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Advances in Clinical Medicine
Vol. 12  No. 11 ( 2022 ), Article ID: 57784 , 6 pages
10.12677/ACM.2022.12111453

PI3K/AKT信号通路在椎间盘退变中的研究 进展

杨涛1，贾舒2，孟纯阳2*

1济宁医学院，山东 济宁

2济宁医学院附属医院，山东 济宁

收稿日期：2022年10月9日；录用日期：2022年11月2日；发布日期：2022年11月14日

摘要

下腰痛已成为一个全球关注的公共卫生问题，而椎间盘退行性变被公认为是引起下腰痛的主要原因之一。目前对下腰痛的治疗仅限于在减轻症状，而不能针对椎间盘内潜在的病理生理变化进行根本性治疗。PI3K/AKT通路的激活可以延缓椎间盘退变的进展。本文综述了PI3K/AKT信号通路的激活和负调控的最新研究进展，并着重介绍了不同的治疗方式通过PI3K/AKT信号通路对椎间盘退变产生的积极作用。相信在不久的将来，干预该信号通路有望成为一种有吸引力的治疗策略。

关键词

下腰痛，椎间盘退变，PI3K/AKT信号通路，分子机制

Research Progress of PI3K/AKT Signaling Pathway in Intervertebral Disc Degeneration

Tao Yang1, Shu Jia2, Chunyang Meng2*

1Jining Medical University, Jining Shandong

2The Affiliated Hospital of Jining Medical University, Jining Shandong

Received: Oct. 9th, 2022; accepted: Nov. 2nd, 2022; published: Nov. 14th, 2022

ABSTRACT

Low back pain has become a global public health problem, and intervertebral disc degeneration is recognized as one of the main causes of low back pain. At present, the treatment of low back pain is limited to relieving symptoms, but cannot fundamentally treat the underlying pathophysiological changes in intervertebral discs. The activation of PI3K/AKT pathway can delay the progression of intervertebral disc degeneration. This article reviews the latest research progress in the activation and negative regulation of PI3K/AKT signal pathway, and focuses on the positive effects of different treatments on intervertebral disc degeneration through PI3K/AKT signal pathway. It is believed that intervention in this signaling pathway is expected to become an attractive therapeutic strategy in the near future.

Keywords:Low Back Pain, Intervertebral Disc Degeneration, PI3K/AKT Signaling Pathway, Molecular Mechanism

Copyright © 2022 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

椎间盘退行性变(Intervertebral disc degeneration, IDD)可引起下腰痛(Low Back Pain, LBP)，是导致患者生活质量下降、残疾的最重要病因之一 [1] ，通常伴随着椎间盘基质金属蛋白酶(MMP)上调、氧化应激加剧、功能性髓核细胞(NPCs)数量减少、髓核组织纤维化等 [2] 。椎间盘由髓核(Nucleus pulposus, NP)、纤维环(Annulus fibrosus, AF)和上下软骨终板(Cartilaginous endplates, CEPs)组成，是人类脊柱的主要组成部分，为日常活动提供机械支撑和脊柱运动 [3] 。在IDD的发展过程中，椎间盘组织的解剖和形态学特征也会发生变化，某一结构的损伤均可导致椎间盘内环境的改变，从而进一步加速退变的进程 [4] [5] 。Pi3k/akt信号通路可调节多种生物学过程，包括细胞凋亡、自噬和氧化应激等，作为细胞内主要的信号传导通路，干预椎间盘组织的PI3K/AKT信号通路作用于下游靶蛋白，或可有效地预防或逆转IDD。本文汇总了近5年的相关研究进展，通过总结与PI3K/AKT信号通路有关的IDD的最新治疗措施，进一步加深对IDD的认识 [6] 。

