Abstract
BackgroundLeptin, an adipocyte-secreted hormone that centrally regulates weight control, may exert proinflammatory effects in the joint, depending on the immune response. Leptin is abundantly expressed in osteoarthritis (OA) cartilage and synovium. However, the relationship between leptin and interleukin-6 (IL-6) in OA synovial fibroblasts (OASFs) remains obscure.Methodology/Principal FindingsStimulation of OASFs with leptin induced IL-6 expression in a concentration- and time-dependent manner. OASFs expressed the long (OBRl) and short (OBRs) isoforms of the leptin receptor. However, OBRl, but not OBRs, antisense oligonucleotide (AS-ODN) abolished the leptin-mediated increase of IL-6 expression. Transfection with insulin receptor substrate (IRS)-1 siRNA decreased leptin-induced IL-6 production. In addition, pretreatment of cells with PI3K, Akt, or AP-1 inhibitor also inhibited the potentiating action of leptin. Leptin-induced AP-1 activation was inhibited by OBRl, IRS-1, PI3K, or Akt inhibitors and siRNAs.Conclusions/SignificanceOur results showed that leptin activates the OBRl receptor, which in turn activates IRS-1, PI3K, Akt, and AP-1 pathway, leading to up-regulation of IL-6 expression.
Highlights
Osteoarthritis (OA) is the most common adult joint disease, and is increasing in frequency and severity [1]
We examined whether PI3K, a critical downstream target of insulin receptor substrate (IRS)-1 [35], is involved in leptintriggered IL-6 production in OA synovial fibroblasts (OASFs)
Leptin levels in the synovial fluid are strongly associated with the radiographic severity of OA [39], indicating a local effect of leptin in articular cartilage, and further suggesting that leptin levels in the synovial fluid could be used as an effective quantitative marker for detection of OA
Summary
Osteoarthritis (OA) is the most common adult joint disease, and is increasing in frequency and severity [1]. In response to the proinflammatory mediators produced by chondrocytes and macrophages, osteoarthritic synovial fibroblasts (OASFs) produce cytokines that promote cartilage degradation, neovascularization, and inflammation [3]. A clinical trial in OA patients showed that IL-6 was associated with an risk of cartilage loss [12]. These findings strongly indicate an important role of IL-6 production during OA pathogenesis. Leptininduced AP-1 activation was inhibited by OBRl, IRS-1, PI3K, or Akt inhibitors and siRNAs. Conclusions/Significance: Our results showed that leptin activates the OBRl receptor, which in turn activates IRS-1, PI3K, Akt, and AP-1 pathway, leading to up-regulation of IL-6 expression
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
