Palladium Nanoparticles Degrade Advanced Glycation End Products via Valosin-Containing Protein Mediated Autophagy to Attenuate High-Glucose/High-Fat-Induced Intervertebral Disc Degeneration

Abstract

Intervertebral disc degeneration (IVDD) is a chronic musculoskeletal disorder causing lower back pain, imposing a considerable burden on global health. Hyperglycemia resulting from diabetes mellitus induces advanced glycation end products (AGEs) accumulation in nucleus pulposus cells, leading to IVDD. Mitigating AGEs accumulation is a novel promising strategy for IVDD management. In our study, palladium nanoparticles (Pd NPs) preferentially colocalized within the endoplasmic reticulum and efficiently degraded AGEs via valosin-containing protein (VCP)-mediated autophagy pathways. Pd NPs promoted the ATPase activity of VCPs, upregulated microtubule-associated proteins 1A/1B light chain 3 (LC3) expression, and increased AGEs-degrading autophagosome production. They ameliorated mitochondrial function, relieved endoplasmic reticulum stress, and counteracted the detrimental oxidative stress microenvironment in a high-glucose/high-fat-induced nucleus pulposus cell degeneration model. Consequently, Pd NPs effectively rescued nucleus pulposus cell degeneration in vitro, restored disc height and partially recovered the degenerated phenotype of IVDD in vivo. We provide novel insights regarding IVDD management by targeting AGEs degradation, showing potential for clinical practice.

Keywords

advanced glycation end products / high-glucose/high-fat / intervertebral disc degeneration / nucleus pulposus / palladium nanoparticles

References

[1] L. Frapin, J. Clouet, V. Delplace, M. Fusellier, J. Guicheux, and C. L.e Visage, “Lessons Learned From Intervertebral Disc Pathophysiology to Guide Rational Design of Sequential Delivery Systems for Therapeutic Biological Factors,” Advanced Drug Delivery Reviews 149-150 (2019): 49.

[2] P. Sampara, R. R. Banala, S. K. Vemuri, A. V. G. Reddy, and G. P. V. Subbaiah, “Understanding the Molecular Biology of Intervertebral Disc Degeneration and Potential Gene Therapy Strategies for Regeneration: A Review,” Gene Therapy 25 (2018): 67.

[3] R.-Z. Yang, W.-N. Xu, H.-L. Zheng, et al., “Involvement of Oxidative Stress-Induced Annulus Fibrosus Cell and Nucleus Pulposus Cell Ferroptosis in Intervertebral Disc Degeneration Pathogenesis,” Journal of Cellular Physiology 236 (2021): 2725.

[4] a) L. M. Jaworski, K. L. Kleinhans, and A. R. Jackson, “Effects of Oxygen Concentration and Culture Time on Porcine Nucleus Pulposus Cell Metabolism: An In Vitro Study,” Frontiers in Bioengineering and Biotechnology 7 (2019): 64. b) G. Fontana, E. See, and A. Pandit, “Current Trends in Biologics Delivery to Restore Intervertebral Disc Anabolism,” Advanced Drug Delivery Reviews 84 (2015): 146.

[5] a) P. Zhang, T. Li, X. Wu, E. C. Nice, C. Huang, and Y. Zhang, “Oxidative Stress and Diabetes: Antioxidative Strategies,” Frontiers of Medicine 14 (2020): 583. b) M. Mahmoud, M. Kokozidou, A. Auffarth, and G. Schulze-Tanzil, “The Relationship between Diabetes Mellitus Type II and Intervertebral Disc Degeneration in Diabetic Rodent Models: A Systematic and Comprehensive Review,” Cells 9 (2020): 2208.

[6] M. V. Risbud and I. M. Shapiro, “Role of Cytokines in Intervertebral Disc Degeneration: Pain and Disc Content,” Nature Reviews Rheumatology 10 (2014): 44.

[7] Y. Zhao, Q. Xiang, J. Lin, S. Jiang, and W. Li, “Oxidative Stress in Intervertebral Disc Degeneration: New Insights from Bioinformatic Strategies,” Oxidative Medicine and Cellular Longevity 2022 (2022): 2239770.

