Lecture 27 - Bones in Rheumatoid Arthritis Flashcards Preview

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Flashcards in Lecture 27 - Bones in Rheumatoid Arthritis Deck (34):
1

Osteopenia

Decrease in bone mass and mineral density
Not as severe as osteoporosis

2

Most debilitating bone problem in RA

Focal bone erosion

3

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

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

4

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

1) Occurs early in RA
2) Occurs in cancellous or trabecular bone near affected joint

5

Focal bone erosion
1)
2)

1) Occurs within cortical bone, at affected joint
2) Normally begins at the join between cartilage and bone

6

Systemic osteoporosis in RA
1)
2)

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

7

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

In situ hybridisation
Staining with RNA probe for bone-degrading enzymes

8

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

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

9

RANKL/OPG ratio at pannus/bone junction in RA

RANKL outweighs OPG
Leads to net bone loss

10

Bone phenotype of RANKL KO mice?

Osteopetrotic

11

Effect of inducing RA in RANKL KO mice

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

Still significant inflammation

12

Effect of OPG.Fc treatment
1)
2)
3)
4)

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

13

OPG.Fc

Osteoprotegerin -immunoglobulin segment complex
A RANKL inhibitor

14

Function of osteoclasts in RA

Osteoclasts are the only cell responsible for bone loss in RA

15

Do focal bone lesions recover with treatment?

No
Continued erosion can be controlled, but erosive lesions often persist

16

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

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

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

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

Wnt antagonists expressed in RA joints
1)
2)

1) DKK1, DKK2, DKK3
2) sFRP1, sFRP2, sFRP4

19

What induces synovial fibroblasts to release DKK?

TNFa

20

What does TNFa make synovial fibroblasts do?

Secrete DKK

21

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

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

22

DKK1 effect

Binds LRP6, which abrogates Wnt signal

23

Cytokines that directly increase osteoclastogenesis
1)
2)
3)

1) RANKL
2) TNFa
3) IL-1

24

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

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

25

Effect of IL-1 and TNF in RA

Directly augment osteoclast differentiation

26

Effects of TNF on osteoclast differentiation
1)
2)

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

27

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

1) Promotes cell survival and fusion
2) Affects more differentiated osteoclasts than TNFa

28

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

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

Conditions for repair of degraded bone in RA

Control of inflammation and synovitis

30

How often are bone lesions healed in RA?

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

31

Factor that might compromise bone repair in RA patients

Low-level 'smouldering' synovitis, detected by MRI

32

Drugs targeting inflammation in RA
1)
2)
3)
4)
5)

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

33

RA drugs targeting bone
1)
2)
3)
4)

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

34

Runx2

Transcription factor for osteoblast development