抑制PTBP1-PRKCZ通路可激活自噬过程，重编程骨髓间充质干细胞命运归宿，进而缓解骨质疏松症

Abstract

Silencing PRKCZ activates autophagy, promotes osteogenic differentiation, and suppresses adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). • PRKCZ expression is upregulated in ovariectomized (OVX) mice, accompanied by impaired autophagy and osteogenic–adipogenic imbalance. • Knockdown of PRKCZ attenuates bone loss and reduces bone marrow adiposity in an OVX-induced osteoporosis mouse model. • PTBP1 directly binds to and stabilizes PRKCZ mRNA, thereby upregulating PRKCZ expression. • Inhibition of the PTBP1–PRKCZ axis activates autophagy to reprogram BMSC fate commitment and ameliorate osteoporosis. Background/Aim Osteoporosis is characterized by disrupted bone homeostasis while dysregulated autophagy contributes to impaired bone remodeling and bone loss. This study investigates the role of the RNA-binding protein polypyrimidine tract binding protein 1 (PTBP1) in osteoporosis progression through regulation of protein kinase C zeta (PRKCZ), and elucidates whether PTBP1 modulates the osteogenic–adipogenic fate commitment of bone marrow mesenchymal stem cells (BMSCs) via autophagy. Methods In vitro, BMSCs were subjected to lentiviral infection and/or autophagy inhibitor 3-methyladenine (3-MA) treatment to systematically evaluate autophagic activity and osteogenic and adipogenic differentiation. RNA immunoprecipitation coupled with quantitative polymerase chain reaction (RIP-qPCR) and RNA stability assays were performed to clarify the molecular regulatory relationship between PTBP1 and PRKCZ. The molecular regulatory relationship between PTBP1 and PRKCZ was verified. In vivo, a bilateral ovariectomy (OVX)-induced osteoporotic mouse model was established. Adeno-associated virus–mediated modulation of PTBP1 and PRKCZ expression was conducted. Osteogenic-adipogenic balance and bone mass were comprehensively assessed. Results Knockdown of PRKCZ markedly enhanced autophagic activity, promoted osteogenic differentiation, and suppressed adipogenic d