Lecture 27 - Bones in Rheumatoid Arthritis Flashcards

1
Q

Osteopenia

A

Decrease in bone mass and mineral density

Not as severe as osteoporosis

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2
Q

Most debilitating bone problem in RA

A

Focal bone erosion

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3
Q

Patterns of bone loss in RA
1)
2)
3)

A

1) Juxta-articular/peri-articular osteopenia
2) Focal bone erosion
3) Systemic osteoporosis

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4
Q

Juxta-articular or peri-articular osteopenia
1)
2)

A

1) Occurs early in RA

2) Occurs in cancellous or trabecular bone near affected joint

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5
Q

Focal bone erosion
1)
2)

A

1) Occurs within cortical bone, at affected joint

2) Normally begins at the join between cartilage and bone

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6
Q

Systemic osteoporosis in RA
1)
2)

A

1) Present in many patients

2) Thinning of trabecular/cancellous bone and cortical bone at sites remote from affected joint (EG: hip, vertebrae)

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7
Q

How were osteoclasts first identified as causative agents of RA bone loss?

A

In situ hybridisation

Staining with RNA probe for bone-degrading enzymes

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8
Q

Sources of RANKL in synovial joints
1)
2)
3)

A

1) Osteoblast-lineage cells
2) T cells
3) Synovial fibroblasts

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9
Q

RANKL/OPG ratio at pannus/bone junction in RA

A

RANKL outweighs OPG

Leads to net bone loss

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10
Q

Bone phenotype of RANKL KO mice?

A

Osteopetrotic

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11
Q

Effect of inducing RA in RANKL KO mice

A

Mice are protected from bone loss, as there are no osteoclasts

Still significant inflammation

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12
Q
Effect of OPG.Fc treatment
1)
2)
3)
4)
A

1) Reduces osteoclast numbers in inflammed joint
2) Focal bone erosion
3) Systemic bone loss in animal models
4) No effect on synovial inflammation

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13
Q

OPG.Fc

A

Osteoprotegerin -immunoglobulin segment complex

A RANKL inhibitor

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14
Q

Function of osteoclasts in RA

A

Osteoclasts are the only cell responsible for bone loss in RA

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15
Q

Do focal bone lesions recover with treatment?

A

No

Continued erosion can be controlled, but erosive lesions often persist

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16
Q

How do we know that new bone formation and osteoblast maturation is inhibited in RA joints?
1)
2)

A

1) Inject fluorochromes (alizarin-red, calcein-green) that are incorporated into new bone
2) These fail to show up at bone surfaces in joints adjacent to inflammation (pannus)

17
Q

State of osteoblast-lineage cells in bone surfaces adjacent to inflammation (pannus)
1)
2)
3)

A

1) Runx2 cells present
2) More mature osteoblast-progenitors are missing osteocalcin, alkaline phosphatase)
3) This means that osteoblasts aren’t maturing, so bone can’t be properly mineralised

18
Q

Wnt antagonists expressed in RA joints
1)
2)

A

1) DKK1, DKK2, DKK3

2) sFRP1, sFRP2, sFRP4

19
Q

What induces synovial fibroblasts to release DKK?

A

TNFa

20
Q

What does TNFa make synovial fibroblasts do?

A

Secrete DKK

21
Q
What happens to bone in TNF.Tg mice when DKK1 is inhibited?
1)
2)
3)
4)
A

1) Increased OPG levels
2) Increased bone formation
3) Decreased bone degradation
4) Osteophyte formation

22
Q

DKK1 effect

A

Binds LRP6, which abrogates Wnt signal

23
Q

Cytokines that directly increase osteoclastogenesis
1)
2)
3)

A

1) RANKL
2) TNFa
3) IL-1

24
Q
Cytokines that induce RANKL release from synovial fibroblasts, T cells and osteoblast-lineage cells
1)
2)
3)
4)
A

1) TNFa
2) IL-1
3) IL-6
4) IL-17

25
Q

Effect of IL-1 and TNF in RA

A

Directly augment osteoclast differentiation

26
Q

Effects of TNF on osteoclast differentiation
1)
2)

A

1) Increase RANK expression on osteoclast progenitors (makes them more sensitive to RANKL)
2) Increases the numbers of osteoclast progenitors

27
Q

Effects of IL-1 on osteoclast differentiation
1)
2)

A

1) Promotes cell survival and fusion

2) Affects more differentiated osteoclasts than TNFa

28
Q
DIrect effects of TNF on osteoblasts in vitro
1)
2)
3)
4)
5)
6)
A

1) Decreases wnt signalling in osteoblast-lineage cell
2) Signals RUNX2 for degradation
3) Decreases osteocalcin and alkaline phsophatase gene expression
4) Decreases capacity of osteoclast-lineage cells to properly mineralise bone
5) Increases RANKL expression
6) Apoptosis

29
Q

Conditions for repair of degraded bone in RA

A

Control of inflammation and synovitis

30
Q

How often are bone lesions healed in RA?

A

About 10% of focal bone lesions (not 10% of patients)

31
Q

Factor that might compromise bone repair in RA patients

A

Low-level ‘smouldering’ synovitis, detected by MRI

32
Q
Drugs targeting inflammation in RA
1)
2)
3)
4)
5)
A

1) Methotrexate
2) Anti-TNF (EG: infliximab)
3) Anti-IL-6R (EG: toculizumab)
4) CTLA4 Ig (EG: abatacept)
5) Anti-CD20 (EG: rituxumab)

33
Q
RA drugs targeting bone 
1)
2)
3)
4)
A

1) Bisphosphonates
2) Anti-RANKL Mabs (denosumab)
3) Anti-sclerostin
4) Anti-DKK1
5) rhPTH1 (parathyroid hormone, teriparatide)

34
Q

Runx2

A

Transcription factor for osteoblast development