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BIOM30002 - M2M > Lecture 28 - Rheumatoid Arthritis - Bone in RA > Flashcards

Lecture 28 - Rheumatoid Arthritis - Bone in RA Flashcards

1
Q

Describe the cells that modulate bone, their function, and the factors that increase their activity

What releases these factors?

A

Osteoclast: bone resorbing
• RANKL
• OPG: Inhibition of RANKL

Osteoblasts:
• Wnt: activation of osteoplasts
• Inhibition: DKK-1, sclerostin, sFRP1

Osteocytes:
Regulate bone formation by increasing and decreasing production of:
• Wnt antagonists DKK-1 and Sclerostin
• RANKL (still controversial, main source is osteoblasts)

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2
Q

What are the key pro-inflammatory cytokines in RA?

What is their effect on bone?

A 
TNF
IL-1
IL-6
IL-17
RANKL

Destruction of bone and cartilage

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3
Q

What are the patterns of bone loss in RA?

Where does each occur?

At what stage of disease does each occur?

A
  1. Juxta-articular / peri-articular osteopenia
    • Reduced bone mineral density
    • Within trabecular bone

• Occurs very early in disease

  1. Focal bone erosion
    • Eating away of bone
    • Contributes to bone deformities
    • Occurs within cortical bone
  2. Systemic osteoporosis
    • Thinning of trabecular/cancellous bone and cortical bone
    • At sites remote from affected joints (e.g. hip, vertebrae)
    • Present in many of the patients, but not all
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4
Q

When was the osteoclast recognised as the cell that resorbs bone in RA?

What were the markers that lead to its identification?

A

1998
Before this, it was thought to be macrophages

In situ hybridisation with an RNA probe that binds to a particular marker (that only osteoclasts express)

Markers:
• Calcitonin receptor (only expressed in osteoclasts on the bone surface)
• TRAP
• Cathepsin K

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5
Q

In RA there are additional sources of RANKL. What are they?

A

• Osteoblast lineage cells

In addition, in RA:
• Synovial fibroblasts
• T cells

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6
Q

Compare relative expression of RANKL and OPG at the pannus-bone interface in RA

How was this determined?

What is the net effect of this?

A

RANKL expression outweighs OPG

This was determined with immunohistochemistry

There are many osteoclast precursors, waiting to be stimulated

Effect:
Net resorption of bone (focal bone erosion)

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7
Q

What is the phenotype of RANKL-/- mice?

A
  • No focal bone erosion
  • Inflammation still present at normal levels

Osteopetrotic
No functional osteoclasts and thick, dense bones

Because:
RANKL is the key osteoclast differentiation factor

However:
No difference in inflammation between this mouse and the control

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8
Q

What is the effect of RANKL-/- on inflammation?

A

Not protective against inflammation

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9
Q

What is the effect of OPG.Fc treatment?

A
  • Decreased osteoclasts
  • Decreased bone erosion
  • Decreased systemic bone loss

However:
No effect on inflammation

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10
Q

Which cells are responsible for bone loss in RA?

A

Osteoclasts are the only cells responsible for bone loss in RA

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11
Q

What happens to osteoblast activity in RA?

What is the result of this?

What brings about these changes in osteoblasts?

A

Impaired activity

As a result:
Focal bone erosion that has already occurred does not resolve when RA is controlled

Rationale:
RA → TNF from synovial macrophages → Synovial fibroblasts release more DKK-1 → DKK-1 inhibits osteoblast activity

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12
Q

What are the key signals that promote osteoblast differentiation?

A

Wnt ligands

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13
Q

Describe impaired osteoblast maturation in RA

What brings about this impairment?

A

At the sites of inflammation in RA there is decreased bone formation due to impairment of osteoblast maturation

Mechanism:

  1. Inflammation, TNF release from synovial macrophages
  2. Increased expression of Wnt ligand antagonists: DKK1 and sFRP1 (in synovial fibroblasts)
  3. Blockage of Wnt signalling
  4. Decreased osteoblast development
  5. Inhibition of bone development

Also: Promotion of bone resorption

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14
Q

What are some Wnt ligand antagonists?

A

DKK-1

sFRP

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15
Q

Briefly describe what happens to the following cells in RA:
• Osteoclasts
• Osteoblasts

A

Osteoclasts: increased activity
→ more RANKL

Osteoblasts: impaired activity
→ more Wnt ligand antagonists: DKK-1, sFRP-1

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16
Q

What is the effect of TNF on synovial fibroblasts?

A

Increased DKK-1 expression (Wnt ligand antagonist → decreased osteoblast activity)

Increased RANKL expression (→ increased osteoclast activity)

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17
Q

What happens to bone in TNF.Tg mouse model of RA when DKK-1 action is inhibited?

A

(hTNF.Tg: mouse model that over-expresses TNF)

Observation:
• Protection from bone loss (due to OPG expression)
• Active bone formation (removal of osteoblast inhibition)

Due to:
• Production of OPG (inhibition of osteoclasts)
• Differentiation into osteblasts

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18
Q

Describe the signal transduction pathway in Wnt signalling

A
  1. Wnt ligand binds Frizzled receptor
  2. Transduction
  3. Stabilisation of B-catenin
  4. B-catenin translocates to the nucleus and turns on gene transcription
    5a. Differentiation into osteoblasts
    5b. OPG production, osteoclasts are inhibited
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19
Q

Generally, what are the effects of pro-inflammatory cytokines on osteoclasts?

