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Systemic inhibition of IL-6/Stat3 signalling protects against experimental osteoarthritis
Augustin Latourte1,2, Chahrazad Cherifi1, Jérémy Maillet1,2
1INSERM U1132, Hôpital Lariboisière, Paris, France.
Objective:
To investigate the impact of systemic inhibition of interleukin 6 (IL-6) or signal transducer and activator of transcription (Stat3) in an experimental model of osteoarthritis (OA).
Methods:
Expression of major catabolic and anabolic factors of cartilage was determined in IL-6-treated mouse chondrocytes and cartilage explants. The anti-IL-6-receptor neutralising antibody MR16-1 was used in the destabilisation of the medial meniscus (DMM) mouse model of OA. Stat3 blockade was investigated by the small molecule Stattic ex vivo and in the DMM model.
Results:
In chondrocytes and cartilage explants, IL-6 treatment reduced proteoglycan content with increased production of matrix metalloproteinase (MMP-3 and MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-4 and ADAMTS-5). IL-6 induced Stat3 and extracellular signal-regulated kinase (ERK) 1/2 signalling but not p38, c-Jun N-terminal kinase or Akt. In the DMM model, Stat3 was activated in cartilage, but neither in the synovium nor in the subchondral bone. Systemic blockade of IL-6 by MR16-1 alleviated DMM-induced OA cartilage lesions, impaired the osteophyte formation and the extent of synovitis. In the same model, Stattic had similar beneficial effects on cartilage and osteophyte formation. Stattic, but not an ERK1/2 inhibitor, significantly counteracted the catabolic effects of IL-6 on cartilage explants and suppressed the IL-6-induced chondrocytes apoptosis.
Conclusion:
IL-6 induces chondrocyte catabolism mainly via Stat3 signalling, a pathway activated in cartilage from joint subjected to DMM. Systemic blockade of IL-6 or STAT-3 can alleviate DMM-induced OA in mice.
Insights
Systemic inhibition of interleukin-6 (IL-6) or signal transducer and activator of transcription (Stat3) alleviates osteoarthritis (OA) in mice. Blocking IL-6 or Stat3 in cartilage reduces catabolism and protects against OA development.
Area of Science:
- Immunology
- Rheumatology
- Molecular Biology
Background:
- Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage breakdown.
- Interleukin-6 (IL-6) and its downstream signaling pathway, Signal transducer and activator of transcription (Stat3), are implicated in OA pathogenesis.
- Understanding the specific roles of IL-6/Stat3 in OA is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting IL-6 or Stat3 in an experimental mouse model of OA.
- To elucidate the molecular mechanisms by which IL-6 affects cartilage homeostasis.
Main Methods:
- IL-6 treatment effects on chondrocytes and cartilage explants were assessed.
- The destabilization of the medial meniscus (DMM) mouse model was used to induce OA.
- Systemic blockade of IL-6 (using MR16-1 antibody) and Stat3 (using Stattic) was performed in the DMM model.
Main Results:
- IL-6 treatment increased matrix degradation and chondrocyte apoptosis, primarily via Stat3 activation.
- Systemic IL-6 or Stat3 blockade in the DMM model significantly reduced OA cartilage lesions, osteophyte formation, and synovitis.
- Stattic effectively counteracted IL-6's catabolic effects on cartilage.
Conclusions:
- IL-6 drives chondrocyte catabolism predominantly through Stat3 signaling in OA.
- Targeting IL-6 or Stat3 systemically offers a promising therapeutic strategy for mitigating OA progression in mice.
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