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Possible chondroprotective effect of canakinumab: an in vitro study on human osteoarthritic chondrocytes
Sara Cheleschi1, Luca Cantarini1, Nicola Antonio Pascarelli1
1Department of Medicine, Surgery and Neuroscience, Rheumatology Unit, University of Siena, Italy.
Insights
Canakinumab neutralizes interleukin-1 beta, protecting osteoarthritic chondrocytes from tumor necrosis factor-alpha. This monoclonal antibody treatment improved cell viability, proteoglycan levels, and reduced nitric oxide and matrix metalloproteinase expression in vitro.
Area of Science:
- Immunology
- Osteoarthritis Research
- Cell Biology
Background:
- Interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) are key inflammatory mediators in osteoarthritis (OA).
- Chondrocytes play a crucial role in maintaining cartilage health, and their dysfunction contributes to OA pathogenesis.
- Monoclonal antibodies targeting inflammatory cytokines are being investigated for therapeutic potential in OA.
Purpose of the Study:
- To investigate the in vitro effects of canakinumab, an IL-1β inhibitor, on human osteoarthritic (OA) chondrocytes.
- To evaluate canakinumab's ability to counteract the detrimental effects of TNF-α on chondrocytes.
- To assess the potential chondroprotective role of canakinumab in an OA model.
Main Methods:
- Human osteoarthritic chondrocytes were cultured with or without TNF-α.
- Cells were treated with two concentrations of canakinumab (1μg/ml and 10μg/ml) for 48 hours.
- Evaluated outcomes included cell viability, proteoglycan (PG) and nitric oxide (NO) release, gene expression of iNOS and MMPs (1, 3, 13), apoptosis, necrosis, and morphology via transmission electron microscopy (TEM).
Main Results:
- TNF-α significantly reduced cell viability, PG levels, and increased NO and MMP gene expression, confirming its catabolic effect.
- Canakinumab treatment restored cell viability, increased PG levels, and significantly decreased NO and MMP gene expression in TNF-α-stimulated chondrocytes.
- Canakinumab demonstrated a protective effect against TNF-α-induced apoptosis and necrosis, supported by TEM findings.
Conclusions:
- Canakinumab effectively counteracts the pro-inflammatory and catabolic effects of TNF-α on human OA chondrocytes in vitro.
- The findings suggest that canakinumab possesses a potential chondroprotective role in osteoarthritis.
- Targeting IL-1β with canakinumab may represent a viable therapeutic strategy for managing OA.
Abstract:
Canakinumab is a human IgGκ monoclonal antibody that neutralizes the activity of interleukin (IL)-1β blocking interaction with IL-1β receptors. Our study aimed to evaluate the in vitro effect of canakinumab on human osteoarthritic (OA) chondrocytes cultivated in the presence or absence of tumor necrosis factor (TNF)-α. Articular cartilage was obtained from the femoral heads of patients with osteoarthritis (OA). Chondrocytes were incubated with two concentrations (1μg/ml and 10μg/ml) of canakinumab alone or with TNF-α (10ng/ml) for 48h. We evaluated cell viability, release of proteoglycans (PG) and nitric oxide (NO) in culture medium, inducible nitric oxide synthase (iNOS) and metalloproteinanes (MMP)-1,3,13 gene expression, apoptosis, necrosis and morphological feature by transmission electron microscopy (TEM). Canakinumab alone did not have cytotoxic effect. Cell viability was reduced significantly (p<0.001) by TNF-α and restored by canakinumab at both concentrations used. TNF-α determined a significant decrease of PG (p<0.001) and an increase of NO (p<0.001) and MMP-1,3,13 gene expression. Canakinumab significantly increased the PG levels and decreased (1μg/ml, p<0.01; 10μg/ml, p<0.01) NO levels in cells cultured with TNF-α. The NO data were confirmed by the immunocytochemistry assay for iNOS. A significant reduction of MMP-1,3,13 gene expression was induced by canakinumab. Our experiments confirmed the pro-apoptotic effect of TNF-α and demonstrated a protective role of canakinumab. The results concerning biochemical data were further confirmed by the morphological findings obtained by TEM. We showed that canakinumab counteracts the negative effects of TNF-α on OA chondrocyte cultures and may have a potential chondroprotective role in OA.
