Lecture 27 - Bones in Rheumatoid Arthritis Flashcards
Osteopenia
Decrease in bone mass and mineral density
Not as severe as osteoporosis
Most debilitating bone problem in RA
Focal bone erosion
Patterns of bone loss in RA
1)
2)
3)
1) Juxta-articular/peri-articular osteopenia
2) Focal bone erosion
3) Systemic osteoporosis
Juxta-articular or peri-articular osteopenia
1)
2)
1) Occurs early in RA
2) Occurs in cancellous or trabecular bone near affected joint
Focal bone erosion
1)
2)
1) Occurs within cortical bone, at affected joint
2) Normally begins at the join between cartilage and bone
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)
How were osteoclasts first identified as causative agents of RA bone loss?
In situ hybridisation
Staining with RNA probe for bone-degrading enzymes
Sources of RANKL in synovial joints
1)
2)
3)
1) Osteoblast-lineage cells
2) T cells
3) Synovial fibroblasts
RANKL/OPG ratio at pannus/bone junction in RA
RANKL outweighs OPG
Leads to net bone loss
Bone phenotype of RANKL KO mice?
Osteopetrotic
Effect of inducing RA in RANKL KO mice
Mice are protected from bone loss, as there are no osteoclasts
Still significant inflammation
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
OPG.Fc
Osteoprotegerin -immunoglobulin segment complex
A RANKL inhibitor
Function of osteoclasts in RA
Osteoclasts are the only cell responsible for bone loss in RA
Do focal bone lesions recover with treatment?
No
Continued erosion can be controlled, but erosive lesions often persist
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)
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
Wnt antagonists expressed in RA joints
1)
2)
1) DKK1, DKK2, DKK3
2) sFRP1, sFRP2, sFRP4
What induces synovial fibroblasts to release DKK?
TNFa
What does TNFa make synovial fibroblasts do?
Secrete DKK
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
DKK1 effect
Binds LRP6, which abrogates Wnt signal
Cytokines that directly increase osteoclastogenesis
1)
2)
3)
1) RANKL
2) TNFa
3) IL-1
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
Effect of IL-1 and TNF in RA
Directly augment osteoclast differentiation
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
Effects of IL-1 on osteoclast differentiation
1)
2)
1) Promotes cell survival and fusion
2) Affects more differentiated osteoclasts than TNFa
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
Conditions for repair of degraded bone in RA
Control of inflammation and synovitis
How often are bone lesions healed in RA?
About 10% of focal bone lesions (not 10% of patients)
Factor that might compromise bone repair in RA patients
Low-level ‘smouldering’ synovitis, detected by MRI
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)
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)
Runx2
Transcription factor for osteoblast development
