Le Stress inflammatoire
Francis Berenbaum Universit茅 Pierre & Marie Curie AP-HP, h么pital Saint-Antoine, Paris
OSTEOARTHRITIS
NORMAL
OSTEOARTHRITIS Subchondral cyst Cartilage
Capsule
Synovial membrane
Subchondral osteosclerosis
Cartilage loss
Synovitis Osteophyte Cartilage erosion
Thickening of the capsule Os sous-chondral
Bijlsma, Berenbaum, Lafeber. The Lancet (2011)
OA : a disease of the whole joint
Sellam & Berenbaum. Nature Reviews Rheum Nov. 2010
OA : the synovial perspective
(personnal collection)
PATHOPHYSIOLOGY OF OSTEOARTHRITIS 20th century
21st century
•A passive consequence of tear and wear •A cartilage disease •A degenerative disease
•A cell-driven mechanism based on soluble mediators •A multiple-tissue disease •A pro-inflammatory disease
Stress inflammatoire et cartilage
1- Chondrocytes are involved in the cartilage degradation process
QUANTITATIVE MODIFICATIONS •matrix degradation +++ •Apoptosis of chondrocytes
NORMAL
OA
QUALITATIVE MODIFICATIONS •Synthesis of a low-quality matrix •Modification of the differentiation state of chondrocytes •Matrix calcification
PATHOPHYSIOLOGY OF OSTEOARTHRITIS
Anabolism Cartilage matrix synthesis
Catabolism Cartilage matrix degradation
Homeostasis
PATHOPHYSIOLOGY OF OSTEOARTHRITIS
Anabolism
Catabolism
Cartilage matrix synthesis dise qu
Normal
ilibrium
Overexpression of Metalloproteinases 1,3,13 by chondrocytes Osteoarthritis
LES METALLOPROTEASES
PATHOLOGY OF OSTEOARTHRITIS
Anabolism Cartilage matrix synthesis dise qu
Normal
Catabolism Soluble mediators : IL-1,PGE2‌ ilibrium
Overexpression of Metalloproteinases 1,3,13 by chondrocytes Osteoarthritis
OA : the cartilage
cartilage degradation
Synthesis of an altered matrix
Proteolysis
Proteinases (MMP, ADAMTS)
Les médiateurs impliqués • • • • •
Métalloprotéases Cytokines et facteurs de croissance Dérivés oxygénés prostaglandines Fragments de matrice
ACTIVATION
Noyau
COX-2
chondrocyte MMPs MĂŠdiateurs inflammatoires
Médiateurs prodégradatifs •IL-1 •TNFα •IL-17 •prostaglandines •ATP •…
Voies de signalisation inductibles
régulation transcriptionelle et post-transcriptionelle COX-2
MMPs Médiateurs inflammatoires
médiateurs pro-dégradatifs
NF-kB, MAPK, Wnt, autres
•IL-1 •TNFα •IL-17 •PGE2 •ATP •…
régulation transcriptionelle et post-transcriptionelle COX-2
MMPs Médiateurs inflammatoires
VOIES DE SIGNALISATION DU CHONDROCYTE
Goldring Best practice, 2006
Interaction Ligands/specific receptors
•Cytokines (including chemokines, adipokines) •Prostaglandins •Reactive oxygen species •RAGE ligands •Extracellular matrix components
MAPK NF-kB Others…
Transcriptional and post-transcriptional regulation COX-2
MMPs ADAMTS Cytokines Reactive oxygen species Prostaglandins
Vieillissement du cartilage et stress inflammatoire
Formation d’AGE dans le cartilage Autofluoresence
Caramélisation du cartilage
68 years
AGE fluorescence/Hyp RFU/nmol
14 years 30000 R2 = 0.5539
20000
Knee Ankle
54 years 2
10000
R = 0.5537
0 0
20
40
60
Age in Years
80
100 Knee p = 0.02 Ankle p = 0.03
Loeser et al.