2. PI3K/AKT信号通路

作为细胞内主要的信号传导通路，正常状态下的PI3K可通过酪氨酸激酶 RTK、G蛋白偶联受体、整合素及细胞因子等方式激活 [7] 。下游的AKT是一种丝氨酸/苏氨酸激酶 [8] 。激活的PI3K将膜结合的磷脂酰肌醇4,5-二磷酸转化为磷脂酰肌醇3,4,5-三磷酸 [9] ，使AKT第308处苏氨酸(Thr308)磷酸化。同时，mTOR复合物2使AKT的473处丝氨酸磷酸化，导致AKT的完全激活 [10] [11] 。激活的AKT与下游靶蛋白相互作用，调节多种生物学过程。

3. PI3K/akt信号通路在IDD治疗中的研究进展

3.1. 药物通过PI3K/akt信号通路治疗IDD

右美托咪定(dexmedetomidine, DEX)是一种强大且高度选择性的α2肾上腺素能受体激动剂，可通过激活PI3K/AKT信号通路发挥抗炎和抗氧化作用 [12] 。超氧化物歧化酶(Superoxide Dismutase, SOD)是生物体内存在的一种抗氧化金属酶，它能够催化超氧阴离子自由基歧化生成氧和过氧化氢，在机体氧化与抗氧化平衡中起到至关重要的作用。Ji等发现用DEX刺激NPCs后，SOD1和SOD2显著增加，而ROS水平也显著降低。过量的ROS会引起线粒体氧化应激，降低线粒体膜电位(Mitochondrial membrane potential, MMP)，诱导细胞凋亡 [13] 。

酪醇是主要多酚化合物之一，主要存在于特级初榨橄榄油、白葡萄酒和其他植物衍生产品中。据报道，酪醇具有广泛的生物活性，包括抗骨质疏松、心脏保护、抗氧化、抗凋亡和抗炎作用。通过上调Sirt1 (sirtuin 1, Sirt1)激活PI3K/AKT通路从而影响SOX9的表达促进蛋白聚糖的合成以缓解IDD的同时，还可抑制髓核细胞中IL-1b，TNF-α等炎症因子的表达 [14] 。然而，在Qi等的研究中，并未进行动物实验，该药物治疗IDD的效果仍需进一步研究。

6-姜酚(6-gingero, l6-GIN)是生姜中的主要药物活性成分，可通过抑制PI3K/AKT信号通路增加自噬通量减少NPMSCs的凋亡延缓IDD的进展 [15] 。PI3K/AKT通路与自噬的发生密切相关，但由于刺激条件、细胞类型和下游效应器的不同，PI3K/AKT信号通路在自噬中发挥的调节作用是复杂的。压力刺激通过抑制PI3K/AKT/mTOR信号通路诱导NP细胞自噬使椎间盘退变的进展加速 [16] 。IL-17A却通过激活PI3K/AKT/Bcl-2信号通路抑制NP细胞的自噬加速椎间盘组织的退变 [17] 。Pi3k/akt信号通路对于自噬的调控在IDD的病理生理过程中的作用十分复杂，待进一步研究。除激活NPMSCs自噬外，6-GIN还可以可在降低H2O2诱导的NPMSCs的ROS水平升高的同时，增加Bcl-2、降低Bax和caspase-3的表达，提示6GIN能够抑制细胞凋亡是通过降低NPSMSCs氧化应激实现的 [15] 。

3.2. 生物制剂通过PI3K/akt信号通路治疗IDD

近些年，关于外泌体治疗IDD的报道逐渐增加。外泌体是由脂质双层膜组成的直径范围为30~150 nm的纳米级细胞外囊泡，可通过其各种生物活性分子的转移影响细胞间通讯 [18] 。Cheng等发现骨髓间充质来源外泌体(bone marrow mesenchymal stem cell derived exosome, BMSC-EXO)富含miR-21。当与BMSC-EXO一起孵育时，NPCs可以吸收外泌体，并且外泌体中的miR-21可以内化到受体NPCs中，通过抑制人第10号染色体缺失的磷酸酶(phosphatase and tensin homolog deleted on chromosome ten, PTEN)，从而激活NPC中的PI3K/AKT通路抑制其凋亡，实现对大鼠针刺尾椎退变间盘的治疗作用 [19] 。

