Interferon Regulatory Factor 1 Inhibits the Adipogenic Differentiation of BMSCs via the AMPK – mTOR Signaling Axis and Induces Their Autophagy to Alleviate Osteoporosis‐Related Bone Marrow Adiposity

Increased bone marrow adiposity is a characteristic of osteoporosis and negatively regulates osteogenesis. Bone marrow mesenchymal stem cells (BMSCs) give rise to bone marrow adipocytes. The transcription factor interferon regulatory factor 1 (IRF1) modulates multiple biological processes, including the adipogenesis of several cell types. However, the role of IRF1 in the commitment of BMSCs to the adipogenic lineage and whether it regulates bone marrow adipogenesis has not been investigated thoroughly. Murine BMSCs (mBMSCs) with Irf1-overexpression or knockdown were established via lentiviral transfection. IRF1's effects on adipogenic differentiation and autophagy of mBMSCs were studied in vitro; its role in adipogenesis in vivo was evaluated via nude mouse subcutaneous transplantation. Irf1-overexpressing mBMSCs were intravenously injected into OVX and aged osteoporotic mice. Besides, RNA sequencing and experimental verification explored the mechanism. IRF1 inhibited the adipogenic differentiation of mBMSCs both in vitro and in vivo. Besides, IRF1 positively regulated autophagy in mBMSCs in vitro. In osteoporotic mice, injection of Irf1-overexpressing mBMSCs effectively decreased bone marrow adiposity. IRF1 may downregulate adipogenic differentiation of mBMSCs by regulating the 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling axis. This study reveals that IRF1 induces protective autophagy and inhibits adipogenic differentiation of mBMSCs. Irf1-overexpressing mBMSCs alleviate osteoporosis-related bone marrow adiposity. Besides, IRF1 possibly regulates the AMPK-mTOR signaling axis. Our findings establish IRF1 as a key factor inhibiting adipogenesis, providing a new potential therapeutic target for preventing and treating osteoporosis-related bone marrow adiposity and other diseases with abnormal adipose metabolism.