[8] F. Cannata, G. Vadala, L. Ambrosio, et al., “Intervertebral Disc Degeneration: A Focus on Obesity and Type 2 Diabetes,” Diabetes Metabolism Research and Reviews 36 (2020): e3224.

[9] C. Zeng, Y. Li, J. Ma, L. Niu, and F. R. Tay, “Clinical/Translational Aspects of Advanced Glycation End-Products,” Trends in Endocrinology and Metabolism 30 (2019): 959.

[10] R. Luo, S. Li, G. Li, et al., “FAM134B-Mediated ER-Phagy Upregulation Attenuates AGEs-Induced Apoptosis and Senescence in Human Nucleus Pulposus Cells,” Oxidative Medicine and Cellular Longevity 2021 (2021): 3843145.

[11] J. Wang, B. Cheng, J. Li, et al., “Chemical Remodeling of Cell-Surface Sialic Acids Through a Palladium-Triggered Bioorthogonal Elimination Reaction,” Angewandte Chemie International Edition 54 (2015): 5364.

[12] E. Indrigo, J. Clavadetscher, S. V. Chankeshwara, A. Lilienkampf, and M. Bradley, “Palladium-Mediated In Situ Synthesis of an Anticancer Agent,” Chemical Communications 52 (2016): 14212.

[13] Y. Wang, A. Biby, Z. Xi, B. Liu, Q. C. Rao, and X. H. Xia, “One-Pot Synthesis of Single-Crystal Palladium Nanoparticles With Controllable Sizes for Applications in Catalysis and Biomedicine,” ACS Applied Nano Materials 2 (2019): 4605.

[14] H. J. Lee, Y. H. Jung, G. E. Choi, et al., “Urolithin a Suppresses High Glucose-Induced Neuronal Amyloidogenesis by Modulating TGM2-Dependent ER-Mitochondria Contacts and Calcium Homeostasis,” Cell Death and Differentiation 28 (2021): 184.

[15] T. Grunhagen, G. Wilde, D. M. Soukane, S. A. Shirazi-Adl, and J. P. G. Urban, “Nutrient Supply and Intervertebral Disc Metabolism,” Journal of Bone and Joint Surgery. American Volume 88 (2006): 30.

[16] K. Alpantaki, A. Kampouroglou, C. Koutserimpas, G. Effraimidis, and A. Hadjipavlou, “Diabetes Mellitus as a Risk Factor for Intervertebral Disc Degeneration: A Critical Review,” European Spine Journal 28 (2019): 2129.

[17] Z. Zhang, J. Lin, M. Nisar, et al., “The sirt1/P53 axis in diabetic intervertebral disc degeneration pathogenesis and therapeutics,” Oxidative Medicine and Cellular Longevity 2019 (2019): 7959573.

[18] C. Cunha, A. J. Silva, P. Pereira, R. Vaz, R. M. Gonçalves, and M. A. Barbosa, “The Inflammatory Response in the Regression of Lumbar Disc Herniation,” Arthritis Research & Therapy 20 (2018): 251.

[19] F. Barutta, S. Bellini, S. Kimura, et al., “Protective Effect of the Tunneling Nanotube-TNFAIP2/M-Sec System on Podocyte Autophagy in Diabetic Nephropathy,” Autophagy 19 (2023): 505.

[20] S. Ashe, D. Nayak, M. Kumari, and B. Nayak, “Ameliorating Effects of Green Synthesized Silver Nanoparticles on Glycated End Product Induced Reactive Oxygen Species Production and Cellular Toxicity in Osteogenic Saos-2 Cells,” ACS Applied Materials & Interfaces 8 (2016): 30005.

[21] a) J. Xu, L. You, and Z. Zhao, “Synthesize of the Chitosan-Tpp Coated Betanin-Quaternary Ammonium-Functionalized Mesoporous Silica Nanoparticles and Mechanism for Inhibition of Advanced Glycation End Products Formation,” Food Chemistry 407 (2023): 135110. b) M. A. Anis and Y. N. Sreerama, “Inhibition of Protein Glycoxidation and Advanced Glycation End-Product Formation by Barnyard Millet (Echinochloa frumentacea) Phenolics,” Food Chemistry 315 (2020): 126265.

