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Published on: June 9, 2018
Dual-PPARα/δ agonist H11 alleviates tendinopathy via modulating the Nrf2/HO-1/GPX4 pathway
Yang Lu1, Shaojie Yang1, Huan Liu1
1Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, PR China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, PR China; Branch of National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, PR China.
Abstract:
Tendinopathy, a prevalent degenerative musculoskeletal disorder, remains a therapeutic challenge due to limited efficacy of existing treatments. Oxidative stress and ferroptosis are pivotal pathological mechanisms in tendinopathy, which are linked to dysregulation of the NRF2/HO-1/GPX4 pathway. This study investigates the therapeutic potential of H11, a dual-PPARα/δ agonist, in mitigating tendinopathy via modulating this pathway. Clinical analysis of human tendinopathic tissues revealed downregulated PPARα/δ and aberrant NRF2/HO-1/GPX4 expression. In vitro, H11 dose-dependently activated PPAR subtypes, alleviated TBHP(tert-butyl hydroperoxide)-induced oxidative stress, and restored mitochondrial membrane potential in Achilles tendon cells. Co-treatment with PPAR subtype-specific inhibitors (GW6471, GSK0660) partially attenuated H11's protective effects, while single-subunit agonists (GW7647, GW50526) showed inferior efficacy compared to H11. NRF2 silencing via siRNA abolished H11-mediated therapeutic outcomes, confirming NRF2's indispensable role. In a collagenase-induced rat tendinopathy model, H11 restored collagen organization, reduced malondialdehyde (MDA) levels, and enhanced glutathione (GSH/GSSG) ratios, concomitant with upregulated PPARα/δ and NRF2/HO-1/GPX4 expression. These results indicate that the PPARα/δ dual-agonist H11 ameliorates tendinopathy by activating PPARα/δ, enhancing antioxidant capacity, and inhibiting ferroptosis via the NRF2/HO-1/GPX4 axis.
Insights
H11, a dual-PPARα/δ agonist, shows promise for treating tendinopathy by activating the NRF2/HO-1/GPX4 pathway, reducing oxidative stress and ferroptosis.
Area of Science:
- Biomedical Science
- Musculoskeletal Research
- Pharmacology
Background:
- Tendinopathy is a challenging degenerative musculoskeletal disorder with limited treatment options.
- Oxidative stress and ferroptosis are key pathological mechanisms in tendinopathy, linked to the NRF2/HO-1/GPX4 pathway.
- Existing treatments for tendinopathy have shown limited efficacy.
Purpose of the Study:
- To investigate the therapeutic potential of H11, a dual-PPARα/δ agonist, in ameliorating tendinopathy.
- To explore H11's mechanism of action involving the NRF2/HO-1/GPX4 pathway.
- To evaluate H11's effects on oxidative stress, ferroptosis, and tissue repair in tendinopathy models.
Main Methods:
- Clinical analysis of human tendinopathic tissues to assess PPARα/δ and NRF2/HO-1/GPX4 expression.
- In vitro studies using Achilles tendon cells to evaluate H11's effects on oxidative stress and mitochondrial function.
- In vivo studies using a collagenase-induced rat tendinopathy model to assess H11's therapeutic efficacy and molecular changes.
Main Results:
- H11 activated PPARα/δ, alleviated tert-butyl hydroperoxide-induced oxidative stress, and restored mitochondrial membrane potential in tendon cells.
- NRF2 silencing abolished H11's therapeutic effects, confirming NRF2's critical role.
- In vivo, H11 improved collagen organization, reduced oxidative stress markers (MDA), and enhanced antioxidant capacity (GSH/GSSG ratios), upregulating PPARα/δ and NRF2/HO-1/GPX4.
Conclusions:
- H11 effectively ameliorates tendinopathy by activating PPARα/δ.
- H11 exerts its therapeutic effects through the NRF2/HO-1/GPX4 axis, enhancing antioxidant capacity and inhibiting ferroptosis.
- H11 represents a potential therapeutic agent for tendinopathy.
