Obesity affects the chondrocyte responsiveness to leptin in patients with osteoarthritis

Abstract

IntroductionIncreasing 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.MethodsChondrocytes 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, TGFβ, 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.ResultsLeptin 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 1α phosphorylation in chondrocytes obtained from obese patients.ConclusionsThe current study clearly showed that characteristics of OA patients and more expecially 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.

Correlations between serum adipocytokine concentrations, disease stage, radiological status and total body fat content in the patients with primary knee osteoarthritis

“…Our results are consistent with an earlier report [35] showing a lower concentration of synovial fluid leptin in patients with advanced OA in comparison to those at the initial stages of the disease, and with another report [36] on overexpression of genes encoding IGF-1, TIMP-2, type II collagen and MMP-13 in the obese patients, which might be responsible for inhibition of the leptin impact on chondrocytes. These results were confirmed in an animal model [37].…”

Obesity-related Adipokines and Shoulder Osteoarthritis

“…The association of obesity and OA of non-weight-bearing joints, such as the hand, lends further support to this hypothesis 1,2 . LEP and resistin have been suggested to have a strong proinflammatory influence 3,4 , while the role of ADIPO in a knee joint is unclear, as some have shown an antiinflammatory effect 5 and others suggest a proinflammatory effect 6 . Similarly, the ADIPO receptors have been identified in the knee joint only 6 .…”

Role of glucose as a modulator of anabolic and catabolic gene expression in normal and osteoarthritic human chondrocytes

“…For instance, a significant positive correlation was found between elevated blood glucose and radiological evidence of OA [Hart et al, 1995]. Accordingly, OA is increasingly envisaged as a ''metabolic disorder'' linked to obesity, diabetes mellitus, dyslipidemia, hypertension, and insulin resistance [Sturmer et al, 2001;Burner and Rosenthal, 2009;Siviero et al, 2009;Pallu et al, 2010;Velasquez and Katz, 2010].…”

“…For instance, a significant positive correlation was found between elevated blood glucose and radiological evidence of OA [Hart et al, 1995]. Accordingly, OA is increasingly envisaged as a ''metabolic disorder'' linked to obesity, diabetes mellitus, dyslipidemia, hypertension, and insulin resistance [Sturmer et al, 2001;Burner and Rosenthal, 2009;Siviero et al, 2009;Pallu et al, 2010;Velasquez and Katz, 2010].These conditions seem to favor the initiation and progression of arthritic diseases, such as OA, by providing catabolic signals that lead, among other responses, to increased production of proteolytic enzymes. These degrade the matrix components causing progressive cartilage destruction, the main feature of OA [Martel-Pelletier et al, 2008;Goldring and Marcu, 2009].…”