« AGE » ET ARTHROSE
« AGE » (« Advanced Glycation End-products ») :
Liaison covalente sucre-AA
Versijl et al. , Current Opin Rheumatol 2003
OA and inflammation : role of aging IL-1 stim./Control MMP-13
8 6
r=0.57 p=0.0001
4 2 0 0
10 20 30 40 50 60 70 80 90 Donor Age
Chondrocytes were treated overnight with 5ng/ml IL-1β and MMP-13 was measured by immunoblotting. Similar to fibronectin fragments, IL1β stimulated MMP-13 increased with age. Forsyth et al, J Gerontol Biol Sci, 2005
Stress inflammatoire et tissu synovial
THE SYNOVIAL TISSUE IS INVOLVED IN THE OA PROCESS
Normal Synovial tissue
Fibrosis
Mild Inflammation
severe inflammation
TISSU SYNOVIAL ARTHROSIQUE
Immunostaining of Chemokines and MMP in OA Synovium Control
MCP-1
MMP-1
MMP-3
Synovial Mononuclear Cell Infiltrates in OA T-Cells (CD3)
B-Cells (CD20)
Plasma Cells (CD138)
Da et al., J Immunol., 2007 Sakkas et al., Arthritis Rheum
Cells of lymphoid origin may contribute to the pathophysiology of OA
Depletion of Synovial Macrophages Reduces Cartilage Damage DIPEN Staining (black)
•
Murine Collagenase-Induced OA
•
Clodronate (liposomal) utilized to deplete synovial macrophages Control
•
Cartilage damage determined by histopathology and DIPEN immunostaining (Neo-epitope for MMP activity)
Blom et al. Arthritis Rheum. 2007
Macrophage Depleted
Synovial macrophages play a role in OA cartilage pathology
Stress inflammatoire et os sous chondral
BONE AND OA
Bone-Cartilage Unit in OA Normal
OA Erosion
Articular cartilage
Tidemark
Calcification
The Bone-Cartilage Unit
From Lories & Luyten, Nature Rev Rheum 2011
Cartilage and Bone in OA
- Permeability of calcified cartilage to small molecules (~ 400 Da) Arkill, Osteoarthritis Cartilage 2008
Cartilage
- Diffusion of fluorescein sodium (360 Da) from subchondral bone to cartilage
Calcified cartilage
Subchondral bone
Pan, J Orthop Res 2009
The Bone-Cartilage Unit
Lories & Luyten, Nature Rev Rheum 2011
A new model for assessment of bone-cartilage communication Mechanical stress applied Mechanical stress appliedon on Flexercell Compression Plus FX-4000C osteoblast-derived matrix osteoblast-derived matrix::
Biopress
10% = 1,67 MPa 1 Hertz
medium
compression
Articular chondrocytes
Bone-cartilage communication
Osteoblast-derived medium induces MMP-13 protein expression in chondrocytes
MMP-13 secretion (Western Blot quantification) UC =uncompressed C =compressed UC = medium from uncompressed osteoblasts CM = medium from compressed osteoblasts
UC
C
Osteoblasts
Control UCM
CM
Chondrocytes
Priam et al. (in preparation)
« Genes and Osteoarthritis »
•Musculoskeletal ageing
•Matrix frailty
•Diabetes
•MetS •Hormones Systemic factors
•Post-trauma •Dysplasia Obesity Local factors
Obésité et stress inflammatoire
THE CONCEPT OF ADIPOCYTOKINES (OR ADIPOKINES)
Tilg & Moschen, Nature Reviews Immunology, 2006
PROTEINS SECRETED BY ADIPOSE TISSUE •Adiponectin •Resistin •Leptin •TNFα •IL-6 •Vaspin •Omentin •Adrenomedulin •Retinol Binding Protein-4
•Angiotensinogen •Adipsin •Fasting-induced adipose factor •PAI-I •Monocyte chemoattractant protein-I •TGF-β •Apelin •Acylation stimulating protein •Visfatin/PBEF/NAMPT
THE PREVALENCE OF HAND OA IS INCREASED IN OBESE PATIENTS !
~TWO-FOLD MORE RISK TO HAVE HAND OA IN OBESE POPULATION !
Yusuf et al. Ann Rheum Dis 2009 (epub)
Systemic factors
Mechanical stress
ROLES OF ADIPOKINES IN ARTHRITIS
From Lago et al. NCPR 2007
A NOVEL PARADIGM FOR THE PATHOPHYSIOLOGY OF OA
Trauma Local inflammation
MetS Low-grade inflammation
OSTEOARTHRITIS
ageing Secretory Inflammatory phenotype
OA induces experimental Alzheimer’s disease
APP/PS1;Col1-IL1βXAT model Kyrkanides et al. J Neuroinfl 2011
A NOVEL PARADIGM FOR THE PATHOPHYSIOLOGY OF OA
Trauma Local inflammation
MetS Low-grade inflammation
ageing Secretory Inflammatory phenotype
OSTEOARTHRITIS
Systemic release of inflammatory mediators
Alzheimer
Atherosclerosis ? Others ?
