A Novel Lipopeptide–Functionalized Metal–Organic Framework for Periodontitis Therapy through the Htra1/FAK/YAP Pathway
Source abstract
Abstract
Periodontitis is a chronic inflammatory disease characterized by plaque accumulation, resulting in immune microenvironment disorders and resorption of alveolar bone. To promote bone healing under inflammatory environments, a functional biomaterial based on disease pathophysiology is designed. A novel fatty acid C10-modified polypeptide, C 10 -KR8, is discovered to have excellent abilities in modulating macrophage repolarization and promoting bone regeneration in periodontitis. To build a multifunctional material localized drug delivery system, C 10 -KR8@ZIF-8 (C 10 -KR8-loaded zeolitic imidazolate framework-8) nanoparticles are constructed to sustainedly release the C 10 -KR8 peptide and Zn elements. By synergistic effects of providing a dynamic immuno-modulatory environment and promoting osteogenesis under pathological conditions, the obtained pH-responsive nanoparticles display excellent bone regeneration capability. Furthermore, coimmunoprecipitation/liquid chromatography-tandem mass spectrometry analysis and proteomics analysis revealed that the C 10 -KR8 peptide directly interacts with the high-temperature requirement protein A1 (Htra1), and C 10 -KR8@ZIF-8 nanoparticles promote the osteogenic differentiation of bone mesenchymal stem cells by activating the focal adhesion kinase (FAK)/phosphatidylinositide 3-kinase (PI3K)/AKT pathway and enhancing the nuclear localization of Yes-associated protein (YAP). Taken together, this study demonstrates C 10 -KR8 peptide regulate osteoimmunology and bone regeneration by Htra1/FAK/YAP pathway and that ZIF-8-based peptide loading platform is a promising strategy for periodontitis.
Source: crossref · Quality: baseline
Research context
OpenAlex topics: Peptidase Inhibition and Analysis · Protease and Inhibitor Mechanisms · S100 Proteins and Annexins
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Department of Stomatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
Department of General Dentistry, Shanghai Ninth People’s Hospital, School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai, 200011, China.
Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
Funding
National Natural Science Foundation of China
References (50)
Show source-provided references
1. Ebersole JL, Dawson D, Emecen-Huja P, Nagarajan R, Howard K, Grady ME, Thompson K, Peyyala R, al-Attar A, Lethbridge K, et al. The periodontal war: Microbes and immunity. Periodontol 2000. 2017;75(1):52–115.10.1111/prd.12222 ↗
2. Slots J. Periodontitis: Facts, fallacies and the future. Periodontol 2000. 2017;75(1):7–23.10.1111/prd.12221 ↗
3. Chan S, Pasternak GM, West MJ. The place of periodontal examination and referral in general medicine. Periodontol 2000. 2017;74(1):194–199.10.1111/prd.12199 ↗
4. Xu Y, Luo Y, Weng Z, Xu H, Zhang W, Li Q, Liu H, Liu L, Wang Y, Liu X, et al. Microenvironment-responsive metal-phenolic nanozyme release platform with antibacterial, ROS scavenging, and osteogenesis for periodontitis. ACS Nano. 2023;17(19):18732–18746.10.1021/acsnano.3c01940 ↗
5. 10.1016/j.biomaterials.2010.07.01910.1016/j.biomaterials.2010.07.019 ↗
6. Wang C, Hong T, Cui P, Wang J, Xia J. Antimicrobial peptides towards clinical application: Delivery and formulation. Adv Drug Deliv Rev. 2021;175: Article 113818.10.1016/j.addr.2021.05.028 ↗
7. Li L, Jiang H, Chen R, Zhou J, Xiao Y, Zhang Y, Yan F. Human β-defensin 3 gene modification promotes the osteogenic differentiation of human periodontal ligament cells and bone repair in periodontitis. Int J Oral Sci. 2020;12(1):13.10.1038/s41368-020-0078-6 ↗
8. 10.1038/nm.387110.1038/nm.3871 ↗
9. 10.4049/jimmunol.169.7.388310.4049/jimmunol.169.7.3883 ↗
