Nanosome-Mediated Delivery Of Protein Kinase D Inhibitor Protects Chondrocytes From Interleukin-1β-Induced Stress And Apoptotic Death

Hongsik Cho,1–3,* Fazal-Ur-Rehman Bhatti,1,3,* Karen A Hasty,1–3 Ae-Kyung Yi4 1Department of Orthopaedic Surgery and Biomedical Engineering, The University of Tennessee Health Science Center, Memphis, TN, USA; 2Department of Orthopaedic Surgery, Campbell Clinic, Memphis, TN, USA;...

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Autores principales:	Cho H, Bhatti FUR, Hasty KA, Yi AK
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	crt0066101 liposome cartilage osteoarthritis cytokine Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/b5e0c19bb6ea42e094615bf98bc2ec69
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spelling	oai:doaj.org-article:b5e0c19bb6ea42e094615bf98bc2ec692021-12-02T06:27:47ZNanosome-Mediated Delivery Of Protein Kinase D Inhibitor Protects Chondrocytes From Interleukin-1β-Induced Stress And Apoptotic Death1178-2013https://doaj.org/article/b5e0c19bb6ea42e094615bf98bc2ec692019-11-01T00:00:00Zhttps://www.dovepress.com/nanosome-mediated-delivery-of-protein-kinase-d-inhibitor-protects-chon-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Hongsik Cho,1–3,* Fazal-Ur-Rehman Bhatti,1,3,* Karen A Hasty,1–3 Ae-Kyung Yi4 1Department of Orthopaedic Surgery and Biomedical Engineering, The University of Tennessee Health Science Center, Memphis, TN, USA; 2Department of Orthopaedic Surgery, Campbell Clinic, Memphis, TN, USA; 3151 Research Service, Veterans Affairs Medical Center, Memphis, TN, USA; 4Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN, USA*These authors contributed equally to this workCorrespondence: Hongsik ChoDepartment of Orthopaedic Surgery and Biomedical Engineering, The University of Tennessee Health Science Center, Research 151, VAMC, 1030 Jefferson Ave, Memphis TN 38104 USATel +1 901 523-8990 (Ext: 6456)Fax +1 901 577-7273Email hcho4@uthsc.eduAe-Kyung YiDepartment of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, 858 Madison Ave., Suite 501C, Memphis, TN 38163, USATel +1 901 448-1775Fax +1 901 448-7360Email ayi@uthsc.eduBackground: Inflammatory stress caused by protein kinase D (PKD) plays a critical role in damaging chondrocytes and extracellular matrix (ECM) during osteoarthritis (OA). The PKD inhibitor (PKDi) (CRT0066101) has been used to overcome inflammation in different cell types. However, the efficacy of a therapeutic drug can be limited due to off-target distribution, slow cellular internalization, and limited lysosomal escape. In order to overcome this issue, we developed nanosomes carrying CRT0066101 (PKDi-Nano) and tested their efficacy in vitro in chondrocytes.Methods: Chondrocytes were subjected to IL-1β-induced inflammatory stress treated with either PKDi or PKDi-Nano. Effects of treatment were measured in terms of cytotoxicity, cellular morphology, viability, apoptosis, phosphorylation of protein kinase B (Akt), and anabolic/catabolic gene expression analyses related to cartilage tissue.Results and Discussion: The effects of PKDi-Nano treatment were more pronounced as compared to PKDi treatment. Cytotoxicity and apoptosis were significantly reduced following PKDi-Nano treatment (P < 0.001). Cellular morphology was also restored to normal size and shape. The viability of chondrocytes was significantly enhanced in PKDi-Nano-treated cells (P < 0.001). The data indicated that PKDi-Nano acted independently of the Akt pathway. Gene expression analyses revealed significant increases in the expression levels of anabolic genes with concomitant decreases in the level of catabolic genes. Our results indicate that PKDi-Nano attenuated the effects of IL-1β via the nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) pathway.Conclusion: Taken together, these results suggest that PKDi-Nano can be used as a successful strategy to reduce IL1β-induced inflammatory stress in chondrocytes.Keywords: CRT0066101, liposome, cartilage, osteoarthritis, cytokine  Cho HBhatti FURHasty KAYi AKDove Medical Pressarticlecrt0066101liposomecartilageosteoarthritiscytokineMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 14, Pp 8835-8846 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	crt0066101 liposome cartilage osteoarthritis cytokine Medicine (General) R5-920
spellingShingle	crt0066101 liposome cartilage osteoarthritis cytokine Medicine (General) R5-920 Cho H Bhatti FUR Hasty KA Yi AK Nanosome-Mediated Delivery Of Protein Kinase D Inhibitor Protects Chondrocytes From Interleukin-1β-Induced Stress And Apoptotic Death
