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?

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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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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