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

Lookup NU author(s): Dr Gary Litherland, Madona Elias, Emeritus Professor Tim Cawston, Emeritus Professor Drew Rowan, Professor David Young

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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-kappa B 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.


Publication metadata

Author(s): Hui W, Litherland GJ, Elias MS, Kitson GI, Cawston TE, Rowan AD, Young DA

Publication type: Article

Publication status: Published

Journal: Annals of the Rheumatic Diseases

Year: 2012

Volume: 71

Issue: 3

Pages: 455-462

Print publication date: 09/11/2011

Date deposited: 16/05/2012

ISSN (print): 0003-4967

ISSN (electronic): 1468-2060

Publisher: BMJ Group

URL: http://dx.doi.org/10.1136/annrheumdis-2011-200372

DOI: 10.1136/annrheumdis-2011-200372


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