description	Hongsik Cho,1–3,* Fazal-Ur-Rehman Bhatti,1,3,* Karen A Hasty,1–3 Ae-Kyung Yi4 1Department of Orthopaedic Surgery and Biomedical Engineering, The University of Tennessee Health Science Center, Memphis, TN, USA; 2Department of Orthopaedic Surgery, Campbell Clinic, Memphis, TN, USA; 3151 Research Service, Veterans Affairs Medical Center, Memphis, TN, USA; 4Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN, USA*These authors contributed equally to this workCorrespondence: Hongsik ChoDepartment of Orthopaedic Surgery and Biomedical Engineering, The University of Tennessee Health Science Center, Research 151, VAMC, 1030 Jefferson Ave, Memphis TN 38104 USATel +1 901 523-8990 (Ext: 6456)Fax +1 901 577-7273Email hcho4@uthsc.eduAe-Kyung YiDepartment of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, 858 Madison Ave., Suite 501C, Memphis, TN 38163, USATel +1 901 448-1775Fax +1 901 448-7360Email ayi@uthsc.eduBackground: Inflammatory stress caused by protein kinase D (PKD) plays a critical role in damaging chondrocytes and extracellular matrix (ECM) during osteoarthritis (OA). The PKD inhibitor (PKDi) (CRT0066101) has been used to overcome inflammation in different cell types. However, the efficacy of a therapeutic drug can be limited due to off-target distribution, slow cellular internalization, and limited lysosomal escape. In order to overcome this issue, we developed nanosomes carrying CRT0066101 (PKDi-Nano) and tested their efficacy in vitro in chondrocytes.Methods: Chondrocytes were subjected to IL-1β-induced inflammatory stress treated with either PKDi or PKDi-Nano. Effects of treatment were measured in terms of cytotoxicity, cellular morphology, viability, apoptosis, phosphorylation of protein kinase B (Akt), and anabolic/catabolic gene expression analyses related to cartilage tissue.Results and Discussion: The effects of PKDi-Nano treatment were more pronounced as compared to PKDi treatment. Cytotoxicity and apoptosis were significantly reduced following PKDi-Nano treatment (P < 0.001). Cellular morphology was also restored to normal size and shape. The viability of chondrocytes was significantly enhanced in PKDi-Nano-treated cells (P < 0.001). The data indicated that PKDi-Nano acted independently of the Akt pathway. Gene expression analyses revealed significant increases in the expression levels of anabolic genes with concomitant decreases in the level of catabolic genes. Our results indicate that PKDi-Nano attenuated the effects of IL-1β via the nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) pathway.Conclusion: Taken together, these results suggest that PKDi-Nano can be used as a successful strategy to reduce IL1β-induced inflammatory stress in chondrocytes.Keywords: CRT0066101, liposome, cartilage, osteoarthritis, cytokine
format	article
author	Cho H Bhatti FUR Hasty KA Yi AK
author_facet	Cho H Bhatti FUR Hasty KA Yi AK
author_sort	Cho H
title	Nanosome-Mediated Delivery Of Protein Kinase D Inhibitor Protects Chondrocytes From Interleukin-1β-Induced Stress And Apoptotic Death
title_short	Nanosome-Mediated Delivery Of Protein Kinase D Inhibitor Protects Chondrocytes From Interleukin-1β-Induced Stress And Apoptotic Death
title_full	Nanosome-Mediated Delivery Of Protein Kinase D Inhibitor Protects Chondrocytes From Interleukin-1β-Induced Stress And Apoptotic Death
title_fullStr	Nanosome-Mediated Delivery Of Protein Kinase D Inhibitor Protects Chondrocytes From Interleukin-1β-Induced Stress And Apoptotic Death
title_full_unstemmed	Nanosome-Mediated Delivery Of Protein Kinase D Inhibitor Protects Chondrocytes From Interleukin-1β-Induced Stress And Apoptotic Death
title_sort	nanosome-mediated delivery of protein kinase d inhibitor protects chondrocytes from interleukin-1β-induced stress and apoptotic death
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/b5e0c19bb6ea42e094615bf98bc2ec69
work_keys_str_mv	AT choh nanosomemediateddeliveryofproteinkinasedinhibitorprotectschondrocytesfrominterleukin1binducedstressandapoptoticdeath AT bhattifur nanosomemediateddeliveryofproteinkinasedinhibitorprotectschondrocytesfrominterleukin1binducedstressandapoptoticdeath AT hastyka nanosomemediateddeliveryofproteinkinasedinhibitorprotectschondrocytesfrominterleukin1binducedstressandapoptoticdeath AT yiak nanosomemediateddeliveryofproteinkinasedinhibitorprotectschondrocytesfrominterleukin1binducedstressandapoptoticdeath
_version_	1718399895752146944

Nanosome-Mediated Delivery Of Protein Kinase D Inhibitor Protects Chondrocytes From Interleukin-1β-Induced Stress And Apoptotic Death

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