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Neurotrophin-3 acts on the endothelial-mesenchymal transition of heterotopic ossification in rats.

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, ?-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.

SUBMITTER: Zhang J

PROVIDER: S-EPMC6433730 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Neurotrophin-3 acts on the endothelial-mesenchymal transition of heterotopic ossification in rats.

Zhang Jie J Wang Liang L Cao He H Chen Nan N Yan Bin B Ao Xiang X Zhao Huiyu H Chu Jun J Huang Minjun M Zhang Zhongmin Z

Journal of cellular and molecular medicine 20190122 4

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 mod ...[more]

PMID: 30672120

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Project description:Heterotopic Ossification (HO) is a potential long-term complication in orthopaedic surgery. It is commonly classified according to the Brooker classification, which is based on radiological findings. To our knowledge the correlation of histological features to the Brooker grade is unknown as is the association between HO and the indication for revision. The aim of this paper is to analyze the ossification grade of HO tissue in patients undergoing revision hip and knee arthroplasty and to propose a histologically based classification system for HO. We also assess the relationship between the grade of HO and the indication for revision (septic and aseptic revision). From January to May 2019 we collected 50 human HO samples from hip and knee revision arthroplasty cases. These tissue samples were double-blinded and sent for histopathological diagnostic. Based on these results, we developed a classification system for the progression of HO. The grade of ossification was based on three characteristics: Grade of heterotopic ossification (Grade 1-3), presence of necrosis (N0 or N1) and the presence of osteomyelitis (HOES-Score Type 1 to 5). Demographic data as well as surgical details and indication for surgery was prospectively collected from clinical records. Fifty tissue samples were harvested from 44 hips and 6 knee joints. Of these 33 exhibited Grade I ossifications (66%), followed by 11 Grade II (22%) and one Grade III (2%). Necrosis was noted in two tissue samples (4%) and 2 more had osteomyelitis findings according to HOES-Score. Six samples (12%) with radiologically suggestive of HO turned out to be wear-induced synovitis, SLIM Type 1. Of these cases 16 were septic (32%) and 34 aseptic (68%) revisions. Most of the HO tissue samples were classified as a low-grade. High-grade ossification-Score is rare. Higher grades of ossification seem to be associated with septic revision cases. Wear-induced synovitis potentially influences HO development. A histological scoring system for ossification grading can be derived from the data presented in this study.

Dataset Information

Neurotrophin-3 acts on the endothelial-mesenchymal transition of heterotopic ossification in rats.

Publications

Neurotrophin-3 acts on the endothelial-mesenchymal transition of heterotopic ossification in rats.

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