Publications by authors named "Shuangfei Ni"

30 Publications

  • Page 1 of 1

Associations of Copper Intake with Bone Mineral Density and Osteoporosis in Adults: Data from the National Health and Nutrition Examination Survey.

Biol Trace Elem Res 2021 Jul 20. Epub 2021 Jul 20.

Department of Orthopaedic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People's Republic of China.

Some studies have suggested an association between serum copper and bone density. Few studies have explored the association between copper intake and osteoporosis and bone mineral density (BMD). Our research aims to assess the associations of copper intake with the risk of osteoporosis in United States adults using the National Health and Nutritional Examination Surveys (NHANES). A total of 8224 individuals were included in our study. Osteoporosis was defined that BMD values surpass 2.5 standard deviations (SD) below the mean of the young adult reference group. Copper intake from diets and supplements was estimated by using two 24-h recall surveys. After adjustment for all the covariates of interest, the odds ratios (ORs) (95% confidence interval (CI)) between the risk of osteoporosis and total copper intake across quartiles 3 and 4 compared with quartile 1 were 0.48 (0.31-0.74) (P < 0.01) and 0.41 (0.26-0.65) (P < 0.01), respectively. The mean total femur BMD and total spine BMD of the highest dietary copper intake quartile (Cu 1.51 mg/d) was 0.03 g/cm and 0.02 g/cm greater than the lowest quartile. Our results indicate that dietary and total copper intake was positively associated with increasing BMD in US adults and negatively associated with the risk of osteoporosis in US adults.
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http://dx.doi.org/10.1007/s12011-021-02845-5DOI Listing
July 2021

EZH2 Mediates miR-146a-5p/HIF-1 to Alleviate Inflammation and Glycolysis after Acute Spinal Cord Injury.

Mediators Inflamm 2021 19;2021:5591582. Epub 2021 May 19.

Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, Henan Province, China.

Acute spinal cord injury (ASCI) is a severe traumatic disease of the central nervous system, the underlying mechanism of which is unclear. This study was intended to study the role of EZH2 and miR-146a-5p/HIF-1 in inflammation and glycolysis after ASCI, providing reference and basis for the clinical treatment and prognosis of ASCI injury. We used lipopolysaccharide (LPS) to induce inflammation of microglia, and we constructed the ASCI animal model. qRT-PCR detected the relative expression levels of EZH2, HIF-1, miR-146a-5p, IL-6, TNF-, IL-17, PKM2, GLUT1, and HK2 in cells and tissues. Western blot was performed to detect the expression levels of EZH2, HIF-1, H3K27me3, IL-6, TNF-, IL-17, PKM2, GLUT1, and HK2. ChIP verified the enrichment of H3K27me3 in the miR-146a-5p promoter region. Bioinformatics predicted the binding sites of HIF-1 and miR-146a-5p, and dual-luciferase reporter assay verified the binding of HIF-1 and miR-146a-5p. ELISA detects the levels of inflammatory factors IL-6, TNF-, and IL-17 in the cerebrospinal fluid of rats. The GC-TOFMS was used to detect the changes of glycolytic metabolites in the cerebrospinal fluid of rats. EZH2 could mediate inflammation and glycolysis of microglia. EZH2 regulates inflammation and glycolysis through HIF-1. EZH2 indirectly regulated the HIF-1 expression by mediating miR-146a-5p. EZH2 mediates miR-146a-5p/HIF-1 to alleviate inflammation and glycolysis in ASCI rats. In the present study, our results demonstrated that EZH2 could mediate miR-146a-5p/HIF-1 to alleviate the inflammation and glycolysis after ASCI. Therefore, EZH2/miR-146a-5p/HIF-1 might be a novel potential target for treating ASCI.
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http://dx.doi.org/10.1155/2021/5591582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159642PMC
May 2021

Resveratrol-enhanced SIRT1-mediated osteogenesis in porous endplates attenuates low back pain and anxiety behaviors.