[22] a) Z. Cai, Y. Li, L. Bai, et al., “Tetrahedral Framework Nucleic Acids Based Small Interfering RNA Targeting Receptor for Advanced Glycation End Products for Diabetic Complications Treatment,” ACS Nano 17 (2023): 22668. b) S.-i. Yamagishi, K. Nakamura, and T. Matsui, “Regulation of Advanced Glycation End Product (AGE)-receptor (RAGE) System by PPAR-Gamma Agonists and Its Implication in Cardiovascular Disease,” Pharmacological Research 60 (2009): 174.

[23] Z. Ye, C. Hu, J. Wang, et al., “Burst of hopping Trafficking Correlated Reversible Dynamic Interactions Between Lipid Droplets and Mitochondria Under Starvation,” Exploration 3 (2023): 20230002.

[24] L. Wrobel, S. M. Hill, A. Djajadikerta, et al., “Compounds Activating VCP D1 ATPase Enhance Both Autophagic and Proteasomal Neurotoxic Protein Clearance,” Nature Communications 13 (2022): 4146.

[25] a) D. Ritz, M. Vuk, P. Kirchner, et al., “Endolysosomal Sorting Oof Ubiquitylated Caveolin-1 is Regulated by VCP and UBXD1 and Impaired by VCP Disease Mutations,” Nature Cell Biology 13 (2011): 1116. b) Y.-C. Chang, Y.-X. Peng, B.-H. Yu, et al., “VCP Maintains Nuclear Size by Regulating the DNA Damage-Associated MDC1-p53-Autophagy Axis in Drosophila,” Nature Communications 12 (2021): 4258. c) Y. Gwon, B. A. Maxwell, R.-M. Kolaitis, P. Zhang, H. J. Kim, and J. P. Taylor, “Ubiquitination of G3BP1 Mediates Stress Granule Disassembly in a Context-Specific Manner,” Science 372 (2021): eabf6548.

[26] J. Fielden, M. Popović, and K. Ramadan, “TEX264 at the Intersection of Autophagy and DNA Repair,” Autophagy 18 (2022): 40.

[27] R.-Q. Yao, C. Ren, Z.-F. Xia, and Y.-M. Yao, “Organelle-Specific Autophagy in Inflammatory Diseases: A Potential Therapeutic Target Underlying the Quality Control Of Multiple Organelles,” Autophagy 17 (2021): 385.

[28] K. Nowotny, D. Schröter, M. Schreiner, and T. Grune, “Dietary Advanced Glycation End Products and Their Relevance for Human Health,” Ageing Research Reviews 47 (2018): 55.

[29] M. B. Manigrasso, P. Rabbani, L. Egaña-Gorroño, et al., “Small-Molecule Antagonism of the Interaction of the Rage Cytoplasmic Domain with Diaph1 Reduces Diabetic Complications in Mice,” Science Translational Medicine 13 (2021): eabf7084.

[30] a) C. Nie, Y. Li, H. Qian, H. Ying, and L. Wang, “Advanced Glycation End Products in Food and Their Effects on Intestinal Tract,” Critical Reviews in Food Science and Nutrition 62 (2022): 3103. b) K. Byun, Y. Yoo, M. Son, et al., “Advanced Glycation End-Products Produced Systemically and by Macrophages: A Common Contributor to Inflammation and Degenerative Diseases,” Pharmacology & Therapeutics 177 (2017): 44.

[31] B. I. Hudson and M. E. Lippman, “Targeting RAGE Signaling in Inflammatory Disease,” Annual Review of Medicine 69 (2018): 349.

[32] Z. Tang, B. Hu, F. Zang, J. Wang, X. Zhang, and H. Chen, “Nrf2 Drives Oxidative Stress-Induced Autophagy in Nucleus Pulposus Cells via a Keap1/Nrf2/p62 Feedback Loop to Protect Intervertebral Disc From degeneration,” Cell Death & Disease 10 (2019): 510.

[33] K. Sun, X. Jing, J. Guo, X. Yao, and F. Guo, “Mitophagy in Degenerative Joint Diseases,” Autophagy 17 (2021): 2082.

