NF-κB activation impedes the transdifferentiation of hypertrophic chondrocytes at the growth plate of mouse embryos in diabetic pregnancy

Background: Diabetes mellitus could cause numerous complications and health problems including abnormality of endochondral bone formation during embryogenesis. However, the underlying mechanisms still remain obscure. Methods: Streptozotoci (STZ) was injected to induce pregestational diabetes mellitu...

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Autores principales:	Xi Liu, Fan Qian, Qiwei Fan, Li Lin, Meiyao He, Peizhi Li, Hongmei Cai, Lisha Ma, Xin Cheng, Xuesong Yang
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Diabetes mellitus Endochondral bone formation Growth plate Hypertrophic zone NF-ĸB signaling bone morphogenetic protein 2, Bmp2 Diseases of the musculoskeletal system RC925-935
Acceso en línea:	https://doaj.org/article/c6d424e094e0452ebf705f048e3b92c7
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spelling	oai:doaj.org-article:c6d424e094e0452ebf705f048e3b92c72021-12-04T04:34:14ZNF-κB activation impedes the transdifferentiation of hypertrophic chondrocytes at the growth plate of mouse embryos in diabetic pregnancy2214-031X10.1016/j.jot.2021.10.009https://doaj.org/article/c6d424e094e0452ebf705f048e3b92c72021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2214031X21000929https://doaj.org/toc/2214-031XBackground: Diabetes mellitus could cause numerous complications and health problems including abnormality of endochondral bone formation during embryogenesis. However, the underlying mechanisms still remain obscure. Methods: Streptozotoci (STZ) was injected to induce pregestational diabetes mellitus (PGDM) mouse model. The femurs of E18.5 mouse embryos from control and PGDM groups were harvested. Morphological staining was implemented to determine the abnormality of the bone development. The expressions of the key genes participating in osteogenesis (e.g., Sox9, Runx2, and Osterix), the NF-κB signaling molecules (e.g., P50, P65, IκBα), and the corresponding regulatory factors (e.g., Bmp2, phospho-p38) were evaluated by immunofluorescence, quantitative PCR and western blot. Finally, in vitro chondrocyte differentiation model was employed to verify the role of NF-κB on the expressions of chondro-osteogenic markers. Results: Alcian blue/alizarin red double staining and H&E staining demonstrated the restriction of skeletal development and relatively extended hypertrophic zone at growth plate in E18.5 STZ-induced diabetic mouse embryos compared to the control. Immunofluorescent staining and qPCR showed that Sox9 expression increased, while Runx2 and Osterix expressions decreased in the growth plate of the offspring of PGDM mice. Immunofluorescence of P65 manifested the activation of NF-κB signaling in growth plate in PGDM mouse embryos. Furthermore, the relatively extended hypertrophic zone was also observed in the growth plate of the NF-κB-activated transgenic mice, as well as the activated p65 up-regulated the expression of Bmp2 and p-p38. In ATDC5 cells, we could observe the high glucose up-regulated the P50 and P65 expressions and down-regulated IκBα expression, but the high glucose-activated NF-κB signaling could be reversed by addition of Bay (inhibitor of NF-κB signaling). The expression changes of Bmp2, Sox9 and Runx2 in presence of high glucose were resumed too. Conclusion: Our data revealed that NF-κB signaling was involved in mediation effects of dysfunctional trans-differentiation of hypertrophic chondrocytes in the embryonic growth plate induced by maternal diabetic mellitus.Xi LiuFan QianQiwei FanLi LinMeiyao HePeizhi LiHongmei CaiLisha MaXin ChengXuesong YangElsevierarticleDiabetes mellitusEndochondral bone formationGrowth plateHypertrophic zoneNF-ĸB signalingbone morphogenetic protein 2, Bmp2Diseases of the musculoskeletal systemRC925-935ENJournal of Orthopaedic Translation, Vol 31, Iss , Pp 52-61 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Diabetes mellitus Endochondral bone formation Growth plate Hypertrophic zone NF-ĸB signaling bone morphogenetic protein 2, Bmp2 Diseases of the musculoskeletal system RC925-935