Pierre & Marie Curie University Paris VI « Joint ageing, cartilage degradation and inflammation» (F. Berenbaum) • • • • • • • •
Xavier Claire Marie-Charlotte Zvezdana Geoffroy Audrey Sabrina Jeremie
Houard (MCU) Jacques (MCU) Laguillon (Thésarde) Mladenovic (Tec) Nourissat (Thésard) Pigenet (tec) Priam (Thésarde) Sellam (MCU-PH)
Adipokines : VISFATIN+++
OSTEOARTHRITIS : A better understanding of the disease for a better treatment Prof. Francis BERENBAUM Pierre & Marie Curie University AP-HP Saint-Antoine hospital, Paris, France
Stockholm, Oct 19th 2011
OA : the bone perspective Spontaneous OA : Increase in subchondral bone cartilage destruction (guinea pig)
density
BEFORE
Experimental post-trauma induced OA : alendronate (inhibiting bone remodeling) decrease cartilage degradation (mice)
bone cells-chondrocyte co-culture : Increase in biomarkers of cartilage degradation (humans)
Bone-Cartilage Unit in OA Normal
OA Erosion
Articular cartilage
Tidemark
Calcification
The Bone-Cartilage Unit
From Lories & Luyten, Nature Rev Rheum 2011
The Bone-Cartilage Unit
Lories & Luyten, Nature Rev Rheum 2011
A new model for assessment of bone-cartilage communication Mechanical stress applied Mechanical stress appliedon on Flexercell Compression Plus FX-4000C osteoblast-derived matrix osteoblast-derived matrix::
Biopress
10% = 1,67 MPa 1 Hertz
medium
compression
Articular chondrocytes
Bone-cartilage communication
Osteoblast-derived medium induces MMP-13 protein expression in chondrocytes
MMP-13 secretion (Western Blot quantification) UC =uncompressed C =compressed UC = medium from uncompressed osteoblasts CM = medium from compressed osteoblasts
UC
C
Osteoblasts
Control UCM
CM
Chondrocytes
Priam et al. (in preparation)
PATHOPHYSIOLOGY OF OSTEOARTHRITIS : background for targeted therapies
TARGET !
adipokines
TARGET ! TARGET !
A targeted DMOAD : The Quest for the Holy Grail ? -
MMP inhibitor : negative results (and side-effects) Risedronate : negative results Oral calcitonin : negative results IL-1RA : negative results Anti-TNF : negative results rhFGF18 : ongoing (presented at OARSI 2011) Strontium ranelate : ongoing
CLASSIFICATION OF ARTHRITIS
CLASSIFICATION OF ARTHRITIS
Risk factors for incidence and progression of OA of the knees, hips and hands
Bijlsma & Klahr. Best Pract Res Clin Rheum 2007
« Mechanical-induced Osteoarthritis »
•Post-trauma •Dysplasia •Overweight Local factors
Role of mechanical stress Mechanical stress
Interaction Ligands/specific receptors
•Cytokines (including chemokines, adipokines) •Prostaglandins •Reactive oxygen species •RAGE ligands •Extracellular matrix components
MAPK NF-kB Others…
Transcriptional and post-transcriptional regulation COX-2
F. Berenbaum Primer in the Rheumatic Diseases, 13th Ed. (dec 07)
MMPs ADAMTS Cytokines Reactive oxygen species Prostaglandins
MECHANORECEPTORS ON CHONDROCYTES
COX-2
mPGES-1
Gabay et al. Osteoarthritis Cartilage 2008 Gosset et al. AR&T 2006
’ 60 d Lo a
de
d de Lo a
Un lo
ad
ed
30
’
Mechanosignalling and OA
***
**
Obesity, Trauma
Mechanical stress Mechanical stress
chondrocyte
COX-2
Loss o f
cartila
ge hom
eostas
is
Osteoarthritis
•
A 2-fold increase of hand OA in obese patients !
RR = 1,9
Yusuf et al. Ann Rheum Dis 2009
Systemic factors
Mechanical stress
« Metabolic-induced Osteoarthritis »
Obesity
Systemic factors
•Post-trauma •Dysplasia
Local factors
OA and adipokines
Gabay & Berenbaum. Curr Rheum Reviews 2009
Obesity
Mechanical stress
Adipokines
Mechanical stress
chondrocyte
COX-2
Loss of cartila ge
homeo
stasis
Obesity-induced OA
• •
Cohort of 482 women (47 years-old) Prevalence of knee OA = 11%
Obesity
« cardiometabolic status » (≥ 2 criteria)
BMI >30
•History of diabetes, antidiabetic drugs, glycemia > 126 g/dL •CRPus ≥ 2 mg/L •HDL ≤45 mg/dL or LDL>160 mg/dL •TG ≥ 200 mg/dL •height/Hip ≥ 0.81 cm •Systolic BP > 135 mmHg, diastolic BP > 85 mmHg or anti-hypertensive drugs Sowers et al. A Rheum Oct 2009
Risk for OA according to BMI and cardiometabolic clustering With knee OA n(%)
Odds ratio (IC 95%), p
Non-obese with NO cardiometabolic parameters (n=212)
10 (4,7%)
1
Non-obese WITH cardiometabolic parameters (n=85)
5 (5,9%)
1,28 (0.43-3.87)
Obese with NO cardiometabolic parameters« (n=47)
6 (12,8%)
3.00 (1.03-8.71), p<0.05
Obese WITH cardiometabolic parameters« (n=138)
32 (23,2%)
6.2 (1.93-13.07), p<0.0001
In obese patients, knee OA more frequent when cardiometabolic parameters are present Sowers et al. A Rheum Oct 2009
« Metabolic-induced Osteoarthritis »
•MetS
Obesity
Systemic factors
•Post-trauma •Dysplasia
Local factors
OA is associated with MetS NHANES III Data â&#x20AC;˘Comparaison of the prevalence of the MetS in subjects w/o OA â&#x20AC;˘To determine whether having OA predicts increased CV risk 59% 23%
44 years old man with OA : Risk of having MetS
x5
!
