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

IF 7.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Aging Cell Pub Date : 2024-06-05 DOI:10.1111/acel.14237
Mingjue Chen, Feiyun Li, Minghao Qu, Xiaowan Jin, Tailin He, Shuangshuang He, Sheng Chen, Qing Yao, Lin Wang, Di Chen, Xiaohao Wu, Guozhi Xiao
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Abstract

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.

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Pip5k1γ通过激活CaMKII-Ampk通路促进老龄小鼠髓核细胞的新陈代谢和椎间盘的稳态。
椎间盘退行性病变(DDD)是一项重大的全球性健康挑战,但其潜在的分子机制仍然难以捉摸。本研究旨在探讨1型磷脂酰肌醇-4-磷酸5-激酶(Pip5k1)在椎间盘(IVD)稳态和疾病中的作用。在小鼠和人类的 IVD 组织中均可检测到三种 Pip5k1 异构体,即 Pip5k1α、Pip5k1β 和 Pip5k1γ,其中 Pip5k1γ 在髓核细胞中的表达量最高。Pip5k1γ在老龄小鼠和重度DDD患者的NP细胞中的表达明显下调。为了确定Pip5k1γ的表达是否为椎间盘稳态所必需,我们建立了一个Pip5k1γfl/fl; AggrecanCreERT2小鼠模型,在表达aggrecan的IVD细胞中条件性敲除Pip5k1γ基因。我们的研究结果表明,在5个月大的成年小鼠中,Pip5k1γ基因的条件性缺失不会影响椎间盘结构或细胞组成。然而,在老龄(15 个月大)小鼠中,这种缺失会导致几种严重的椎间盘退行性缺陷,包括 NP 细胞减少、自发性纤维化和裂隙形成,以及 NP 和纤维环之间边界的缺失。在分子水平上,Pip5k1γ的缺失降低了NP细胞的合成代谢,但并未明显影响其分解代谢或抗分解代谢活性。此外,Pip5k1γ的缺失明显抑制了NP细胞中保护性Ampk通路的激活,从而加速了NP细胞的衰老。值得注意的是,Pip5k1γ的缺乏削弱了二甲双胍(一种强效的Ampk激活剂)激活Ampk通路和减轻腰椎不稳定(LSI)诱导的小鼠椎间盘病变的效果。总之,我们的研究揭示了Pip5k1γ在促进新陈代谢和维持椎间盘稳态中的新作用,表明它是治疗DDD的潜在靶点。
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来源期刊
Aging Cell
Aging Cell 生物-老年医学
CiteScore
14.40
自引率
2.60%
发文量
212
审稿时长
8 weeks
期刊介绍: Aging Cell, an Open Access journal, delves into fundamental aspects of aging biology. It comprehensively explores geroscience, emphasizing research on the mechanisms underlying the aging process and the connections between aging and age-related diseases.
期刊最新文献
Issue Information Featured Cover Correction to ‘Increased transcriptome variation and localised DNA methylation changes in oocytes from aged mice revealed by parallel single-cell analysis’ RETRACTION: 1,25-Dihydroxyvitamin D exerts an antiaging role by activation of Nrf2-antioxidant signaling and inactivation of p16/p53-senescence signaling Issue Information
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