spellingShingle	Diabetes mellitus Endochondral bone formation Growth plate Hypertrophic zone NF-ĸB signaling bone morphogenetic protein 2, Bmp2 Diseases of the musculoskeletal system RC925-935 Xi Liu Fan Qian Qiwei Fan Li Lin Meiyao He Peizhi Li Hongmei Cai Lisha Ma Xin Cheng Xuesong Yang NF-κB activation impedes the transdifferentiation of hypertrophic chondrocytes at the growth plate of mouse embryos in diabetic pregnancy
description	Background: Diabetes mellitus could cause numerous complications and health problems including abnormality of endochondral bone formation during embryogenesis. However, the underlying mechanisms still remain obscure. Methods: Streptozotoci (STZ) was injected to induce pregestational diabetes mellitus (PGDM) mouse model. The femurs of E18.5 mouse embryos from control and PGDM groups were harvested. Morphological staining was implemented to determine the abnormality of the bone development. The expressions of the key genes participating in osteogenesis (e.g., Sox9, Runx2, and Osterix), the NF-κB signaling molecules (e.g., P50, P65, IκBα), and the corresponding regulatory factors (e.g., Bmp2, phospho-p38) were evaluated by immunofluorescence, quantitative PCR and western blot. Finally, in vitro chondrocyte differentiation model was employed to verify the role of NF-κB on the expressions of chondro-osteogenic markers. Results: Alcian blue/alizarin red double staining and H&E staining demonstrated the restriction of skeletal development and relatively extended hypertrophic zone at growth plate in E18.5 STZ-induced diabetic mouse embryos compared to the control. Immunofluorescent staining and qPCR showed that Sox9 expression increased, while Runx2 and Osterix expressions decreased in the growth plate of the offspring of PGDM mice. Immunofluorescence of P65 manifested the activation of NF-κB signaling in growth plate in PGDM mouse embryos. Furthermore, the relatively extended hypertrophic zone was also observed in the growth plate of the NF-κB-activated transgenic mice, as well as the activated p65 up-regulated the expression of Bmp2 and p-p38. In ATDC5 cells, we could observe the high glucose up-regulated the P50 and P65 expressions and down-regulated IκBα expression, but the high glucose-activated NF-κB signaling could be reversed by addition of Bay (inhibitor of NF-κB signaling). The expression changes of Bmp2, Sox9 and Runx2 in presence of high glucose were resumed too. Conclusion: Our data revealed that NF-κB signaling was involved in mediation effects of dysfunctional trans-differentiation of hypertrophic chondrocytes in the embryonic growth plate induced by maternal diabetic mellitus.
format	article
author	Xi Liu Fan Qian Qiwei Fan Li Lin Meiyao He Peizhi Li Hongmei Cai Lisha Ma Xin Cheng Xuesong Yang
author_facet	Xi Liu Fan Qian Qiwei Fan Li Lin Meiyao He Peizhi Li Hongmei Cai Lisha Ma Xin Cheng Xuesong Yang
author_sort	Xi Liu
title	NF-κB activation impedes the transdifferentiation of hypertrophic chondrocytes at the growth plate of mouse embryos in diabetic pregnancy
title_short	NF-κB activation impedes the transdifferentiation of hypertrophic chondrocytes at the growth plate of mouse embryos in diabetic pregnancy
title_full	NF-κB activation impedes the transdifferentiation of hypertrophic chondrocytes at the growth plate of mouse embryos in diabetic pregnancy
title_fullStr	NF-κB activation impedes the transdifferentiation of hypertrophic chondrocytes at the growth plate of mouse embryos in diabetic pregnancy
title_full_unstemmed	NF-κB activation impedes the transdifferentiation of hypertrophic chondrocytes at the growth plate of mouse embryos in diabetic pregnancy
title_sort	nf-κb activation impedes the transdifferentiation of hypertrophic chondrocytes at the growth plate of mouse embryos in diabetic pregnancy
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/c6d424e094e0452ebf705f048e3b92c7
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NF-κB activation impedes the transdifferentiation of hypertrophic chondrocytes at the growth plate of mouse embryos in diabetic pregnancy

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