CEP是位于椎间盘上下两侧的透明软骨。研究表明，CEP组织中的祖细胞可分化为成骨细胞、脂肪细胞和软骨细胞 [4] 。这些祖细胞被定义为软骨终板干细胞，它们在维持CEPs结构和功能的完整性方面非常重要。雌激素受体分布在所有 IVD 结构中，包括NP细胞和CEPs等 [20] 。随着IDD的加重，退化的CEP组织中雌激素受体数量下降，炎症因子水平上升 [21] 。而CEP炎症可能进一步加速IDD的进展，luo等通过TBHP诱导CEP炎症，提取正常软骨终板干细胞(Cartilage endplate stem cells, CESCs)外泌体(N-exo)与退化CESCs外泌体(D-exo)，发现N-Exos比D-Exos更能有效地抑制NPCs凋亡、减缓椎间盘退变。PI3K/AKT抑制剂LY294002可以逆转N-EXOs的治疗作用表明N-EXOs可能通过激活PI3K/AKT信号通路发挥作用 [4] 。

外泌体具有低免疫原性和易存贮等优点，有望使其从生物分子水平治疗IDD，在IDD治疗领域具有极大的应用潜力。除此之外，体内激素水平的高低对IDD的生物学过程产生重要影响。调节IDD患者体内激素的水平有望成为预防IDD的有效手段。

雌激素对绝经后妇女的下腰痛有治疗作用，大鼠在去除卵巢后，IDD的严重程度增加，提示雌激素减少与IDD有关 [22] 。研究发现，17β-雌二醇(17β-estradiol, E2)可通过增加II型胶原和蛋白聚糖含量，降低MMP-3和MMP-13以预防IDD [23] 。MMP-3的基因多态性已被证实与人椎间盘退变的严重程度有关 [24] 。FOXO3属于FOXO家族，细胞核中的FOXO3与MMP-3启动子区域结合，调节MMP-3的表达。Gao等发现，雌二醇(E2)可作用于PI3K/AKT通路，磷酸化AKT引发蛋白酶体依赖性降解，促进FOXO3的核外移位，使得髓核细胞核中FOXO3含量减少，MMP3表达下调，从而恢复IDD中下调的II型胶原和聚集蛋白聚糖 [25] 。E2作用于pi3k/akt信号通路，除可调节ECM代谢外，还能抑制髓核细胞的凋亡。Wang等发现，E2可以时间依赖性方式(0~48小时)增加p-AKT的表达，有效保护NP细胞免受TNF-α诱导的细胞凋亡 [26] 。Yang等研究进一步证实E2可以通过PI3K/AKT/caspase-3途径对抗大鼠NPCs中IL-1β诱导的细胞凋亡 [27] ，进一步阐明了雌激素治疗IDD的作用机制。

1,25(OH)2D3作为临床上的常用药，通常用来促进患者对Ca2+的吸收。近些年，有学者报道，其对IDD同样具有治疗作用。Wang等报道。1,25(OH)2D3显著抑制了H2O2诱导后大鼠髓核间充质干细胞(nucleus pulposus mesenchymal stem cells, NPMSCs)中ROS水平和MMP-J聚集体的上调，并且这种治疗作用可被PI3K抑制剂LY294002阻断。表明1,25(OH)2D3可能通过活化PI3K/AKT信号通路发挥抗氧化应激的作用以保护NPMSCs [28] 。Tong等发现1,25(OH)2D3处理12小时可有效增加H2O2诱导的大鼠AFCs中细胞活力，增加线粒体膜电位，降低ROS水平，增加线粒体ATP含量，保留氧化呼吸链中关键酶的活性，从而保护线粒体免受H2O2诱导的损伤 [5] 。进一步阐明了1,25(OH)2D3的作用机制。

