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

Lecture 27 - Rheumatoid Arthritis - Bone Flashcards

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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
Expession of which molecule is vital for rendering bone competent for mineralisation?
Alkaline phosphatase
26
Describe differentiation into osteoclasts
1. Haematopoietic stem cell 2. Myeloid precursor -- M-CSF signalling -- • Myeloid precursor proliferation 3. Osteoclast precursor • expressing RANK -- RANKL expression from osteoblasts -- • Binds to RANK on osteoclast precursor 4. Mono-nucleated precursors -- fusion -- 5. Bone-resorbing osteoclast • Multinucleated • Attached to bone surface
27
What are the progenitor cells for the following: • Osteoblasts • Osteoclasts • Osteocytes
Osteoblasts: • Mesenchymal stem cell Osteoclasts: • Haematopoietic stem cell • Myeloid lineage Osteocytes: • Mesenchymal stem cell (differentiate from osteoblasts)
28
What is another name for RANKL?
Receptor activator of NFκB-ligand
29
An osteoclast is only an osteoclast when it is...
Sitting on the bone surface
30
Describe the role of RANKL in osteoclast differentiation
RANKL expressed by osteoblasts RANK expressed on surface of osteoclast precursors RANKL signalling stimulates the differentiation into osteoclasts capable of resorbing bone
31
Describe regulation of RANKL signalling in osteoclast differentiation
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
What type of molecule is RANKL?
Member of TNF superfamily
33
Describe the main features and functions of RANKL What is seen in RANKL -/- mice?
Mostly membrane bound, but can be cleaved to a soluble form Function: • Induces osteoclast differentiation and activation RANKL -/-: • Severe osteopetrosis
34
What is RANK also called? Describe features Where is it expressed? What is seen in RANK -/- mice?
Receptor activator of NFκB * Member of TNF receptor superfamily * Expressed on osteoclasts and their precursors RANK -/-: • Severe osteopetrosis
35
Why is RANKL 'sufficient'?
It is the only factor required for osteoclast differentiation and function
36
Describe the features and function of OGP What is seen in OPG -/- mice?
"Osteoprotegerin" • Soluble decoy receptor for RANKL • Member of TNF receptor superfamily (however structurally distinct form RANK) • Blocks differentiation into Osteoclasts OPG -/-: • Osteoporosis
37
What happens when there is an imbalance between RANKL and OPG?
Increased RANKL: • Net bone loss Increased OPG: • Net bone gain
38
Which molecules are important for: • Proliferation of myeloid precursors into osteoclasts • Osteoclast differentiation and function?
Proliferation of myeloid cells into osteoclasts: M-CSF Osteoclast differentiation and Fx: RANKL
39
Which molecules are important for differentiation into osteoblasts?
Wnt ligands | among others
40
Describe Wnt signalling
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 →→→ 4. Increase in osteoblast activity: • Increased OPG production (→ decrease in osteoclast activity)
41
What two processes does Wnt signalling bring about? | How does it do this?
1. Increased osteoblast activity 2. Decreased osteoclast activity • Expression of osteoprotegerin
42
Describe regulation of Wnt signalling
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 2. Increased osteoclast activity • loss of OPG expression
43
What is sFRP-1?
Secreted frizzled related proteins Soluble decoy receptor for Wnt ligands Prevent Wnt from signalling → decreased osteoblast activity
44
What is the most abundant bone cell?
Osteocytes
45
Describe intercellular communication in osteocytes
Canaliculi: • Dendrite-like cell processes Enable intercellular communication with: • Other osteocytes • Osteoblasts • Osteoclasts (at the bone surface)
46
Which cells are the 'mechanostat'?
Osteocytes
47
``` Are the following inhibitors or promoters of bone formation: • DKK-1 • OPG • RANKL • Sclerostin • Wnt ligands ```
``` DKK-1: inhibitor OPG: promoter RANKL: inhibitor Sclerostin: inhibitor Wnt ligands: promoter ```
48
Describe how osteocytes regulate bone formation
Express DKK-1 and sclerostin These molecules inhibit Wnt signalling → decreased osteoblast activity → inhibition of bone formation
49
What is sclerostosis? | Describe the disease pathogenesis
``` Mutation in sclerostin → Increased Wnt signalling → Over-expression of OPG → Under-active osteoclasts → Increased bone mass ``` → Osteosclerosis
50
Describe mechanosensation in osteocytes
→ Increased mechanical load • Reduced expression of DKK-1 and sclerostin → a. Increased osteoblastic bone formation b. Decreased osteoclastic bone resorption (increased OPG)
51
Do osteocytes produce RANKL?
Still controversial: • Some say yes, and some no The key source of RANKL is osteoblasts
52
What is seen in bones in people with RA?
Osteoporosis
53
What are some approved therapeutics for Osteoporosis?
-- 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 -- 3. 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
What is the effect of Bisphosphonates and Anti-RANKL Ab on • Osteoclasts • Bone?
* Decreased number * Decreased function Decreased fracture risk Decreased bone loss Bone volume doesn't necessarily increase
55
Describe the mode of action of rPTH
(Recombinant parathyroid hormone) 1. Stimulation of osteoblast precursors: • Mesenchymal stem cells • Osteoprogenitor 2. Downregulation of: • Sclerostin • DKK-1 → Promotion of osteoblastic bone formation
56
Compare results in rhPTH and anti-sclerostin mAb
Anti-sclerostin mAb is still in trials, but is leading to better increases in bone density than rhPTH
57
Compare stem cell origin of the following cells: • Osteoblast • Osteoclast • Osteocyte
Osteoblast: mesenchymal stem cell Osteoclast: haematopoietic stem cell Osteocyte: mesenchymal SC NB Differentiates from mature osteoblast
58
Outline how Wnt signalling in osteoblasts can lead to inhibition of osteoclast activity
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
What is the role of M-CSF?
Proliferation of myeloid precusors and survival of osteoclast progenitors and mature osteoclasts
60
Where do Wnt ligands come from?
They are made locally within the bone microenvironment e.g. By Osteoblasts
61
Where do osteocytes reside?
Within the bone matrix, in the lacunae
62
What is the name of anti-sclerostin mAb?
Romosozumab

BIOM30002 - M2M (36 decks)

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