Lecture 27 - Bones in Rheumatoid Arthritis

Question 1

Osteopenia

Answer 1

Decrease in bone mass and mineral density

Not as severe as osteoporosis

Question 2

Most debilitating bone problem in RA

Answer 2

Focal bone erosion

Question 3

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

Answer 3

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

Question 4

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

Answer 4

1) Occurs early in RA

2) Occurs in cancellous or trabecular bone near affected joint

Question 5

Focal bone erosion
1)
2)

Answer 5

1) Occurs within cortical bone, at affected joint

2) Normally begins at the join between cartilage and bone

Question 6

Systemic osteoporosis in RA
1)
2)

Answer 6

1) Present in many patients

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

Question 7

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

Answer 7

In situ hybridisation

Staining with RNA probe for bone-degrading enzymes

Question 8

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

Answer 8

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

Question 9

RANKL/OPG ratio at pannus/bone junction in RA

Answer 9

RANKL outweighs OPG

Leads to net bone loss

Question 10

Bone phenotype of RANKL KO mice?

Answer 10

Osteopetrotic

Question 11

Effect of inducing RA in RANKL KO mice

Answer 11

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

Still significant inflammation

Question 12

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

Answer 12

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

Question 13

OPG.Fc

Answer 13

Osteoprotegerin -immunoglobulin segment complex

A RANKL inhibitor

Question 14

Function of osteoclasts in RA

Answer 14

Osteoclasts are the only cell responsible for bone loss in RA

Question 15

Do focal bone lesions recover with treatment?

Answer 15

No

Continued erosion can be controlled, but erosive lesions often persist

Question 16

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

Answer 16

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)

Question 17

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

Answer 17

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

Question 18

Wnt antagonists expressed in RA joints
1)
2)

Answer 18

1) DKK1, DKK2, DKK3

2) sFRP1, sFRP2, sFRP4

Question 19

What induces synovial fibroblasts to release DKK?

Answer 19

TNFa

Question 20

What does TNFa make synovial fibroblasts do?

Answer 20

Secrete DKK

Question 21

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

Answer 21

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

Question 22

DKK1 effect

Answer 22

Binds LRP6, which abrogates Wnt signal

Question 23

Cytokines that directly increase osteoclastogenesis
1)
2)
3)

Answer 23

1) RANKL
2) TNFa
3) IL-1

Question 24

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

Answer 24

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

Question 25

Effect of IL-1 and TNF in RA

Answer 25

Directly augment osteoclast differentiation

Question 26

Effects of TNF on osteoclast differentiation 1) 2)

Answer 26

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

Question 27

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

Answer 27

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

Question 28

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

Answer 28

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

Question 29

Conditions for repair of degraded bone in RA

Answer 29

Control of inflammation and synovitis

Question 30

How often are bone lesions healed in RA?

Answer 30

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

Question 31

Factor that might compromise bone repair in RA patients

Answer 31

Low-level 'smouldering' synovitis, detected by MRI

Question 32

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

Answer 32

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

Question 33

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

Answer 33

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

Question 34

Runx2

Answer 34

Transcription factor for osteoblast development