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

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

Fingerprint

White Adipose Tissue
Cartilage
Leptin
Matrix Metalloproteinases
Up-Regulation
Joints
Chemical activation
Tissue
Degradation
Collagen
Chondrocytes
Interleukin-1
Adipose Tissue
Fats
Adipokines
Bioassay
Knee Osteoarthritis
Gelatin
Conditioned Culture Medium
Knee Joint

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

Cite this

Hui, Wang ; Litherland, Gary J ; Elias, Martina S ; Kitson, Gareth I ; Cawston, Tim E ; Rowan, Andrew D ; Young, David A. / Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases. In: Annals of the Rheumatic Diseases. 2012 ; Vol. 71, No. 3. pp. 455-62.
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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-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.",
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author = "Wang Hui and Litherland, {Gary J} and Elias, {Martina S} and Kitson, {Gareth I} and Cawston, {Tim E} and Rowan, {Andrew D} and Young, {David A}",
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Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases. / Hui, Wang; Litherland, Gary J; Elias, Martina S; Kitson, Gareth I; Cawston, Tim E; Rowan, Andrew D; Young, David A.

In: Annals of the Rheumatic Diseases, Vol. 71, No. 3, 03.2012, p. 455-62.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases

AU - Hui, Wang

AU - Litherland, Gary J

AU - Elias, Martina S

AU - Kitson, Gareth I

AU - Cawston, Tim E

AU - Rowan, Andrew D

AU - Young, David A

PY - 2012/3

Y1 - 2012/3

N2 - 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.

AB - 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.

KW - Adipose Tissue, White

KW - Animals

KW - Cartilage, Articular

KW - Cattle

KW - Cells, Cultured

KW - Collagen

KW - Collagenases

KW - Culture Media, Conditioned

KW - Dose-Response Relationship, Drug

KW - Gene Expression Regulation, Enzymologic

KW - Humans

KW - Inflammation Mediators

KW - Leptin

KW - Matrix Metalloproteinases

KW - Mitogen-Activated Protein Kinase Kinases

KW - Nasal Cartilages

KW - Proto-Oncogene Proteins c-akt

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - STAT Transcription Factors

KW - Signal Transduction

KW - Tissue Culture Techniques

U2 - 10.1136/annrheumdis-2011-200372

DO - 10.1136/annrheumdis-2011-200372

M3 - Article

VL - 71

SP - 455

EP - 462

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

IS - 3

ER -