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Published on: July 26, 2017
High-throughput screening identifies FDA approved drug mitiglinide as a novel pyroptosis inhibitor and therapeutic
Hanwen Zhang1, Tanxin Yu1, Nanfang Zhuo2
1Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325088 Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325035 Zhejiang Province, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325035 Zhejiang Province, China.
Introduction:
Osteoarthritis (OA), a leading cause of joint dysfunction, is characterized by progressive cartilage degradation linked to chondrocyte pyroptosis, yet disease-modifying therapies remain elusive. In this study, we conducted the first systematic drug repurposing screen in chondrocytes, aiming at identifying drugs that may suppress pyroptosis and verifying the therapeutic effects on OA.
Methods:
Mitiglinide's effects on chondrocyte viability were quantified via CCK-8 assays and live/dead staining. Pyroptosis inhibition, extracellular matrix (ECM) homeostasis, and NF-κB activation were measured by western blot and immunofluorescence. Network pharmacology analysis and molecular docking were applied to predict the interacting protein of mitiglinide, while Nrf2 was knocked down by siRNAs to confirm its role in mitiglinide regulated pyroptosis and ECM. In vivo, destabilization of the medial meniscus (DMM) model -induced OA mice received mitiglinide for 8 weeks, with efficacy evaluated through X-ray, OARSI-graded histopathology, immunohistochemistry, Hematoxylin-Eosin and Safranin O-Fast green staining.
Results:
Through high-throughput screening (HTS) of 1,228 FDA-approved drugs, we identified a list of pyroptosis inhibitors, and mitiglinide was suggested as one of the most potent pyroptosis inhibitors in chondrocyte. Mechanistic studies demonstrated that mitiglinide may directly target Nrf2 and suppress its downstream NF-κB-driven NLRP3 inflammasome activation; it may also promote ECM homeostasis in chondrocytes. In vivo study showed that mitiglinide may effectively attenuate OA pathology in mice.
Conclusion:
Mitiglinide, identified via FDA-drug-library screening, alleviates OA progression by suppressing NLRP3 inflammasome activation and ECM degradation via activation of the Nrf2/HO-1 signaling pathway. This positions mitiglinide as a repurposed disease-modifying OA drug candidate.
Insights
Mitiglinide, an FDA-approved drug, was identified as a potent inhibitor of chondrocyte pyroptosis, offering a new therapeutic strategy for osteoarthritis (OA) by reducing cartilage degradation.
Area of Science:
- Biomedical research
- Drug discovery
- Osteoarthritis research
Background:
- Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage breakdown.
- Chondrocyte pyroptosis is a key factor in OA pathogenesis.
- Effective disease-modifying treatments for OA are currently lacking.
Purpose of the Study:
- To conduct a systematic drug repurposing screen to identify compounds that inhibit chondrocyte pyroptosis.
- To evaluate the therapeutic potential of identified compounds in an osteoarthritis model.
Main Methods:
- High-throughput screening of 1,228 FDA-approved drugs in chondrocytes.
- Assessing drug effects on chondrocyte viability, pyroptosis, and extracellular matrix (ECM) homeostasis.
- Investigating molecular mechanisms involving Nrf2 and NF-κB signaling pathways.
- Evaluating therapeutic efficacy in a mouse model of osteoarthritis (OA) induced by destabilization of the medial meniscus (DMM).
Main Results:
- Mitiglinide was identified as a potent inhibitor of chondrocyte pyroptosis.
- Mitiglinide suppressed NF-κB-driven NLRP3 inflammasome activation and promoted ECM homeostasis.
- In vivo studies demonstrated that mitiglinide effectively attenuated OA pathology in mice.
Conclusions:
- Mitiglinide alleviates OA progression by inhibiting NLRP3 inflammasome activation and ECM degradation.
- The mechanism involves the activation of the Nrf2/HO-1 signaling pathway.
- Mitiglinide shows promise as a repurposed disease-modifying drug candidate for osteoarthritis.
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