Puenpatom et al. Postgrad Med J 2009
Each of the 5 CV risk factors are more prevalent in the OA population NHANES III Data â&#x20AC;&#x201C; General population
Puenpatom et al. Postgrad Med J 2009
Ann Rheum Dis 2011
« Metabolic-induced Osteoarthritis »
•MetS •Diabetes
Obesity
Systemic factors
•Post-trauma •Dysplasia
Local factors
OA and atherosclerosis • In women, association between hand OA and : – Coronary calcifications OR = 1,42 (1,14-1,76) p=0,002 – Carotids plaques OR = 1,25 (1,04-1,49) p=0,016 • Adjusted on age, smoking, cholesterol, triglycerides, BMI, BP, statins
• Association between popliteal arterial wall thickness and generalized OA (adjusted on sex, age, BMI) Jonsson ARD 2009, GARP Jonsson ARD 2009, AGES Reykajvik Study
Similarities between OA and atherosclerosis â&#x20AC;˘ -
â&#x20AC;˘
Osteoarthritis
Age Obesity Failure of repair damage cartlage Destruction by proteinases Aneural articular Integrated role of cartilage and bone Synovial macrophages produce inflammatory mediators
-
Atherosclerosis
Age Obesity Failure of repair damage endothelium Destruction by proteinases Aneural atherosclerotic matrix Integrated role of endothelium and SM cells macrophages produce inflammatory mediators
2011
• • •
n=1163 (southwest England) , >35 years old with knee or hip symptomatic Mean follow-up : 14 years Comparison with general population, same age and gender (SMR:standardized mortality ratios)
Excess mortality in OA patients, mainly due to CV events.
Gabriel and Michaud Arthritis Research & Therapy 2009
« Aging-induced Osteoarthritis »
•Musculoskeletal ageing
•Matrix frailty
•Diabetes
•MetS •Hormones Systemic factors
•Post-trauma •Dysplasia Obesity Local factors
AGE Formation in Cartilage Autofluoresence
Cartilage caramelisation
68 years
AGE fluorescence/Hyp RFU/nmol
14 years 30000 R2 = 0.5539
20000
Knee Ankle
54 years 2
10000
R = 0.5537
0 0
20
40
60
Age in Years
80
100 Knee p = 0.02 Ankle p = 0.03
Loeser et al.
« AGE » AND OA
« AGE » (« Advanced Glycation End-products ») :
covalent binding between sugar and AA
Versijl et al. , Current Opin Rheumatol 2003
Aging increases the response to IL-1β IL-1 stim./Control MMP-13
8 6
r=0.57 p=0.0001
4 2 0 0
10 20 30 40 50 60 70 80 90 Donor Age
Chondrocytes were treated overnight with 5ng/ml IL-1b and MMP-13 was measured by immunoblotting. Similar to fibronectin fragments, IL-1b stimulated MMP-13 increased with age. Forsyth et al, J Gerontol Biol Sci, 2005
Senescence-associated secretory phenotype
CoppĂŠ et al. Annu Rev Pathol 2010
Senescence-associated secretory phenotype
CoppĂŠ et al. Annu Rev Pathol 2010
The concept of « inflamm-aging »
Franceschi et al. Annals New York Academy of Science 2000
The concept of « inflamm-aging »
Franceschi et al. Annals New York Academy of Science 2000
•Claire Jacques (MCU) •Xavier Houard (MCU) •Jérémie Sellam (MCU-PH) •Audrey Pigenet (Tech) •Sabrina Priam (Thes.) •Carole Bougaut (Post-doc) •Marjolaine Gosset