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

Mingjue,Chen1; Feiyun,Li1; Minghao,Qu2,3; Xiaowan,Jin1; Tailin,He1; Shuangshuang,He1; Sheng,Chen4; Qing,Yao1; Lin,Wang2,3; Di,Chen5; Xiaohao,Wu6,7; Guozhi,Xiao1

2024-04-26

10.1111/acel.14237

Aging Cell   影响因子和分区

1474-9718

1474-9726

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 Pip5k1 alpha, Pip5k1 beta, and Pip5k1 gamma, were detectable in mouse and human IVD tissues, with Pip5k1 gamma displaying a highest expression in nucleus pulposus (NP) cells. The expression of Pip5k1 gamma was significantly down-regulated in the NP cells of aged mice and patients with severe DDD. To determine whether Pip5k1 gamma expression is required for disc homeostasis, we generated a Pip5k1 gamma(fl/fl); Aggrecan(CreERT2) mouse model for the conditional knockout of the Pip5k1 gamma gene in aggrecan-expressing IVD cells. Our findings revealed that the conditional deletion of Pip5k1 gamma 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 Pip5k1 gamma reduced the anabolism of NP cells without markedly affecting their catabolic or anti-catabolic activities. Moreover, the loss of Pip5k1 gamma significantly dampened the activation of the protective Ampk pathway in NP cells, thereby accelerating NP cell senescence. Notably, Pip5k1 gamma 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 Pip5k1 gamma in promoting anabolism and maintaining disc homeostasis, suggesting it as a potential therapeutic target for DDD.

aging Ampk CaMKII disc degeneration metformin nucleus pulposus Pip5k1 gamma

SCI

英语

第一 ; 共同第一 ; 通讯

National Natural Science Foundation of China["82230081","82250710175","8226116039","81991513","82302767"] ; Shenzhen Fundamental Research Program[JCYJ20220818100617036] ; Guangdong Provincial Science and Technology Innovation Council[2017B030301018] ; Shenzhen Key Laboratory of Cell Microenvironment Grant[ZDSYS20140509142721429] ; Science Foundation of Wuhan Union Hospital[2022xhyn032] ; null[2019YFA0906004]

Cell Biology ; Geriatrics & Gerontology

Cell Biology ; Geriatrics & Gerontology

WOS:001241158100001

Wiley

MOLECULAR BIOLOGY & GENETICS

人工提交

1.Department of Biochemistry, School of Medicine, Shenzhen Key Laboratory of Cell Microenvironment, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen, China
2.School of Medicine, Southern University of Science and Technology, Shenzhen, China
3.Southern University of Science and Technology Hospital, Shenzhen, China
4.Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
5.Research Center for Human Tissues and Organs Degeneration, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
6.Division of Immunology and Rheumatology, Stanford University, Stanford, California, USA
7.VA Palo Alto Health Care System, Palo Alto, California, USA

Mingjue,Chen,Feiyun,Li,Minghao,Qu,等. Pip5k1γ promotes anabolism of nucleus pulposus cells and intervertebral disc homeostasis by activating CaMKII‐Ampk pathway in aged mice[J]. Aging Cell,2024:e14237.

Mingjue,Chen.,Feiyun,Li.,Minghao,Qu.,Xiaowan,Jin.,Tailin,He.,...&Guozhi,Xiao.(2024).Pip5k1γ promotes anabolism of nucleus pulposus cells and intervertebral disc homeostasis by activating CaMKII‐Ampk pathway in aged mice.Aging Cell,e14237.

Mingjue,Chen,et al."Pip5k1γ promotes anabolism of nucleus pulposus cells and intervertebral disc homeostasis by activating CaMKII‐Ampk pathway in aged mice".Aging Cell (2024):e14237.