ECCEO2012final3

ADIPOKINES, OBESITY AND OSTEOARTHRITIS : New developments Prof. Francis BERENBAUM Pierre & Marie Curie University AP-HP Saint-Antoine hospital, Paris, France

ECCEO, Bordeaux, Mar 23, 2012

Obesity is a risk factor for knee OA

EFFECTS OF OBESITY ON KNEE OA

Kulie et al. J Am Board Fam Med 2011

Obesity Trends* Among U.S. Adults BRFSS, 1985 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

Obesity Trends* Among U.S. Adults BRFSS, 1986 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

Obesity Trends* Among U.S. Adults BRFSS, 1987 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

Obesity Trends* Among U.S. Adults BRFSS, 1988 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

Obesity Trends* Among U.S. Adults BRFSS, 1989 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

Obesity Trends* Among U.S. Adults BRFSS, 1990 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

Obesity Trends* Among U.S. Adults BRFSS, 1991 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

Obesity Trends* Among U.S. Adults BRFSS, 1992 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

Obesity Trends* Among U.S. Adults BRFSS, 1993 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

Obesity Trends* Among U.S. Adults BRFSS, 1994 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

Obesity Trends* Among U.S. Adults BRFSS, 1995 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

Obesity Trends* Among U.S. Adults BRFSS, 1996 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

Obesity Trends* Among U.S. Adults BRFSS, 1997 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

>20%

Obesity Trends* Among U.S. Adults BRFSS, 1998 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

>20%

Obesity Trends* Among U.S. Adults BRFSS, 1999 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

>20%

Obesity Trends* Among U.S. Adults BRFSS, 2000 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

>20%

Obesity Trends* Among U.S. Adults BRFSS, 2001 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

20%–24%

>25%

Obesity Trends* Among U.S. Adults BRFSS, 2002 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

20%–24%

>25%

Obesity Trends* Among U.S. Adults BRFSS, 2003 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

20%–24%

>25%

Obesity Trends* Among U.S. Adults BRFSS, 2004 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

20%–24%

>25%

Obesity Trends* Among U.S. Adults BRFSS, 2005 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

20%–24%

25%–29%

≥30%

Obesity Trends* Among U.S. Adults BRFSS, 2006 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

20%–24%

25%–29%

≥30%

Obesity Trends* Among U.S. Adults BRFSS, 2007 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

20%–24%

25%–29%

≥30%

Obesity Trends* Among U.S. Adults BRFSS, 2008 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

20%–24%

25%–29%

≥30%

Obesity Trends* Among U.S. Adults BRFSS, 2009 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

20%–24%

25%–29%

≥30%

Obesity Trends* Among U.S. Adults BRFSS, 2010 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data

<10%

10%–14%

15%–19%

20%–24%

25%–29%

≥30%

RELATIONSHIPS BETWEEN OBESITY AND ARTHRITIS

Age-adjusted, weighted percentage of adults with arthritis who were categorized as obese

Median unadjusted, weighted prevalence of obesity among adults with and without arthritis

Global Prevalence of Obesity in Adult Females With examples of the top 5 Countries in each Region

North America USA 33% Barbados 31% Mexico 29% St Lucia 28% Bahamas 28%

European Region Albania 36% Malta 35% Turkey 29% Slovakia 28% Czech Republic 26%

Eastern Mediterranean Jordan 60% Qatar 45% Saudi Arabia 44% Palestine 43% Lebanon 38%

% Obese 0-9.9% 10-14.9% 15-19.9% 20-24.9% 25-29.9% ≥30% Self Reported data

South Central America Panama 36% Paraguay 36% Peru (urban) 23% Chile (urban) 23% Dominican Republic 18%

Africa Seychelles 28% South Africa 28% Ghana 20% Mauritania 19% Cameroon (urban) 14%

© International Obesity TaskForce, London –January 2007

South East Asia & Pacific Region Nauru 78% Tonga 70% Samoa 63% Niue 46% French Polynesia 44%

Pathology of Osteoarthritis

Sellam & Berenbaum, Nature Reviews Rheum 2010

CARTILAGE HOMEOSTASIS IS ALTERED IN OA

F. Berenbaum EULAR Textbook

Role of 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

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

’ 60 ad ed Lo

ad ed Lo

Un lo a

de d

30

’

Mechanosignalling and OA

COX-2

mPGES-1

***

**

Gabay et al. Osteoarthritis Cartilage 2008 Gosset et al. AR&T 2006

Obesity, Trauma

Mechanical stress Mechanical stress

chondrocyte

COX-2

Loss o f

cartila

ge hom

e o st a s

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

INFLAMMATION IN ADIPOSE TISSUE

Osborne & Olefsky, Nature Med 2012

INFLAMMATION IN ADIPOSE TISSUE

Osborne & Olefsky, Nature Med 2012

ADIPOKINES IN THE CONTEXT OF A JOINT

Gomez et al. 2011

OVERALL EFFECTS OF ADIPOKINES ON JOINT CELLS

Conde et al. Arthritis 2011

OA and adipokines

Gabay & Berenbaum. Curr Rheum Reviews 2009

Leptin Leptin deficiency does not increase OA risk  Leptin production by OA subchondral osteoblasts is increased, and is involved in altered production of alkaline phosphatase, TGFβ, osteocalcin and type I collagen  OA chondrocytes respond differently to leptin compared with chondrocytes in obese individuals 

