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Neurotrophin-3 acts on the endothelial-mesenchymal transition of heterotopic ossification in rats.
J Cell Mol Med. 2019 04; 23(4):2595-2609.JC

Abstract

Despite the fact that extensive studies have focused on heterotopic ossification (HO), its molecular mechanism remains unclear. The endothelial-mesenchymal transition (EndMT), which may be partially modulated by neuroendocrine cytokines is thought to play a major role in HO. Neurotrophin-3 (NT-3), which has neuroendocrine characteristics is believed to promote skeletal remodeling. Herein, we suggest that that NT-3 may promote HO formation through regulation of EndMT. Here, we used an in vivo model of HO and an in vitro model of EndMT induction to elucidate the effect and underlying mechanism of NT-3 on EndMT in HO. Our results showed that heterotopic bone and cartilage arose from EndMT and NT-3 promoted HO formation in vivo. Our in vitro results showed that NT-3 up-regulated mesenchymal markers (FSP-1, α-SMA and N-cadherin) and mesenchymal stem cell (MSC) markers (STRO-1, CD44 and CD90) and down-regulated endothelial markers (Tie-1, VE-cadherin and CD31). Moreover, NT-3 enhanced a chondrogenesis marker (Sox9) and osteogenesis markers (OCN and Runx2) via activation of EndMT. However, both EndMT specific inhibitor and tropomyosin-related kinase C (TrkC) specific inhibitor rescued NT-3-induced HO formation and EndMT induction in vivo and in vitro. In conclusion, our findings demonstrate that NT-3 promotes HO formation via modulation of EndMT both in vivo and in vitro, which offers a new potential target for the prevention and therapy of HO.

Authors+Show Affiliations

Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, PR China. Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China.Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, PR China. Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China.Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, PR China. Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China.Department of Plastic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, PR China.Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, PR China. Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China.Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, PR China. Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China.Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, PR China. Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China.Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, PR China. Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China.Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, PR China. Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China.Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, PR China. Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong, PR China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30672120

Citation

Zhang, Jie, et al. "Neurotrophin-3 Acts On the Endothelial-mesenchymal Transition of Heterotopic Ossification in Rats." Journal of Cellular and Molecular Medicine, vol. 23, no. 4, 2019, pp. 2595-2609.
Zhang J, Wang L, Cao H, et al. Neurotrophin-3 acts on the endothelial-mesenchymal transition of heterotopic ossification in rats. J Cell Mol Med. 2019;23(4):2595-2609.
Zhang, J., Wang, L., Cao, H., Chen, N., Yan, B., Ao, X., Zhao, H., Chu, J., Huang, M., & Zhang, Z. (2019). Neurotrophin-3 acts on the endothelial-mesenchymal transition of heterotopic ossification in rats. Journal of Cellular and Molecular Medicine, 23(4), 2595-2609. https://doi.org/10.1111/jcmm.14150
Zhang J, et al. Neurotrophin-3 Acts On the Endothelial-mesenchymal Transition of Heterotopic Ossification in Rats. J Cell Mol Med. 2019;23(4):2595-2609. PubMed PMID: 30672120.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neurotrophin-3 acts on the endothelial-mesenchymal transition of heterotopic ossification in rats. AU - Zhang,Jie, AU - Wang,Liang, AU - Cao,He, AU - Chen,Nan, AU - Yan,Bin, AU - Ao,Xiang, AU - Zhao,Huiyu, AU - Chu,Jun, AU - Huang,Minjun, AU - Zhang,Zhongmin, Y1 - 2019/01/22/ PY - 2018/06/07/received PY - 2018/12/13/revised PY - 2018/12/20/accepted PY - 2019/1/24/pubmed PY - 2020/7/16/medline PY - 2019/1/24/entrez KW - EndMT KW - heterotopic ossification KW - neuroendocrine KW - neurotrophin-3 SP - 2595 EP - 2609 JF - Journal of cellular and molecular medicine JO - J Cell Mol Med VL - 23 IS - 4 N2 - Despite the fact that extensive studies have focused on heterotopic ossification (HO), its molecular mechanism remains unclear. The endothelial-mesenchymal transition (EndMT), which may be partially modulated by neuroendocrine cytokines is thought to play a major role in HO. Neurotrophin-3 (NT-3), which has neuroendocrine characteristics is believed to promote skeletal remodeling. Herein, we suggest that that NT-3 may promote HO formation through regulation of EndMT. Here, we used an in vivo model of HO and an in vitro model of EndMT induction to elucidate the effect and underlying mechanism of NT-3 on EndMT in HO. Our results showed that heterotopic bone and cartilage arose from EndMT and NT-3 promoted HO formation in vivo. Our in vitro results showed that NT-3 up-regulated mesenchymal markers (FSP-1, α-SMA and N-cadherin) and mesenchymal stem cell (MSC) markers (STRO-1, CD44 and CD90) and down-regulated endothelial markers (Tie-1, VE-cadherin and CD31). Moreover, NT-3 enhanced a chondrogenesis marker (Sox9) and osteogenesis markers (OCN and Runx2) via activation of EndMT. However, both EndMT specific inhibitor and tropomyosin-related kinase C (TrkC) specific inhibitor rescued NT-3-induced HO formation and EndMT induction in vivo and in vitro. In conclusion, our findings demonstrate that NT-3 promotes HO formation via modulation of EndMT both in vivo and in vitro, which offers a new potential target for the prevention and therapy of HO. SN - 1582-4934 UR - https://www.unboundmedicine.com/medline/citation/30672120/Neurotrophin_3_acts_on_the_endothelial_mesenchymal_transition_of_heterotopic_ossification_in_rats_ L2 - https://doi.org/10.1111/jcmm.14150 DB - PRIME DP - Unbound Medicine ER -