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Published on: May 21, 2018
Spermidine attenuates chondrocyte inflammation and cellular pyroptosis through the AhR/NF-κB axis and the
Xiaocheng Guo1, Xinyuan Feng1, Yue Yang1
1Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China.
Introduction:
Osteoarthritis (OA) is a prevalent chronic degenerative disease, marked by a complex interplay of mechanical stress, inflammation, and metabolic imbalances. Recent studies have highlighted the potential of spermidine (SPD), a naturally occurring polyamine known for its anti-inflammatory and antioxidant properties, as a promising therapeutic agent for OA. This study delves into the therapeutic efficacy and mechanistic pathways of SPD in mitigating OA symptoms.
Methods:
Forty Sprague-Dawley rats were randomly assigned to four groups, including the CG (sham operation), model (anterior cruciate ligament transection [ACLT], and treatment (ACLT + two different doses of SPD) groups. In vivo, correlations between OA severity and different interventions were assessed by ELISA, X-rays, CT imaging, histological staining, and immunohistochemistry. In vitro, IL-1β was used to trigger chondrocyte inflammation, and SPD's cytotoxicity was assessed in primary rat chondrocytes. Next, inflammatory markers, extracellular matrix (ECM) proteins, and pathway marker proteins were detected in chondrocytes administered IL-1β alone, SPD, or aryl hydrocarbon receptor (AhR) silencing, by qRT-PCR, Griess reaction, ELISA, Western blot, and immunofluorescence. Morphological alterations and pyroptosis in chondrocytes were examined by transmission electron microscopy (TEM) and flow cytometry.
Results:
Our research reveals that SPD exerts significant anti-inflammatory and antipyroptotic effects on IL-1β-treated chondrocytes and in anterior cruciate ligament transection (ACLT) rat models of OA, primarily through interaction with the Aryl hydrocarbon receptor (AhR). Specifically, SPD's binding to AhR plays a crucial role in modulating the inflammatory response and cellular pyroptosis by inhibiting both the AhR/NF-κB and NLRP3/caspase-1/GSDMD signaling pathways. Furthermore, the knockdown of AhR was found to negate the beneficial effects of SPD, underscoring the centrality of the AhR pathway in SPD's action mechanism. Additionally, SPD was observed to promote the preservation of cartilage integrity and suppress ECM degradation, further supporting its potential as an effective intervention for OA.
Discussion:
Collectively, our findings propose SPD as a novel therapeutic approach for OA treatment, targeting the AhR pathway to counteract the disease's progression and highlighting the need for further clinical evaluation to fully establish its therapeutic utility.
Insights
Spermidine (SPD) shows anti-inflammatory and anti-pyroptotic effects in osteoarthritis models by interacting with the Aryl hydrocarbon receptor (AhR). This interaction inhibits key inflammatory pathways, preserving cartilage and suggesting SPD as a novel OA therapeutic.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Osteoarthritis (OA) is a degenerative joint disease driven by inflammation and metabolic factors.
- Spermidine (SPD), a natural polyamine, exhibits anti-inflammatory and antioxidant properties with therapeutic potential for OA.
Purpose of the Study:
- To investigate the therapeutic efficacy of spermidine (SPD) in osteoarthritis (OA).
- To elucidate the mechanistic pathways underlying SPD's effects on OA, particularly its interaction with the Aryl hydrocarbon receptor (AhR).
Main Methods:
- In vivo studies utilized anterior cruciate ligament transection (ACLT) rat models of OA, assessing severity via imaging and histology.
- In vitro studies used IL-1β-induced chondrocyte inflammation, evaluating SPD's effects on inflammatory markers, extracellular matrix (ECM) proteins, and pyroptosis.
- Techniques included ELISA, qRT-PCR, Western blot, immunofluorescence, transmission electron microscopy (TEM), and flow cytometry.
Main Results:
- SPD demonstrated significant anti-inflammatory and anti-pyroptotic effects in both ACLT rat models and IL-1β-treated chondrocytes.
- SPD's therapeutic action is mediated through interaction with the Aryl hydrocarbon receptor (AhR), inhibiting AhR/NF-κB and NLRP3/caspase-1/GSDMD signaling pathways.
- AhR knockdown negated SPD's benefits, confirming the AhR pathway's centrality. SPD also preserved cartilage integrity and reduced ECM degradation.
Conclusions:
- Spermidine (SPD) represents a novel therapeutic candidate for osteoarthritis (OA).
- Targeting the Aryl hydrocarbon receptor (AhR) pathway with SPD can mitigate OA progression.
- Further clinical evaluation is warranted to confirm SPD's therapeutic utility in OA patients.