Gomez et al. 2011

Leptin induces cartilage degradation via upregulation and activation of matrix metalloproteinases

Hui et al. ARD 2012

Obesity affects the chondrocyte responsiveness to leptin in patients with osteoarthritis

Pallu et al. O&C 2011

ADIPONECTIN IN OA Adiponectin levels are increased in patients with OA  Adiponectin induces IL-6, IL-8, NO, CCL2 and MMP production by OA chondrocytes  Synovial fluid adiponectin levels correlate with OA severity  Adiponectin levels are increased in erosive OA  Production of adiponectin in the infrapatelar fat pad is increased in OA  Synovial fluid adiponectin:leptin ratio correlates with pain in OA 

Gomez et al. 2011

ADIPONECTIN IN OA

OA chondrocytes

Kang et al. AR&T 2010

Visfatin/Nampt : a pleiotropic protein 

Cytokine activity : (extracellular)

- pro-inflammatory cytokine (Samal, 1994). Induction of proinflammatory and pro-degradative mediators

cytokine eNampt

?

Visfatin/Nampt : a pleiotropic protein Cytokinique activity : (extracellular)



- pro-inflammatory cytokine (Samal, 1994). Induction of proinflammatory and pro-degradative mediators 

enzyme

cytokine

eNampt eNampt

? ?

Nicotinamide Phosphoribosyltransferase (Nampt) - Rate-limiting enzyme for nicotinamide dinucleotide (NAD) synthesis (Rongvaux, 2002)

?

iNampt

Enzymatic activity :

(intra- and extracellular)

NMN

NAM

?

NAM

NMN Nmnat

SIRT1,2 NAD

NMN : nicotinamide mononucléotide Nmnat : nicotinamide mononucléotide adenylyltransférase NAD : nicotinamide dinucléotide

Visfatin/Nampt : a pleiotropic protein Cytokinique activity : (extracellular)



- pro-inflammatory cytokine (Samal, 1994). Induction of proinflammatory and pro-degradative mediators 

enzyme

cytokine

eNampt eNampt

? ?

Nicotinamide Phosphoribosyltransferase (Nampt) - Rate-limiting enzyme for nicotinamide dinucleotide (NAD) synthesis (Rongvaux, 2002)

?

iNampt

Enzymatic activity :

(intra- and extracellular)

NMN

NAM

?

APO866

NAM

NMN Nmnat

SIRT1,2 NAD

NMN : nicotinamide mononucléotide Nmnat : nicotinamide mononucléotide adenylyltransférase NAD : nicotinamide dinucléotide

HOW VISFATIN/NAMPT INCREASES PGE2 PRODUCTION IN CHONDROCYTES ?

enzyme eNampt

cytokine eNampt

APO866 NMN

NAM

?

? ?

?

iNampt

NAM

NMN Nmnat

SIRT1,2 NAD

NMN : nicotinamide mononucléotide Nmnat : nicotinamide mononucléotide adenylyltransférase NAD : nicotinamide dinucléotide

Gosset et al. A&R 2008, Gosset et al. J Biol Chem (in press)

EFFECTS OF VISFATIN ON MENISCAL EXPLANTS

McNulty et al. Connect Tissue Res 2011

Obesity

Mechanical stress

Adipokines

Mechanical stress

chondrocyte

COX-2

Loss of

cartila ge

homeo stasis

Obesity-induced OA

WILL ADIPOKINES BE THE NEXT GENERATION OF BIOMARKERS IN OA ?

Effect of massive weight loss on knee pain/disability, low-grade inflammation,metabolic status and joint biomarkers in obese patients with knee OA

Richette et al. ARD 2010

Association between baseline serum adipokines levels and long-term progression of hand osteoarthritis 164p, 6 years follow-up

Patients in the two highest tertiles of adiponectin have a decreased risk of 70% for HOA progression in comparison with patients in the lowest tertile

Yusuf et al. ARD 2011

Leptin and visfatin concentration in synovial fluid

McNulty et al. Connect Tissue Res 2011

Increased synovial fluid visfatin is positively linked to cartilage degradation biomarkers in osteoarthritis N=30

Duan et al. Rheumatol Int 2011

WILL ADIPOKINES BE THE NEXT TARGETS FOR THE TREATMENT OF OA ?

A PROPOSAL FOR A NEW CLASSIFICATION FOR OA

Bijlsma, Berenbaum, Lafeber. The Lancet 2011

Pierre & Marie Curie University AP-HP Saint-Antoine hospital Claire Jacques  Xavier Houard  MC Laiguillon  Jérémie Sellam  Audrey Pigenet  Sabrina Priam  G. Nourissat  Carole Bougaut  Danièle Citadelle  Szvesdana Milanovic 

Marjolaine Gosset