FASEB J 2021 03;35(3):e21414

Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Low back pain (LBP) is a major clinical problem that lacks effective treatments. The sensory innervation in porous vertebral endplates and anxiety contributes to spinal hyperalgesia. We hypothesized that SIRT1 activator resveratrol alleviates LBP and anxiety via promotion of osteogenesis in the porous endplates. The hyperalgesia and anxiety-related behaviors; sensory innervation, inflammation and porosity of endplates; and osteogenic/osteoclastic factors expression were measured following resveratrol treatment after lumbar spine instability (LSI) surgery. To explore whether resveratrol promotes endplates osteogenesis and thus alleviates LBP through activation of SIRT1 in the osteoprogenitor cells of endplates, SIRT1 mice were employed. Additionally, the levels of inflammation markers, phosphorylation of cAMP response element-binding protein (pCREB), and brain-derived neurotrophic factor (BDNF) in hippocampus were evaluated. After 4 or 8 weeks LSI surgery, the mice suffered from hyperalgesia and anxiety, which were efficiently attenuated by resveratrol at 8 weeks. Resveratrol treatment-enhanced osteogenesis and decreased endplates porosities accompanied with the reduction of TNFα, IL-1β, and COX2 levels and CGRP+ nerve fibers innervation in porous endplates. Resveratrol-mediated endplates osteogenesis, decreased endplates porosities, and analgesic and antianxiety effects were abrogated in SIRT1 mice. Furthermore, resveratrol relieved inflammation and increased pCREB and BDNF expression in the hippocampus after 8 weeks, which alleviate anxiety-related behaviors. This study provides that resveratrol-mediated porous endplates osteogenesis via the activation of SIRT1 markedly blocked sensory innervation and inflammation in endplates, therefore, alleviating LSI surgery-induced LBP and hippocampus-related anxiety.
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http://dx.doi.org/10.1096/fj.202002524RDOI Listing
March 2021

Resveratrol-enhanced SIRT1-mediated osteogenesis in porous endplates attenuates low back pain and anxiety behaviors.

FASEB J 2021 03;35(3):e21414

Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Low back pain (LBP) is a major clinical problem that lacks effective treatments. The sensory innervation in porous vertebral endplates and anxiety contributes to spinal hyperalgesia. We hypothesized that SIRT1 activator resveratrol alleviates LBP and anxiety via promotion of osteogenesis in the porous endplates. The hyperalgesia and anxiety-related behaviors; sensory innervation, inflammation and porosity of endplates; and osteogenic/osteoclastic factors expression were measured following resveratrol treatment after lumbar spine instability (LSI) surgery. To explore whether resveratrol promotes endplates osteogenesis and thus alleviates LBP through activation of SIRT1 in the osteoprogenitor cells of endplates, SIRT1 mice were employed. Additionally, the levels of inflammation markers, phosphorylation of cAMP response element-binding protein (pCREB), and brain-derived neurotrophic factor (BDNF) in hippocampus were evaluated. After 4 or 8 weeks LSI surgery, the mice suffered from hyperalgesia and anxiety, which were efficiently attenuated by resveratrol at 8 weeks. Resveratrol treatment-enhanced osteogenesis and decreased endplates porosities accompanied with the reduction of TNFα, IL-1β, and COX2 levels and CGRP+ nerve fibers innervation in porous endplates. Resveratrol-mediated endplates osteogenesis, decreased endplates porosities, and analgesic and antianxiety effects were abrogated in SIRT1 mice. Furthermore, resveratrol relieved inflammation and increased pCREB and BDNF expression in the hippocampus after 8 weeks, which alleviate anxiety-related behaviors. This study provides that resveratrol-mediated porous endplates osteogenesis via the activation of SIRT1 markedly blocked sensory innervation and inflammation in endplates, therefore, alleviating LSI surgery-induced LBP and hippocampus-related anxiety.
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http://dx.doi.org/10.1096/fj.202002524RDOI Listing
March 2021

A combinatorial method to visualize the neuronal network in the mouse spinal cord: combination of a modified Golgi-Cox method and synchrotron radiation micro-computed tomography.

