Molecular interplay between inflammation, biomechanics and joint remodelling in arthritis
Rik Lories, MD PhD
Laboratory for Skeletal Development & Joint Disorders, Division of Rheumatology, KU Leuven, Belgium
Inflammatory joint diseases
“A group of chronic musculoskeletal conditions with common inflammatory pathways and are characterized by organ and tissuedamage, increased morbidity and mortality, and reduced quality of life”
Adaptive and innate
immune mechanisms
Tissue homeostasis
repair & remodelling
Arthritis: from symptoms to pathology
“Rubor, tumor, calor, dolor et functio laesa”
Inflammation Joint destruction Joint remodeling
Lories & Luyten, Arthritis Res Therapy 2007; 9:207
Two major types of chronic arthritis
Rheumatoid Arthritis (RA)
• peripheral joints• symmetrical polyarthritis• female > males• HLA-DRB1 – shared epitope• Reumatoid Factor & anti-
CCP positive• + 1% of the population
Spondyloarthritis (SpA)
• axial skeleton• asymmetrical oligoarthritis• males > females• HLA-B27 association • Reumatoid Factor negative• + 1% of the population
The original question
Inflammation in AS
T1 and T2 STIR MRI images of the spine
Appel et al. Arthritis Rheum 2006; 54:2845-51
Appel et al. Arthritis Res Therapy 2006; 8:R143
The ankylosing spondylitis paradox
osteoporosis& fractures
ankylosis and loss of mobility
Effect of anti-TNF on ankylosis
AS patients who received infliximab from baseline through week 96 did not show inhibition of structural damage progression at year 2, when compared with radiographic data from the historical control OASIS cohort.
Van der Heijde et al, Arthritis Rheum 2008; 58:3063-70
The relationship between inflammation and bone damage in AS is not fully defined and the question remains: is there a linear relationship between inflammation in AS and other SpA and subsequent joint ankylosis? The original histological studies by Bywaters suggested that bone ankylosis may be independent of the associated inflammation... Also, experimental models of AS and in particular the ANKENT mouse have prominent joint fusion without much discernible inflammation. It is noteworthy, too, that diffuse idiopathic skeletal hyperostosis (DISH), is not regarded as having an inflammatory component.
In spondyloarthropathy, new bone formation is characteristic. Coupling of inflammation and subsequent ankylosis has not been demonstrated. Progressive ankylosis may persist despite absence of clinical disease activity. It is not excluded that continued suppression of inflammation may result in accelerated bone formation and ankylosis once the pathological cascade has been triggered. Therapeutic strategies specifically targeting cartilage and bone formation may therefore be required to gain full control of the disease either as an alternative or a complementary approach to immune-suppressing drugs.
Marzo-Ortega et al J Rheum 2002; 29(8):1583-5
Lories et al. J Clin Investig 2005; 115:1571-9
relationship inflammation – ankylosis?
Nordling et al. Arthritis Rheum. 1992 35(6):717-22
Holmdahl et al. Clin Exp Immunol. 1992 88(3):467-72
Corthay et al. Arthritis Rheum. 2000 43(4):844-51
Lories et al. Ann Rheum Dis. 2004 63(5):595-8
spontaneous arthritis in aging male DBA/1 mice
• Spontaneously ( after grouped cage) occurring in aging male DBA1 mice – “stress-induced arthritis”
• Involving hindpaws: PIPs, less often DIPs and ankles• Proposed at discovery as another model of RA• Synovitis not the striking feature • Entheseal cartilage and bone formation• T-cell independent ? (TCR-KO studies)• Model not limited to DBA/1 strain (e.g. Balb/c)
endochondral bone formation
Is the DBA/1 model useful?
• ADVANTAGES
– Almost 100% incidence– Simple clinical evaluation– Limited disease– Clearly defined processes– Model of AS/SpA/PsA
• DISADVANTAGES
– No axial disease– Inflammatory aspects
unclear– No HLA-B27
association
A tool to study molecularmechanisms of ankylosis and links
between inflammation and remodeling
Is damage necessary for new bone formation?
