The repair effect of α-ketoglutarate combined with mesenchymal stem cells on osteoarthritis via the hedgehog protein pathway

Abstract

Objective

Mesenchymal stem cell (MSC) therapy represents a promising treatment strategy for osteoarthritis (OA). Nevertheless, the therapeutic efficacy of MSCs may be attenuated under conditions of cellular senescence or when the available clinical quantity is insufficient. α-Ketoglutarate (AKG) exerts beneficial effects on skeletal tissues and the activity of stem cells. Consequently, the present study was designed to explore the potential of AKG in augmenting the viability of MSCs and the potential of their combined utilization in the treatment of OA.

Methods

MSCs with senescence induced by in vitro passaging served as the experimental subjects. The effects of AKG on the activity of senescent MSCs were investigated via morphological observation, scratch assay, and DAPI staining. Bioinformatics methods were employed to explore the action targets and pathways of AKG in the treatment of OA, providing a theoretical basis and experimental evidence for further experiments. The feasibility of this pathway was verified at the animal level. A rat model of OA was induced by intra-articular injection of sodium monoiodoacetate (MIA). Platelet-rich plasma (PRP), a representative drug for clinical OA treatment, was used as a positive control. The efficacy of combined high-dose and low-dose medications was evaluated through morphological observation and pathological section staining.

Results

The outcomes of the in vitro cellular experiments indicate that AKG is capable of decreasing the quantity of MSCs exhibiting senescent morphological features, enhancing the migratory capacity of MSCs, and suppressing the apoptotic process of MSCs. Consequently, AKG exerts a reparative influence on senescent MSCs. Bioinformatics analysis indicated that AKG exerts its repairing effect on OA by inhibiting the Hedgehog (HH) signaling pathway. Additionally, at the animal experiment level, we found that the synergistic effect of high-dose AKG combined with MSCs could more significantly alleviate the severity of OA. It enhances matrix synthesis, reduces endochondral ossification, and promotes cartilage repair through the HH pathway.

Conclusion

Our research indicates that AKG has a significant effect on enhancing the activity of MSCs. The combined treatment can promote the repair of articular cartilage in OA rats through the HH pathway, and it provides a novel approach for the treatment of OA.