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. 2025 May 19:66:204-212.
doi: 10.1016/j.jor.2025.05.022. eCollection 2025 Aug.

The influence of PPARγ mediated MAPK and NF-κB activation in AGEs stimulated apoptosis and autophagy in human chondrocytes

Zhao-Jun Wang  1 , Wei Wang  1 , Kai-Xing Jia  1 , Hai-Bin Zhang  2 , Jian-An Wang  1 , Cheng Chen  2
Affiliations

The influence of PPARγ mediated MAPK and NF-κB activation in AGEs stimulated apoptosis and autophagy in human chondrocytes

Zhao-Jun Wang et al. J Orthop. .

Abstract

Background: Advanced Glycation End Products (AGEs), which accumulate in metabolic syndrome patients and the elderly, are implicated in osteoarthritis (OA) pathogenesis. Peroxisome proliferator-activated receptor-γ (PPARγ), a nuclear receptor, has emerged as a potential therapeutic target for OA. This study investigates the molecular mechanisms by which PPARγ regulates AGEs-induced apoptosis and autophagy in human chondrocytes.

Methods: Primary human chondrocytes were exposed to AGEs, either with or without the PPARγ agonist pioglitazone, as well as specific inhibitors targeting MAPK and NF-κB pathways. Autophagy levels were assessed via Western blot analysis of LC3-II, transmission electron microscopy (TEM), and GFP-LC3 imaging. Apoptosis was evaluated by measuring cleaved caspase-3, cleaved PARP, and FITC Annexin V using Western blot and flow cytometry. PPARγ expression was quantified via real-time PCR, while MAPK and NF-κB pathway activation was examined by analyzing phosphorylated ERK, JNK, p38, and IκBα levels. Additionally, MMP-13 and TNF-α expression was measured using ELISA.

Results: High-dose AGEs treatment in human chondrocytes led to increased apoptosis, reduced autophagy, downregulation of PPARγ, and activation of MAPK and NF-κB pathways. Pioglitazone treatment elevated autophagy marker LC3-II while suppressing phosphorylation of MAPK components ERK and p38. Notably, inhibitors of JNK and p38 partially reversed AGEs-induced PPARγ suppression and restored autophagy. AGEs also activated the NF-κB pathway, an effect counteracted by pioglitazone. Furthermore, NF-κB inhibition enhanced autophagy in AGEs-treated chondrocytes. Compared to AGEs alone, pioglitazone, specific MAPK inhibitors (SP600125 and SB203580, but not PD98059), and NF-κB inhibitors reduced MMP-13 and TNF-α expression.

Conclusions: PPARγ activation via pioglitazone mitigates AGEs-driven chondrocyte apoptosis and reinstates autophagy by regulating MAPK and NF-κB signaling. These results suggest that PPARγ agonism could serve as a dual-target therapeutic approach for OA, with pioglitazone emerging as a potential disease-modifying agent. Further clinical research is needed to confirm its therapeutic benefits in OA management.

Keywords: AGEs; Apoptosis; Autophagy; MAPK; NF-κB; OA; PPARγ.

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Conflict of interest statement

The Authors declare that there are no conflicts of interest.

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