Anti-RANKL Ab on
• Osteoclasts
• Bone?

A
  • Decreased number
  • Decreased function

Decreased fracture risk
Decreased bone loss
Bone volume doesn’t necessarily increase

55
Q

Describe the mode of action of rPTH

A

(Recombinant parathyroid hormone)

  1. Stimulation of osteoblast precursors:
    • Mesenchymal stem cells
    • Osteoprogenitor
  2. Downregulation of:
    • Sclerostin
    • DKK-1

→ Promotion of osteoblastic bone formation

56
Q

Compare results in rhPTH and anti-sclerostin mAb

A

Anti-sclerostin mAb is still in trials, but is leading to better increases in bone density than rhPTH

57
Q

Compare stem cell origin of the following cells:
• Osteoblast
• Osteoclast
• Osteocyte

A

Osteoblast: mesenchymal stem cell

Osteoclast: haematopoietic stem cell

Osteocyte: mesenchymal SC
NB Differentiates from mature osteoblast

58
Q

Outline how Wnt signalling in osteoblasts can lead to inhibition of osteoclast activity

A

Wnt signalling leads to the intracellular stabilisation beta catenin, which turns of gene transcription for OPG

OPG ‘mops up’ RANKL, and thus osteoclast activity is inhibited

59
Q

What is the role of M-CSF?

A

Proliferation of myeloid precusors and survival of osteoclast progenitors and mature osteoclasts

60
Q

Where do Wnt ligands come from?

A

They are made locally within the bone microenvironment

e.g. By Osteoblasts

61
Q

Where do osteocytes reside?

A

Within the bone matrix, in the lacunae

62
Q

What is the name of anti-sclerostin mAb?

A

Romosozumab

BIOM30002 - M2M (36 decks)

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