0
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osteophyte score
ControlZoledronate
Osteophytes and enthesophytes develop in the spontaneous model and in collagenase inducedosteoarthritis despite bisphosphonate treatment
Lories et al, Rheumatology 2008; 47(5):605-8 and unpublished data
Lories et al, Arthritis Res & Therapy 2009; 11: 221
Defining molecular targets for ankylosis
Lories et al, Arthritis Res & Therapy 2009; 11: 221
Effect of a BMP antagonist
Incidence Severity
Lories et al, J. Clin Investig 2005; 115:1571-9
Lories et al. Arthritis Rheum 2006; 54: 1736-1745
Wnt signaling and ankylosis
D. Diarra et al, Nature med 2007; 13(2):156-63Anti-DKK1
lessons from animal models (1)
Lories & Luyten, Nature Rev Rheum 2009; 5:420-1
Inflammation inhibits chondrogenesis
TNFα inhibits TGFβ and BMP induced chondrogenesis in periosteal cell micromasscultures. Data are mean + standard deviation from triplicates. Relative values of absorptiometry at 620 nm after Alcian blue staining are given as compared to controls.
Lories et al., Arthritis and Rheumatism 2007
Effect of anti-TNF in SpAD model
Administration of etanercept (25 µg twice a week) does not inhibit clinical severity of arthritis (n = 20 per group). No differences in pathology severity score between etanercept treated (25 µg twice a week) and control mice. Data are presented as mean, quartiles, percentile 10 and 90 (n = 18 and 14 respectively per group).
Lories et al, Arthritis Rheum 2007; 56(2):489-97
Corticosteroids and SpAD
Daily administration of dexamethasone (0.5 mg/kg) does not inhibit clinical incidence or severity of arthritis (n = 12 per group).
Braem et al, EWRR 2010
Dex inhibits inflammation in SpAD
Daily administration of dexamethasone (0.5 mg/kg) reduces 18FDG uptake
Braem et al, EWRR 2010
acute inflammation - enthesis
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1L 1R 2L 2R 3L 3R 4L 4R 5L 5R 6L 6R 7L 7R 8L 8R 9L 9R 10L 10R 11L 11R 12L 12R
12 weeks 16 weeks
Expression
levels
relative
to GAPD
H (*
10‐4)
CXCL1/GRO1
CXCL6/GCP2
Neutrophil chemokine expression in 12 and 16 w old mice
At the time of disease onset, neutrophil chemokines are upregulated in some mice as detected by real-time PCR.
BMP2 induces chemokine expression
mRNA Expression in hBMCs (24 h)
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no treatment Dexamethasone
Fold Cha
nge
GCP‐2SDF1
CXCL1
Human bone marrow derived mesenchymal stem cells stimulated withBMP2 in the presence or absence of dexamethasone
Identification of BMP target cells (p-smad1/5 IF)
Entheseal progenitor cells, not in cartilage cells
Lories et al., J Clin Invest 2005
Stress - stretch and BMP activation
Id1 Luciferase Activity
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25000
Untreated BMP2 1nMRLU
Sham
StretchId1 mRNA
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Untreated BMP2
Fold Change
Sham
Stretch
Mesenchymal progenitor cells subjected to cell stretch in a dedicated bioreactor
The entheseal stress hypothesis revisited
Lories et al, Arthritis Res Therapy 2009; 11(2):221
Conclusions and suggestions
• Current evidence from animal models suggeststhat inflammation and new bone formation are linked but largely molecularly uncoupledprocesses
• The relationship between biomechanical stress, (micro)damage, acute inflammation and chronicactivation of the immune system should be high on the AS research agenda
• BMP and Wnt signaling are potential therapeutictargets to prevent or delay ankylosis
• Additional genetic studies on ankylosis and links with DISH and FOP are essential