A 
1. Direct:
Cytokines act directly on osteoclasts to increase their activity:
 • RANKL
 • IL-1
 • TNF
  1. Indirect:
    Cytokines act on other cells
    • TNF, IL-1, IL-6
    • Cells: Synovial fibroblasts, osteoblast-lineage cells, T cells
    • These cells then regulate RANKL production
20
Q

Describe the effect of the following on osteoclasts
• TNF
• IL-1

A
  1. TNF
    Acts more on osteoclast progenitor cells
    • Increased RANK expression
    • Increased n° of osteoclast progenitors
  2. IL-1
    Acts more on later stages of osteoclast differentiation
    • Promotion of cell fusion
    • Promotion of cell survival
21
Q

What are the effects of pro-inflammatory cytokines on osteoblasts?

A

TNF:

In general: decreased osteoblast activity

  • Decreased Wnt signalling
  • Decreased RUNX2 protein levels (thus decreased osteoblast differentiation)
  • Decreased alkaline phosphatase expression
  • Decrease osteocalcin gene expression
  • Increased RANKL expression
  • Decreased capacity of osteoblast lineage cells to form properly mineralised bone
  • Increased apoptosis
22
Q

What is RUNX2?

A

Key TF required for osteoblast differentiation

23
Q

What is alkaline phophatase needed for?

A

Expressed in osteoblasts

Required for mineralisation of bone

24
Q

What is osteocalcin?

A

Expressed in osteoblasts

One of the molecules that maintain calcium within the bone matrix

25
Q

What is critical for repair of focal bone erosion in RA?

A

Strict control of inflammation

Through:
• TNFi
• IL-1 inhibitors
• IL-6 inhibitors

26
Q

Is repair of focal bone erosion common?

In which patients is it seen?

A

No
Only seen in 10% of bone erosion foci

Seen mostly in patients who are:
• in remission or who have low disease activity
• taking a TNF inhibitor

27
Q

What is often seen even in RA remission?

A

Smouldering synovitis

Hands may look normal
However, synovitis still occurring within the joints

This may compromise the bone repair

28
Q

What is seen in mouse models of arthritis in terms of repair of focal bone erosion?

A

Focal bone erosion can be repaired, BUT ONLY when synovitis and local inflammation resolves

29
Q

Which therapeutic agents can increase repair of bone erosion?

A

– Targeting inflammation –

  • Methotrexate
  • Anti-TNF mAbs (e.g. infliximab etc.)
  • Anti-IL-6R mAb (Toculizumab)

– Targeting bone –
1. Osteoblasts
• rhPTH: recombinant Parathyroid hormone (Teriparatide)

  • Anti-sclerostin mAb
  • Anti-DKK1 mAb
  1. Osteoclasts
    • Bisphosphonates

• Anti-RANKL mAb (Denosumab)

30
Q

What is the name of the anti-RANKL mAb?

A

Denosumab

31
Q

What is Teriparatide?

A

Recombinant Parathyroid hormone

Quite beneficial in targeting of bone in treatment of RA

32
Q 
Describe the effect of inflammation (i.e. TNF, IL-1, IL-6) on the following:
 • RANKL
 • OPG
 • Wnt signalling
 • Wnt antagonists
 • Osteoclast activity
 • Osteoblast activity
 • Osteocyte
A

RANKL: increased

OPG: decreased

Wnt signalling: decreased

Wnt antagonists: increased

Osteoclasts: increased

Osteoblasts: inhibition of maturation

Osteocyte: we still don’t know

33
Q

What are the main drivers of the following in RA:
• Increased osteoclast activity
• Decreased osteoblast activity

A

Increased osteoclast activity:
• TNF stimulation of synovial fibroblasts
• Synovial fibroblast production of RANKL

Decreased osteoblast activity:
• TNF stimulation of synovial fibroblasts
• Synovial fibroblasts production of Wnt antagonist

34
Q

What can and can’t targeting of osteoclasts in RA bring about?

A

Can:
• Reduce bone erosion

Cannot:
• Reduce inflammation of synovium
• Resolve bone erosion

35
Q

Where does DKK-1 come from in RA?

A

Synovial fibroblasts

36
Q

What is the master regulator of bone formation?

A

DKK-1

37
Q

What is the drug name for rhPTH?

A

Teriparatide

38
Q

Which therapeutic agents can target osteoclasts?

A
  • Bisphosphonates

* Denosumab (Anti-RANKL)

39
Q

What is the effect of bisphosphonates?

A

Inhibition of osteoclasts

40
Q

Which therapeutic agents can / could target osteoblasts?

A
  • Teriparatide (rhPTH)
  • Anti-DKK-1
  • Anti-sclerostin
41
Q

Where is the extra DKK-1 coming from in the RA joint?

A

From the synovial fibroblasts

TNF causes the synovial fibroblasts to produce DKK-1

42
Q

What do osteocytes release?

A
  • DKK-1
  • Sclerostin
  • RANKL
43
Q

What is the only approved anabolic therapy for osteoporosis?

A

Teriparatide

Human recombinant parathyroid hormone

44
Q

Why are there increased Wnt antagonists in RA?

A

Inflammation leads to increased expression of Wnt ligand antagonists in synovial fibroblasts

45
Q

Why is there increased RANKL in RA?

A

Inflammation (TNF, IL-1, IL-6) leads to increased expression of RANKL (Early-mid stage osteoblasts, T cells, synovial fibroblasts)

BIOM30002 - M2M (36 decks)

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