OSTEOARTHRITIS : FROM PHENOTYPE TO GENOTYPE Francis BERENBAUM Pierre et Marie Curie University Saint-Antoine Hospital, AP-HP, Paris
OA PHENOTYPES : THE CLASSICAL VIEW
• Localization : hip / knee / hand / spine • « primary » (idiopathic) vs « secondary » (to inflammatory arthritis, crystal-induced, etc.)
• Gender • Race • Kellgren-Lawrence classification for diagnosis/severity => Genetic studies based on this classification
« Study subjects with a radiographic Kellgren and Lawrence (K/L) grade ≥2 or total knee replacement were included as cases in the analysis. When clinical criteria were considered (Greek, Spanish and GARP study groups), the American College of Rheumatology classification criteria were used. Subjects who had no known affected joints among those assessed acted as controls. For example, in a cohort that assesses knee, hip and hand OA, controls were participants with no affected hip or hand joints for the knee OA analysis. Population-based controls were used for the arcOGEN study. »
Evangelou et al. ARD 2011
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 (in press)
CARTILAGE AND OA QUANTITATIVE ALTERATIONS •Matrix degradation +++ •Chondrocyte apoptosis
NORMAL
OA
QUALITATIVE ALTERATIONS •Synthesis of a matrix of bad quality •Alterations in chondrocyte differentiation •Matrix calcification
OA : a disease of the whole joint
Sellam & Berenbaum. Nature Reviews Rheum Nov. 2010
« 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
***
Gabay et al. Osteoarthritis Cartilage 2008
60 ’ Lo ad ed
30 ’ Lo ad ed
Un lo ad ed
Mechanosignalling and OA
**
Obesity, Trauma
Mechanical stress Mechanical stress
chondrocyte
COX-2
Loss o f
cartila
ge hom
e o st a s
is
Osteoarthritis
« Metabolic-induced Osteoarthritis »
Obesity
Systemic factors
•Post-trauma •Dysplasia
Local factors
A 2-fold increase of hand OA in obese patients !
RR = 1,9
Yusuf et al. Ann Rheum Dis 2009
Systemic factors
Mechanical stress
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
« Metabolic-induced Osteoarthritis »
•MetS •Diabetes
Obesity
Systemic factors
•Post-trauma •Dysplasia
Local factors
• Cohort of 482 women (47 years-old) • Knee OA with KL≥2 • Knee pain Obesity
« cardiométabolic 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
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
Ann Rheum Dis 2011
(in press)
« Aging-induced Osteoarthritis »
•Musculoskeletal ageing
•Matrix frailty
•Diabetes
•MetS •Hormones Systemic factors
•Post-trauma •Dysplasia Obesity Local factors
MUSCULOSKELETAL AGING
Changes in cell and tissue function • Sarcopenia • Loss of proprioception and balance • Increased joint laxity
Stress oxydatif et arthrose
Loeser R. O&C 2009
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
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
« Aging-induced Osteoarthritis »
•Musculoskeletal ageing
•Matrix frailty
•Diabetes GENES
•MetS
•Post-trauma •Dysplasia
Obesity Systemic factors
Local factors
GENETIC ASSOCIATIONS WITH KNEE OA AS IDENTIFIED BY GWAS
« Aging-induced Osteoarthritis »
•Musculoskeletal ageing
•Matrix frailty
•Diabetes GENES
•MetS
•Post-trauma •Dysplasia
Obesity Systemic factors
Local factors
GENETIC VARIANTS ASSOCIATED WITH OBESITY
Ahlqvist et al. Clin Chem 2011
Identification of T2D susceptibility genes
Bonnefond et al. 2010
GENES FOR LONGEVITY
Yuan et al. ILAR J 2011
•Claire Jacques (MCU) •Xavier Houard (MCU) •Jérémie Sellam (MCU-PH) •Audrey Pigenet (Tech) •Sabrina Priam (Thes.) •G. Nourissat (Thes.) •Carole Bougaut (Post-doc) •Marjolaine Gosset