Obesity affects the chondrocyte responsiveness to leptin in patients with osteoarthritis.
BACKGROUND
Increasing evidence support the regulatory role of leptin in osteoarthritis (OA). As high circulating concentrations of leptin disrupt the physiological function of the adipokine in obese individuals, the current study has been undertaken to determine whether the elevated levels of leptin found in the joint from obese OA patients also induce changes in the chondrocyte response to leptin.


METHODS
Chondrocytes isolated from OA patients with various body mass index (BMI) were treated with 20, 100 or 500 ng/ml of leptin. The expression of cartilage-specific components (aggrecan, type 2 collagen), as well as regulatory (IGF-1, TGFbeta, MMP-13, TIMP 2) or inflammatory (COX-2, iNOS, IL-1) factors was investigated by real-time PCR to evaluate chondrocyte responsiveness to leptin. Furthermore, the effect of body mass index (BMI) on leptin signalling pathways was analyzed with an enzyme-linked immunosorbent assay for STATs activation.


RESULTS
Leptin at 20 ng/ml was unable to modulate gene expression in chondrocytes, except for MMP-13 in obese OA patients. Higher leptin levels induced the expression of IGF-1, type 2 collagen, TIMP-2 and MMP-13. However, the activity of the adipokine was shown to be critically dependent on both the concentration and the BMI of the patients with a negative association between the activation of regulated genes and BMI for 100 ng/ml of adipokine, but a positive association between chondrocyte responsiveness and BMI for the highest leptin dose. In addition, the gene encoding MMP-13 was identified as a target of leptin for chondrocytes originated from obese patients while mRNA level of TIMP-2 was increased in leptin-treated chondrocytes collected from normal or overweight patients. The adipokine at 500 ng/ml triggered signal transduction through a STAT-dependent pathway while 100 ng/ml of leptin failed to activate STAT 3 but induced STAT 1alpha phosphorylation in chondrocytes obtained from obese patients.


CONCLUSIONS
The current study clearly showed that characteristics of OA patients and more especially obesity may affect the responsiveness of cultured chondrocytes to leptin. In addition, the BMI-dependent effect of leptin for the expression of TIMP-2 and MMP-13 may explain why obesity is associated with an increased risk for OA.
UMR S658 INSERM, Hôpital Porte Madeleine, 1 Rue Porte Madeleine, BP 2439, 45032 Orléans, France.
Stéphane
S
Pallu
Pierre-Jean
PJ
Francin
Cécile
C
Guillaume
Pascale
P
Gegout-Pottie
Patrick
P
Netter
Didier
D
Mainard
Bernard
B
Terlain
Nathalie
N
Presle
D000368:Aged; D000369:Aged, 80 and over; D015992:Body Mass Index; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D024043:Collagen Type II / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D020370:Osteoarthritis, Knee / Q000378:metabolism* / Q000473:pathology; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D024043:Collagen Type II; D020738:Leptin; D050791:STAT Transcription Factors; D019716:Tissue Inhibitor of Metalloproteinase-2; D007334:Insulin-Like Growth Factor I; D053509:Matrix Metalloproteinase 13