4. 结语

尽管激活的PI3K/AKT途径已被证明通过多种机制保护IVD，但仍有许多问题需要探明和解决。同一种椎间盘组织中信号通路的激活或抑制可能对椎间盘退变产生相同的影响，有两种原因，其一是信号通路并非是独立运作的，需要进一步的研究该信号通路如何与其它介质相互作用。其二是在椎间盘退变的不同阶段，组织中同一信号通路激活或抑制的状态可能会发生改变。但不可否认的是，许多对椎间盘退变有治疗效果的药物、生物制剂(外泌体)等都通过PI3K/AKT信号通路产生积极的影响。因此，应对椎间盘退变与该信号通路的关系做进一步的研究，有助于开发IDD的新型靶向生物治疗方法。

文章引用

杨 涛,贾 舒,孟纯阳. PI3K/AKT信号通路在椎间盘退变中的研究进展
Research Progress of PI3K/AKT Signaling Pathway in Intervertebral Disc Degeneration[J]. 临床医学进展, 2022, 12(11): 10075-10080. https://doi.org/10.12677/ACM.2022.12111453

参考文献

  1. 1. Ouyang, Z.H., Wang, W.J., Yan, Y.G., Wang, B. and Lv, G.H. (2017) The PI3K/Akt Pathway: A Critical Player in Intervertebral Disc Degeneration. Oncotarget, 8, 57870-57881. https://doi.org/10.18632/oncotarget.18628

  2. 2. Xu, S., Li, Y., Lu, Y., Huang, J., Ren, J., Zhang, S., et al. (2018) LZTS2 Inhibits PI3K/AKT Activation and Radioresistance in Nasopharyngeal Carcinoma by Interacting with p85. Cancer Letters, 420, 38-48. https://doi.org/10.1016/j.canlet.2018.01.067

  3. 3. Roy, N.K., Monisha, J., Padmavathi, G., Lalhruaitluanga, H., Kumar, N.S., Singh, A.K., et al. (2019) Isoform-Specific Role of Akt in Oral Squamous Cell Carcinoma. Biomolecules, 9, Article No. 253. https://doi.org/10.3390/biom9070253

  4. 4. Fu, Y., Li, S. Tong, H., Li, S. and Yan, Y. (2019) WDR13 Promotes the Differentiation of Bovine Skeletal Muscle-Derived Satellite Cells by Affecting PI3K/AKT Signaling. Cell Biology In-ternational, 43, 799-808. https://doi.org/10.1002/cbin.11160

  5. 5. Kawakami, Y., Nishimoto, H., Kitaura, J., Maeda-Yamamoto, M., Kato, R.M., Littman, D.R., et al. (2004) Protein Kinase C βII Regulates Akt Phosphorylation on Ser-473 in a Cell Type- and Stimulus-Specific Fashion. Journal of Biological Chemistry, 279, 47720-47725. https://doi.org/10.1074/jbc.M408797200

  6. 6. Nakano, N., Matsuda, S., Ichimura, M., Minami, A., Ogino, M., Murai, T. and Kitagishi, Y. (2017) PI3K/AKT Signaling Mediated by G Protein-Coupled Receptors Is Involved in Neu-rodegenerative Parkinson’s Disease (Review). International Journal of Molecular Medicine, 39, 253-260. https://doi.org/10.3892/ijmm.2016.2833

  7. 7. Shen, J.L., Xu, S.X., Zhou, H., Liu, H.Z., Jiang, W., Hao, J., et al. (2017) IL-1β Induces Apoptosis and Autophagy via Mitochondria Pathway in Human Degenerative Nucleus Pulposus Cells. Scientific Reports, 7, Article No. 41067. https://doi.org/10.1038/srep41067

  8. 8. Qi, S., Li, C., Kong, X. and Zheng, Q. (2020) Dexmedetomidine Sup-presses Oxidative Stress and Inflammation of Nucleus Pulposus Cells by Activating the PI3K/Akt Signaling Pathway. Pharmazie, 75, 505-509.

