phenotype_genotype27_05_11

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