10. Ramos R, Silva JP, Rodrigues AC, Costa R, Guardão L, Schmitt F, Soares R, Vilanova M, Domingues L, Gama M. Wound healing activity of the human antimicrobial peptide LL37. Peptides. 2011;32(7):1469–1476.10.1016/j.peptides.2011.06.005 ↗
11. Yu X, Quan J, Long W, Chen H, Wang R, Guo J, Lin X, Mai S. LL-37 inhibits LPS-induced inflammation and stimulates the osteogenic differentiation of BMSCs via P2X7 receptor and MAPK signaling pathway. Exp Cell Res. 2018;372(2):178–187.10.1016/j.yexcr.2018.09.024 ↗
12. Li L, Peng Y, Yuan Q, Sun J, Zhuang A, Bi X. Cathelicidin LL37 promotes osteogenic differentiation in vitro and bone regeneration in vivo. Front Bioeng Biotechnol. 2021;9: Article 638494.10.3389/fbioe.2021.638494 ↗
13. Zhuo H, Zhang X, Li M, Zhang Q, Wang Y. Antibacterial and anti-inflammatory properties of a novel antimicrobial peptide derived from LL-37. Antibiotics. 2022;11(6):754.10.3390/antibiotics11060754 ↗
14. Mechesso AF, Su Y, Xie J, Wang G. Enhanced antimicrobial screening sensitivity enabled the identification of an ultrashort peptide KR-8 for engineering of LL-37mini to combat drug-resistant pathogens. ACS Infect Dis. 2023;9(11):2215–2225.10.1021/acsinfecdis.3c00293 ↗
15. Grimsey E, Collis DWP, Mikut R, Hilpert K. The effect of lipidation and glycosylation on short cationic antimicrobial peptides. Biochim Biophys Biomem Acta. 2020;1862(8): Article 183195.10.1016/j.bbamem.2020.183195 ↗
16. Kamysz E, Sikorska E, Jaśkiewicz M, Bauer M, Neubauer D, Bartoszewska S, Barańska-Rybak W, Kamysz W. Lipidated analogs of the LL-37-derived peptide fragment KR12—Structural analysis, surface-active properties and antimicrobial activity. Int J Mol Sci. 2020;21(9):887.10.3390/ijms21030887 ↗
17. 10.1021/acsinfecdis.1c0010110.1021/acsinfecdis.1c00101 ↗
18. 10.1039/C4DT03530E10.1039/C4DT03530E ↗
19. McKinlay AC, Morris RE, Horcajada P, Férey G, Gref R, Couvreur P, Serre C. BioMOFs: Metal-organic frameworks for biological and medical applications. Angew Chem Int Ed. 2010;49(36):6260–6266.10.1002/anie.201000048 ↗
20. El Ouardi M, El Aouni A, Ait Ahsaine H, Zbair M, BaQais A, Saadi M. ZIF-8 metal organic framework composites as hydrogen evolution reaction photocatalyst: A review of the current state. Chemosphere. 2022;308(Pt 3): Article 136483.10.1016/j.chemosphere.2022.136483 ↗
21. Wang Y, Yan J, Wen N, Xiong H, Cai S, He Q, Hu Y, Peng D, Liu Z, Liu Y. Metal-organic frameworks for stimuli-responsive drug delivery. Biomaterials. 2020;230: Article 119619.10.1016/j.biomaterials.2019.119619 ↗
22. Tang R, Ren Y, Zhang Y, Yin M, Ren X, Zhu Q, Gao C, Zhang W, Liu G, Liu B. Glucose-driven transformable complex eliminates biofilm and alleviates inflammation for diabetic periodontitis therapy. Mater Today Bio. 2023;20: Article 100678.10.1016/j.mtbio.2023.100678 ↗
23. Gao X, Xue Y, Zhu Z, Chen J, Liu Y, Cheng X, Zhang X, Wang J, Pei X, Wan Q. Nanoscale zeolitic imidazolate framework-8 activator of canonical MAPK signaling for bone repair. ACS Appl Mater Interfaces. 2021;13(1):97–111.10.1021/acsami.0c15945 ↗
24. Hoseinpour V, Shariatinia Z. Applications of zeolitic imidazolate framework-8 (ZIF-8) in bone tissue engineering: A review. Tissue Cell. 2021;72: Article 101588.10.1016/j.tice.2021.101588 ↗
25. Liu Y, Li T, Sun M, Cheng Z, Jia W, Jiao K, Wang S, Jiang K, Yang Y, Dai Z, et al. ZIF-8 modified multifunctional injectable photopolymerizable GelMA hydrogel for the treatment of periodontitis. Acta Biomater. 2022;146:37–48.10.1016/j.actbio.2022.03.046 ↗
26. 10.1016/j.poly.2018.09.02810.1016/j.poly.2018.09.028 ↗
27. Shen M, Forghani F, Kong X, Liu D, Ye X, Chen S, Ding T. Antibacterial applications of metal–organic frameworks and their composites. Compr Rev Food Sci Food Saf. 2020;19(4):1397–1419.10.1111/1541-4337.12515 ↗
28. 10.1039/c2dt30357d10.1039/c2dt30357d ↗
29. Ni C, Zhou J, Kong N, Bian T, Zhang Y, Huang X, Xiao Y, Yang W, Yan F. Gold nanoparticles modulate the crosstalk between macrophages and periodontal ligament cells for periodontitis treatment. Biomaterials. 2019;206:115–132.10.1016/j.biomaterials.2019.03.039 ↗