[34] b) A. Singh, R. Kukreti, L. Saso, and S. Kukreti, “Mechanistic Insight into Oxidative Stress-Triggered Signaling Pathways and Type 2 Diabetes,” Molecules 27 (2022): 950.

[35] C. Carvalho and S. Cardoso, “Diabetes-Alzheimer's Disease Link: Targeting Mitochondrial Dysfunction and Redox Imbalance,” Antioxidants & Redox Signaling 34 (2021): 631.

[36] T. Zhou, X. Yang, Z. Chen, et al., “Prussian Blue Nanoparticles Stabilize SOD1 From Ubiquitination-Proteasome Degradation to Rescue Intervertebral Disc Degeneration,” Advanced Science 9 (2022): e2105466.

[37] X. Yang, Y. Chen, J. Guo, et al., “Polydopamine Nanoparticles Targeting Ferroptosis Mitigate Intervertebral Disc Degeneration via Reactive Oxygen Species Depletion, Iron Ions Chelation, and GPX4 Ubiquitination Suppression,” Advanced Science 10 (2023): e2207216.

[38] Y. Li, D. Huang, and L. Jia, et al., “LonP1 Links Mitochondria-ER Interaction to Regulate Heart Function,” Research 6 (2023): 0175.

[39] B. Basha, S. M. Samuel, C. R. Triggle, and H. Ding, “Endothelial Dysfunction in Diabetes Mellitus: Possible Involvement of Endoplasmic Reticulum Stress?,” Experimental Diabetes Research 2012 (2012): 481840.

[40] a) D. T. Rutkowski and R. J. Kaufman, “A Trip to the ER: Coping With stress,” Trends in Cell Biology 14 (2004): 20. b) I. Tabas and D. Ron, “Integrating the mechanisms of Apoptosis Induced by Endoplasmic Reticulum Stress,” Nature Cell Biology 13 (2011): 184. c) G. Jing, J. J. Wang, and S. X. Zhang, “ER Stress and Apoptosis: A New Mechanism for Retinal Cell Death,” Experimental Diabetes Research 2012 (2012): 589589.

[41] a) J. H. Lin, H. Li, D. Yasumura, et al., “IRE1 Signaling Affects Cell Fate During the Unfolded Protein Response,” Science 318 (2007): 944. b) L. Chen, S. Xu, L. Liu, et al., “Cab45S inhibits the ER stress-induced IRE1-JNK Pathway and Apoptosis via GRP78/BiP,” Cell Death & Disease 5 (2014): e1219.

[42] Z. Liao, R. Luo, G. Li, et al., “Exosomes From Mesenchymal Stem Cells Modulate Endoplasmic Reticulum Stress to Protect Against Nucleus Pulposus Cell Death and Ameliorate Intervertebral Disc Degeneration In Vivo,” Theranostics 9 (2019): 4084.

[43] M. A. Miller, B. Askevold, H. Mikula, R. H. Kohler, D. Pirovich, and R. Weissleder, “Nano-palladium is a Cellular Catalyst for In Vivo Chemistry,” Nature Communications 8 (2017): 15906.

[44] J. Cheng, Y. Zhang, L. Ma, et al., “Macrophage-Derived Extracellular Vesicles-Coated Palladium Nanoformulations Modulate Inflammatory and Immune Homeostasis for Targeting Therapy of Ulcerative Colitis,” Advanced Science 10 (2023): e2304002.

[45] C.-d. Oh, H.-J. Im, J. Suh, A. Chee, H. An, and D. Chen, “Rho-Associated Kinase Inhibitor Immortalizes Rat Nucleus Pulposus and Annulus Fibrosus Cells,” Spine 41 (2016): E255.

[46] M.-L. Ji, H. Jiang, X.-J. Zhang, et al., “Preclinical Development of a MicroRNA-Based Therapy for Intervertebral Disc Degeneration,” Nature Communications 9 (2018): 5051.

RIGHTS & PERMISSIONS

2025 The Author(s). Exploration published by Henan University and John Wiley & Sons Australia, Ltd.