Journal Article

Pip5k1γ promotes anabolism of nucleus pulposus cells and intervertebral disc homeostasis by activating CaMKII‐Ampk pathway in aged mice

Chen, Mingjue, He, Shuangshuang, Yao, Qing, He, Tailin, Chen, Di, Chen, Sheng, Li, Feiyun, Qu, Minghao, Jin, Xiaowan, Wang, Lin, Wu, Xiaohao, Xiao, Guozhi

2024

Overview

Degenerative disc disease (DDD) represents a significant global health challenge, yet its underlying molecular mechanisms remain elusive. This study aimed to investigate the role of type 1 phosphatidylinositol 4‐phosphate 5‐kinase (Pip5k1) in intervertebral disc (IVD) homeostasis and disease. All three Pip5k1 isoforms, namely Pip5k1α, Pip5k1β, and Pip5k1γ, were detectable in mouse and human IVD tissues, with Pip5k1γ displaying a highest expression in nucleus pulposus (NP) cells. The expression of Pip5k1γ was significantly down‐regulated in the NP cells of aged mice and patients with severe DDD. To determine whether Pip5k1γ expression is required for disc homeostasis, we generated a Pip5k1γfl/fl; AggrecanCreERT2 mouse model for the conditional knockout of the Pip5k1γ gene in aggrecan‐expressing IVD cells. Our findings revealed that the conditional deletion of Pip5k1γ did not affect the disc structure or cellular composition in 5‐month‐old adult mice. However, in aged (15‐month‐old) mice, this deletion led to several severe degenerative disc defects, including decreased NP cellularity, spontaneous fibrosis and cleft formation, and a loss of the boundary between NP and annulus fibrosus. At the molecular level, the absence of Pip5k1γ reduced the anabolism of NP cells without markedly affecting their catabolic or anti‐catabolic activities. Moreover, the loss of Pip5k1γ significantly dampened the activation of the protective Ampk pathway in NP cells, thereby accelerating NP cell senescence. Notably, Pip5k1γ deficiency blunted the effectiveness of metformin, a potent Ampk activator, in activating the Ampk pathway and mitigating lumbar spine instability (LSI)‐induced disc lesions in mice. Overall, our study unveils a novel role for Pip5k1γ in promoting anabolism and maintaining disc homeostasis, suggesting it as a potential therapeutic target for DDD. This study identifies the lipid kinase Pip5k1γ as a crucial factor for maintaining intervertebral disc homeostasis, revealing its significant down‐regulation in aged and severely degenerated discs. Conditional deletion of Pip5k1γ in mice leads to advanced disc degeneration, underscoring its importance in extracellular matrix anabolism and the activation of the Ampk pathway. These findings suggest Pip5k1γ as a potential therapeutic target for degenerative disc disease.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Adenosine / Aggrecan / Aging / Aging - metabolism / AMP-Activated Protein Kinases - metabolism / Ampk / Animals / Back pain / Ca2+/calmodulin-dependent protein kinase II / CaMKII / Cell activation / Clonal deletion / Degenerative disc disease / disc degeneration / Extracellular matrix / Fibrosis / Gene deletion / Homeostasis / Humans / Hypoxia / Intervertebral Disc - metabolism / Intervertebral Disc - pathology / Intervertebral Disc Degeneration - genetics / Intervertebral Disc Degeneration - metabolism / Intervertebral Disc Degeneration - pathology / Intervertebral discs / Isoforms / Kinases / Metformin / Mice / Molecular modelling / Nucleus pulposus / Nucleus Pulposus - metabolism / Nucleus Pulposus - pathology / Phosphotransferases (Alcohol Group Acceptor) - genetics / Phosphotransferases (Alcohol Group Acceptor) - metabolism / Pip5k1γ / Proteins / Public health / Senescence / Signal Transduction / Spine (lumbar) / Stem cells / Surgery / Therapeutic targets