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