  9. 9. Qi, W., Ren, D., Wang, P., Song, Z., Wu, H., Yao, S., et al. (2020) Upregulation of Sirt1 by Tyrosol Suppresses Apoptosis and Inflammation and Modulates Extracellular Matrix Remodeling in Interleu-kin-1β-Stimulated Human Nucleus Pulposus Cells through Activation of PI3K/Akt Pathway. International Im-munopharmacology, 88, Article ID: 106904. https://doi.org/10.1016/j.intimp.2020.106904

  10. 10. Nan, L.P., Wang, F., Liu, Y., Wu, Z., Feng, X.M., et al. (2020) 6-Gingerol Protects Nucleus Pulposus-Derived Mesenchymal Stem Cells from Oxidative Injury by Activating Autopha-gy. World Journal of Stem Cells, 12, 1603-1622. https://doi.org/10.4252/wjsc.v12.i12.1603

  11. 11. Li, Z.L., Wang, J., Deng, X.Y., Huang, D.H., Shao, Z.W. and Ma, K.G. (2021) Compression Stress Induces Nucleus Pulposus Cell Autophagy by Inhibition of the PI3K/AKT/mTOR Pathway and Activation of the JNK Pathway. Connective Tissue Research, 62, 337-349. https://doi.org/10.1080/03008207.2020.1736578

  12. 12. He, W.S., Zou, M.X., Yan, Y.G., Yao, N.Z., Chen, W.K., Li, Z., et al. (2020) Interleukin-17A Promotes Human Disc Degeneration by Inhibiting Autophagy through the Activation of the Phosphatidylinositol 3-Kinase/Akt/Bcl2 Signaling Pathway. World Neurosurgery, 143, e215-e223. https://doi.org/10.1016/j.wneu.2020.07.117

  13. 13. Krut, Z., Pelled, G., Gazit, D. and Gazit, Z. (2021) Stem Cells and Exosomes: New Therapies for Intervertebral Disc Degeneration. Cells, 10, Article No. 2241. https://doi.org/10.3390/cells10092241

  14. 14. Cheng, X.F., Zhang, G.Y., Zhang, L., Hu, Y., Zhang, K., Sun, X.J., et al. (2018) Mesenchymal Stem Cells Deliver Exogenous miR-21 via Exosomes to Inhibit Nucleus Pulposus Cell Apopto-sis and Reduce Intervertebral Disc Degeneration. Journal of Cellular and Molecular Medicine, 22, 261-276. https://doi.org/10.1111/jcmm.13316

  15. 15. Yang, S., Zhang, F., Ma, J. and Ding, W. (2020) Intervertebral Disc Ageing and Degeneration: The Antiapoptotic Effect of Oestrogen. Ageing Research Reviews, 57, Article ID: 100978. https://doi.org/10.1016/j.arr.2019.100978

  16. 16. Sheng, B., Zhou, J., Liu, X., Yuan, Y., Zhang, Y., Liu, H., et al. (2018) Protective Effect of Estrogen against Calcification in the Cartilage Endplate. International Journal of Clinical and Experimental Pathology, 11, 1660-1666.

  17. 17. Ao, P., Huang, W., Li, J., Wu, T., Xu, L., Deng, Z., et al. (2018) 17β-Estradiol Protects Nucleus Pulposus Cells from Serum Deprivation-Induced Apoptosis and Regulates Expression of MMP-3 and MMP-13 through Promotion of Autophagy. Biochemical and Biophysical Research Communications, 503, 791-797. https://doi.org/10.1016/j.bbrc.2018.06.077

  18. 18. Liu, S., Yang, S.D., Huo, X.W., Yang, D.L., Ma, L. and Ding, W.Y. (2018) 17β-Estradiol Inhibits Intervertebral Disc Degeneration by Down-Regulating MMP-3 and MMP-13 and Up-Regulating Type II Collagen in a Rat Model. Artificial Cells, Nanomedicine, and Biotechnology, 46, 182-191. https://doi.org/10.1080/21691401.2018.1453826

  19. 19. Vos, T., Allen, C., Arora, M., Barber, R., Bhutta, Z., Brown, A., Carter, A., Casey, D., Khera, S., Tavakkoli, M. and GBD 2015 Disease and Injury Incidence and Prevalence Collaborators (2016) Global, Regional, and National Incidence, Prevalence, and Years Lived with Disability for 310 Diseases and Injuries, 1990-2015: A Systematic Analysis for the Global Burden of Disease Study 2015. Lancet, 388, 1545-1602.