30. 10.4049/jimmunol.130200510.4049/jimmunol.1302005 ↗
31. 10.1016/j.biomaterials.2017.12.02510.1016/j.biomaterials.2017.12.025 ↗
32. Zhuang Z, Yoshizawa-Smith S, Glowacki A, Maltos K, Pacheco C, Shehabeldin M, Mulkeen M, Myers N, Chong R, Verdelis K, et al. Induction of M2 macrophages prevents bone loss in murine periodontitis models. J Dent Res. 2019;98(2):200–208.10.1177/0022034518805984 ↗
33. Guder C, Gravius S, Burger C, Wirtz DC, Schildberg FA. Osteoimmunology: A current update of the interplay between bone and the immune system. Front Immunol. 2020;11:58.10.3389/fimmu.2020.00058 ↗
34. Vallés G, Bensiamar F, Maestro-Paramio L, García-Rey E, Vilaboa N, Saldaña L. Influence of inflammatory conditions provided by macrophages on osteogenic ability of mesenchymal stem cells. Stem Cell Res Ther. 2020;11(1):57.10.1186/s13287-020-1578-1 ↗
35. Giménez-Marqués M, Hidalgo T, Serre C, Horcajada P. Nanostructured metal–organic frameworks and their bio-related applications. Coord Chem Rev. 2016;307(57):342–360.10.1016/j.ccr.2015.08.008 ↗
36. Mi B, Xiong Y, Zhao Y, Lin Z, Lu L, Liu G, Zhao Y. Metal–organic framework-integrated composites for bone tissue regeneration. Adv Funct Materials. 2023;34(8):2308656.10.1002/adfm.202308656 ↗
37. Lao A, Wu J, Li D, Shen A, Li Y, Zhuang Y, Lin K, Wu J, Liu J. Functionalized metal–organic framework-modified hydrogel that breaks the vicious cycle of inflammation and ROS for repairing of diabetic bone defects. Small. 2023;19(36):2206919.10.1002/smll.202206919 ↗
38. 10.3109/07388551.2016.116332310.3109/07388551.2016.1163323 ↗
39. 10.1007/s10735-015-9612-910.1007/s10735-015-9612-9 ↗
40. Glanz S, Mirsaidi A, López-Fagundo C, Filliat G, Tiaden AN, Richards PJ. Loss-of-function of HtrA1 abrogates all-trans retinoic acid-induced osteogenic differentiation of mouse adipose-derived stromal cells through deficiencies in p70S6K activation. Stem Cells Dev. 2016;25(9):687–698.10.1089/scd.2015.0368 ↗
41. Filliat G, Mirsaidi A, Tiaden AN, Kuhn GA, Weber FE, Oka C, Richards PJ. Role of HTRA1 in bone formation and regeneration: In vitro and in vivo evaluation. PLoS One. 2017;12(7): Article e0181600.10.1371/journal.pone.0181600 ↗
42. Arnaout MA. Cell adhesion molecules in inflammation and thrombosis: Status and prospects. Am J Kidney Dis. 1993;21(1):72–76.10.1016/S0272-6386(12)80725-6 ↗
43. Yuan C, Gou X, Deng J, Dong Z, Ye P, Hu Z. FAK and BMP-9 synergistically trigger osteogenic differentiation and bone formation of adipose derived stem cells through enhancing Wnt-β-catenin signaling. Biomed Pharmacother. 2018;105:753–757.10.1016/j.biopha.2018.04.185 ↗
44. 10.1016/j.apsb.2022.09.02010.1016/j.apsb.2022.09.020 ↗
45. Song J, Ye B, Liu H, Bi R, Zhang N, Hu J, Luo E. Fak-Mapk, Hippo and Wnt signalling pathway expression and regulation in distraction osteogenesis. Cell Prolif. 2018;51(4): Article e12453.10.1111/cpr.12453 ↗
46. Zhang C, Zhu H, Ren X, Gao B, Cheng B, Liu S, Sha B, Li Z, Zhang Z, Lv Y, et al. Mechanics-driven nuclear localization of YAP can be reversed by N-cadherin ligation in mesenchymal stem cells. Nat Commun. 2021;12(1):6229.10.1038/s41467-021-26454-x ↗
47. Guo L, Cai T, Chen K, Wang R, Wang J, Cui C, Yuan J, Zhang K, Liu Z, Deng Y, et al. Kindlin-2 regulates mesenchymal stem cell differentiation through control of YAP1/TAZ. J Cell Biol. 2018;217(4):1431–1451.10.1083/jcb.201612177 ↗
48. 10.1126/sciadv.adg047810.1126/sciadv.adg0478 ↗
49. Shen Y, Jing D, Zhao Z. The effect of AKT in extracellular matrix stiffness induced osteogenic differentiation of hBMSCs. Cell Signal. 2022;99: Article 110404.10.1016/j.cellsig.2022.110404 ↗
50. Miao S, Zhou J, Liu B, Lei X, Wang T, Hao X, Cheng P, Wu H, Song Y, Pei G, et al. A 3D bioprinted nano-laponite hydrogel construct promotes osteogenesis by activating PI3K/AKT signaling pathway. Mater Today Bio. 2022;16: Article 100342.10.1016/j.mtbio.2022.100342 ↗