PIM3 enhances nucleus pulposus cell function and extracellular matrix integrity via kinase-dependent activation of the Akt/mTOR signaling axis in intervertebral disc degeneration.

Intervertebral disc degeneration (IDD), a condition characterized by extracellular matrix (ECM) degradation and nucleus pulposus (NP) cell senescence, compromises disc function. The Akt signaling pathway is essential for NP cell viability and ECM homeostasis. This study identifies the serine/threonine kinase PIM3 as significantly downregulated in degenerated human NP tissues. Notably, PIM3 mRNA expression levels were found to be negatively correlated with the clinical severity of IDD (Pfirrmann grade). The functional role of PIM3 was investigated through knockdown and overexpression experiments in human NP cells. PIM3 overexpression restored cell viability, suppressed senescence, and enhanced ECM protein levels in degenerated NP cells, while its knockdown in normal cells produced the opposite results. These protective effects were critically dependent on the kinase activity of PIM3. Mechanistically, PIM3 was found to physically interact with and activate the Akt signaling pathway, thereby regulating downstream molecules, including mTOR and FoxO1, to modulate cell viability and senescence. In an IDD rat model, AAV-mediated PIM3 overexpression improved ECM integrity, reduced senescence and activated the Akt pathway, mitigating disc degeneration. In conclusion, this study establishes PIM3 as a key regulator of NP cell homeostasis that acts through direct engagement with the Akt/mTOR/FoxO1 axis. Its correlation with disease severity and the kinase-dependent nature of its function highlight PIM3 as a promising, mechanistically-defined therapeutic target for treating IDD.