Conditional deletion of Pink1 in mesenchymal stem cells suppresses osteogenesis through downregulation of Apoh transcription

Abstract

Background

Previous research indicates a strong association between PINK1 and osteogenic differentiation of mesenchymal stem cells (MSCs) through the maintenance of mitochondrial homeostasis. Nevertheless, additional inquiry is needed to fully elucidate PINK1's involvement in transcriptional regulation.

Methods

To comprehensively investigate Pink1's influence on the osteogenic differentiation of mesenchymal stem cells (MSCs), we utilized Prx1-Cre mice for targeted Pink1 deletion, producing Pink1^f/f; Prx1-Cre (Pink1-KO) and Pink1^f/f (Control) mice. Additionally, transcriptome sequencing analysis, RT-qPCR, Western blot, and ChIP assays were conducted.

Results

The Pink1-KO group showed significant reductions in both trabecular and cortical bone mass relative to controls. Additionally, Pink1 deletion decreased the expression of osteogenic differentiation and adipogenic markers. While previous research highlighted the adverse impact of reduced Pink1 on mitophagy and mitochondrial integrity, our study further identifies a decline in autophagy with Pink1 downregulation. The nuclear localization of PINK1 hints at its broader roles, though detailed insights into its nuclear functions are pending. Consequently, we undertook transcriptome sequencing analysis, which suggested Pink1 might influence MSC osteogenic differentiation through cholesterol metabolism-related pathways. Further validations via RT-qPCR, Western blot, and ChIP assays demonstrated PINK1's interaction with the Apoh promoter, enhancing its transcription. Notably, the knockdown of Apoh impairs osteogenic differentiation in BMSCs, whereas the upregulation of Apoh mitigates the adverse effects of Pink1 deficiency on osteogenesis.

Conclusions

Our data suggest Pink1 deficiency compromises osteoblastic differentiation in MSCs, partially through disrupted Apoh transcription regulation.