title: Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases.
abstract: OBJECTIVE
  To investigate the effect of leptin on cartilage destruction.
  
  
  METHODS
  Collagen release was assessed in bovine cartilage explant cultures, while collagenolytic and gelatinolytic activities in culture supernatants were determined by bioassay and gelatin zymography. The expression of matrix metalloproteinases (MMP) was analysed by real-time RT-PCR. Signalling pathway activation was studied by immunoblotting. Leptin levels in cultured osteoarthritic joint infrapatellar fat pad or peri-enthesal deposit supernatants were measured by immunoassay.
  
  
  RESULTS
  Leptin, either alone or in synergy with IL-1, significantly induced collagen release from bovine cartilage by upregulating collagenolytic and gelatinolytic activity. In chondrocytes, leptin induced MMP1 and MMP13 expression with a concomitant activation of STAT1, STAT3, STAT5, MAPK (JNK, Erk, p38), Akt and NF-κB signalling pathways. Selective inhibitor blockade of PI3K, p38, Erk and Akt pathways significantly reduced MMP1 and MMP13 expression in chondrocytes, and reduced cartilage collagen release induced by leptin or leptin plus IL-1. JNK inhibition had no effect on leptin-induced MMP13 expression or leptin plus IL-1-induced cartilage collagen release. Conditioned media from cultured white adipose tissue (WAT) from osteoarthritis knee joint fat pads contained leptin, induced cartilage collagen release and increased MMP1 and MMP13 expression in chondrocytes; the latter being partly blocked with an anti-leptin antibody.
  
  
  CONCLUSIONS
  Leptin acts as a pro-inflammatory adipokine with a catabolic role on cartilage metabolism via the upregulation of proteolytic enzymes and acts synergistically with other pro-inflammatory stimuli. This suggests that the infrapatellar fat pad and other WAT in arthritic joints are local producers of leptin, which may contribute to the inflammatory and degenerative processes in cartilage catabolism, providing a mechanistic link between obesity and osteoarthritis.
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Wang
authors.initials: W
authors.lastname: Hui
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Litherland
authors.forename: Martina S
authors.initials: MS
authors.lastname: Elias
authors.forename: Gareth I
authors.initials: GI
authors.lastname: Kitson
authors.forename: Tim E
authors.initials: TE
authors.lastname: Cawston
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Rowan
authors.forename: David A
authors.initials: DA
authors.lastname: Young
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000096:biosynthesis / Q000235:genetics; D017077:Culture Media, Conditioned; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D020738:Leptin / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D020782:Matrix Metalloproteinases / Q000378:metabolism / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D055171:Nasal Cartilages / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D046509:Tissue Culture Techniques
chemical_list: D017077:Culture Media, Conditioned; D018836:Inflammation Mediators; D020738:Leptin; D050791:STAT Transcription Factors; D003094:Collagen; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D017364:Collagenases; D020782:Matrix Metalloproteinases