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This research investigates the chondroprotective effect of empagliflozin on osteoarthritis by focusing on inflammation, autophagy, and senescence.

April 8, 2026Open Access

Empagliflozin Alleviates Osteoarthritis Progression by Attenuating Inflammation, Restoring Impaired Autophagy, and Ameliorating Chondrocyte Senescence

Key Points

This research investigates the chondroprotective effect of empagliflozin on osteoarthritis by focusing on inflammation, autophagy, and senescence.
Established an OA model in vitro using IL-1β on primary chondrocytes from mice.
Conducted in vivo assessments using DMM surgery on mice to induce OA.
Utilized Western blot and qRT-PCR for gene expression analysis.
Employed immunofluorescence for target protein detection and SA-β-gal staining for cellular senescence evaluation.
Applied network pharmacology to identify relevant pathways for validation.
EMP promoted anabolic processes and inhibited inflammation in IL-1β stimulated chondrocytes.
Enhanced autophagic activity and reduced senescent characteristics in vitro were observed with EMP treatment.
Mechanistic studies revealed EMP's regulation of the PI3K/Akt/mTOR and AMPK pathways.
In vivo studies showed EMP's efficacy in ameliorating OA-related phenotypes in DMM models.
EMP demonstrated a greater suppression of inflammatory markers compared to Kartogenin.

Abstract

Background: Osteoarthritis (OA) is a multifactorial disease, including inflammation, autophagy and senescence. Published work has indicated that empagliflozin (EMP) exhibits robust anti-inflammatory and anti-senescence effects, while its role in autophagy appears paradoxical. Here, we aim to identify the chondroprotective effect of EMP on OA. Methods: An OA model was established both in vitro, by stimulating primary chondrocytes (isolated from C57BL/6J mice) with IL-1β, and in vivo, by performing (Destabilized medial meniscus) DMM surgery on C57BL/6J mice. (Western blot) WB and (quantitative real-time polymerase chain reaction) qRT-PCR analysis were employed to detect the gene expression. (Immunofluorescence) IF staining was employed to detect the expression and location of target protein. SA-β-gal staining was employed to evaluate cellular senescence. Autophagic flux was assessed using a GFP-RFP-LC3 adenoviral vector. Network pharmacology was applied to identify potential pathways for experimental validation. The effects of EMP in vivo were evaluated by μ-CT, histological and (Immunohistochemistry) IHC staining. Results: EMP promoted anabolism, inhibited the inflammatory response and catabolism in IL-1β stimulated chondrocytes. EMP enhanced autophagic activity and attenuated senescent phenotype in vitro. Mechanistically, EMP regulated the PI3K/Akt/mTOR and AMPK pathways. The chondroprotective effects of EMP were reversed by (3- methyladenine) 3-MA. EMP also ameliorated OA-related phenotype in DMM models. Compared with (Kartogenin) KGN, EMP showed more pronounced suppression of inflammatory and catabolic markers, while both compounds similarly promoted anabolic marker expression. Conclusions: These in vitro and in vivo data collectively indicates that EMP can alleviate OA both in IL-1β stimulated chondrocytes and DMM induced models. Beyond its established role in diabetes management, EMP is evaluated in the context of OA, emerging as a novel and promising therapeutic agent for OA.

Empagliflozin Alleviates Osteoarthritis Progression by Attenuating Inflammation, Restoring Impaired Autophagy, and Ameliorating Chondrocyte Senescence

Key Points

Abstract

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