  20. 20. Saberi, A., Salehi, Z., Naderinabi, B., Ansari, S.H. and Mashayekhi, S. (2018) Genetic Dimension of Intervertebral Disc Degeneration: Polymorphism of Matrix Metallopro-teinase 1 and 3 in the North Iranian Population. Turkish Neurosurgery, 28, 447-453. https://doi.org/10.5137/1019-5149.JTN.19978-17.0

  21. 21. Cazzanelli, P. and Wuertz-Kozak, K. (2020) Mi-croRNAs in Intervertebral Disc Degeneration, Apoptosis, Inflammation, and Mechanobiology. International Journal of Molecular Sciences, 21, Article No. 3601. https://doi.org/10.3390/ijms21103601

  22. 22. Dowdell, J., Erwin, M., Choma, T., Vaccaro, A., Iatridis, J. and Cho, S.K. (2017) Intervertebral Disk Degeneration and Repair. Neurosurgery, 80, S46-S54. https://doi.org/10.1093/neuros/nyw078

  23. 23. Luo, L., Jian, X., Sun, H., Qin, J., Wang, Y., Zhang, J., et al. (2021) Cartilage Endplate Stem Cells Inhibit Intervertebral Disc Degeneration by Releasing Exosomes to Nucleus Pulposus Cells to Activate Akt/Autophagy. Stem Cells, 39, 467-481. https://doi.org/10.1002/stem.3322

  24. 24. Gao, X.W., Su, X.T., Lu, Z.H. and Ou, J. (2020) 17β-Estradiol Prevents Extracellular Matrix Degradation by Downregulating MMP3 Expression via PI3K/Akt/FOXO3 Pathway. Spine, 45, 292-299. https://doi.org/10.1097/BRS.0000000000003263

  25. 25. Wang, T., Yang, S.D., Liu, S., Wang, H., Liu, H. and Ding, W.Y. (2021) 17β-Estradiol Inhibites Tumor Necrosis Factor-α Induced Apoptosis of Human Nucleus Pulposus Cells via the PI3K/Akt Pathway. Medical Science Monitor, 22, 4312-4322. https://doi.org/10.12659/MSM.900310

  26. 26. Yang, S.D., Ma, L., Yang, D.L., Ding, W.Y. (2016) Combined Effect of 17β-Estradiol and Resveratrol against Apoptosis Induced by Interleukin-1β in Rat Nucleus Pulposus Cells via PI3K/Akt/Caspase-3 Pathway. PeerJ, 4, e1640. https://doi.org/10.7717/peerj.1640

  27. 27. Tong, T., Liu, Z., Zhang, H., Sun, J., Zhang, D., Wang, F., et al. (2019) Age-Dependent Expression of the Vitamin D Receptor and the Protective Effect of Vitamin D Receptor Activation on H2O2-Induced Apoptosis in Rat Intervertebral Disc Cells. The Journal of Steroid Biochemistry and Molecular Biology, 190, 126-138. https://doi.org/10.1016/j.jsbmb.2019.03.013

  28. 28. Wang, J.W., Zhu, L., Shi, P.Z., Wang, P.C., Dai, Y., Wang, Y.X., et al. (2022) 1,25(OH)2D3 Mitigates Oxidative Stress-Induced Damage to Nucleus Pulposus-Derived Mesenchymal Stem Cells through PI3K/Akt Pathway. Oxidative Medicine and Cellular Longevity, 2022, Article ID: 1427110. https://doi.org/10.1155/2022/1427110

    29. NOTES

    *通讯作者Email: mengchunyang1600@mail.jnmc.edu.cn

期刊菜单