Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases

Wang Hui, Gary J Litherland, Martina S Elias, Gareth I Kitson, Tim E Cawston, Andrew D Rowan, David A Young

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

OBJECTIVES: 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.

Original languageEnglish
Pages (from-to)455-62
Number of pages8
JournalAnnals of the Rheumatic Diseases
Volume71
Issue number3
DOIs
Publication statusPublished - Mar 2012
Externally publishedYes

Keywords

  • Adipose Tissue, White
  • Animals
  • Cartilage, Articular
  • Cattle
  • Cells, Cultured
  • Collagen
  • Collagenases
  • Culture Media, Conditioned
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Inflammation Mediators
  • Leptin
  • Matrix Metalloproteinases
  • Mitogen-Activated Protein Kinase Kinases
  • Nasal Cartilages
  • Proto-Oncogene Proteins c-akt
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT Transcription Factors
  • Signal Transduction
  • Tissue Culture Techniques

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  • Research Output

    • 119 Citations
    • 11 Article
    • 3 Meeting Abstract

    Protein kinase D3 modulates MMP1 and MMP13 expression in human chondrocytes

    Baker, J., Falconer, A., Wilkinson, D. J., Europe-Finner, G. N., Litherland, G. & Rowan, A. D., 13 Apr 2018, In : PLoS ONE. 13, 4, 19 p., e0195864.

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    Open Access
  • 9 Citations (Scopus)

    Cytokine-Induced MMP13 Expression in Human Chondrocytes is dependent on Activating Transcription Factor 3 (ATF3) regulation

    Chan, C. M., Macdonald, C. D., Litherland, G., Wilkinson, D. J., Skelton, A., Europe-Finner, G. N. & Rowan, A. D., 12 Dec 2016, In : Journal of Biological Chemistry.

    Research output: Contribution to journalArticle

    Open Access
  • 17 Citations (Scopus)

    Tribbles and arthritis: what are the links?

    Rowan, A. D. & Litherland, G. J., Oct 2015, In : Biochemical Society Transactions. 43, p. 1051-1056

    Research output: Contribution to journalArticle

    3 Citations (Scopus)

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