Histochem Cell Biol 2021 Apr 4;155(4):477-489. Epub 2021 Jan 4.

Department of Spine Surgery, Xiangya Hospital, Central South University, Xiangya Road No. 87, Changsha, 410008, Hunan, People's Republic of China.

Exploring the three-dimensional (3D) morphology of neurons is essential to understanding spinal cord function and associated diseases comprehensively. However, 3D imaging of the neuronal network in the broad region of the spinal cord at cellular resolution remains a challenge in the field of neuroscience. In this study, to obtain high-resolution 3D imaging of a detailed neuronal network in the mass of the spinal cord, the combination of synchrotron radiation micro-computed tomography (SRμCT) and the Golgi-cox staining were used. We optimized the Golgi-Cox method (GCM) and developed a modified GCM (M-GCM), which improved background staining, reduced the number of artefacts, and diminished the impact of incomplete vasculature compared to the current GCM. Moreover, we achieved high-resolution 3D imaging of the detailed neuronal network in the spinal cord through the combination of SRμCT and M-GCM. Our results showed that the M-GCM increased the contrast between the neuronal structure and its surrounding extracellular matrix. Compared to the GCM, the M-GCM also diminished the impact of the artefacts and incomplete vasculature on the 3D image. Additionally, the 3D neuronal architecture was successfully quantified using a combination of SRμCT and M-GCM. The SRμCT was shown to be a valuable non-destructive tool for 3D visualization of the neuronal network in the broad 3D region of the spinal cord. Such a combinatorial method will, therefore, transform the presentation of Golgi staining from 2 to 3D, providing significant improvements in the 3D rendering of the neuronal network.
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http://dx.doi.org/10.1007/s00418-020-01949-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062354PMC
April 2021

Silencing SGK1 alleviates osteoarthritis through epigenetic regulation of CREB1 and ABCA1 expression.

Life Sci 2021 Mar 7;268:118733. Epub 2020 Nov 7.

Department of Orthopaedics, the First Affiliated Hospital of Zhengzhou University, No. 1, Eastern Jianshe Road, Zhengzhou 450000, Henan Province, PR China. Electronic address:

Aim: Osteoarthritis (OA) is the most common joint disorder and a leading cause of disability. While early proactive management is crucial in alleviating symptoms in OA patients, currently available therapeutic approaches are yet to achieve an ideal level of efficacy. The path to the development of a potent treatment begins with the thorough understanding of the pathophysiology of OA. The present study aims to explore the mechanism by which SGK1 is involved in OA progression.

Methods: Firstly, the potential target gene of SGK1 was screened and SGK1 expression was determined in OA through bioinformatics analysis. Mouse OA model was then established and chondrocytes were extracted, after which inflammation was induced with lipopolysaccharide (LPS). Following LPS treatment, the chondrocytes were transfected with synthesized plasmids to explore the impact of SGK1, CREB1, and ABCA1 on apoptosis, proliferation and inflammation in OA. ChIP-PCR and dual-luciferase reporter gene assay were conducted to determine the binding relation between SGK1 and CREB1 as well as between CREB1 and ABCA1.

Results: OA mice presented with high expression of SGK1. Interestingly, we found that SGK1 inhibited CREB1 expression in chondrocytes, thereby inducing inflammation and suppressing chondrocyte proliferation. CREB1 was found to have a positive correlation with ABCA1 expression, while down-regulation of CREB1 resulted in the inhibition of cell proliferation and aggravated inflammation, which could be reversed by overexpressed ABCA1.

Conclusion: Taken altogether, silencing of SGK1 alleviated OA through epigenetic regulation of CREB1 and ABCA1 expression. These findings may provide novel insight into SGK1-based strategy for OA treatment.
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http://dx.doi.org/10.1016/j.lfs.2020.118733DOI Listing
March 2021

SRμCT Reveals 3D Microstructural Alterations of the Vascular and Neuronal Network in a Rat Model of Chronic Compressive Thoracic Spinal Cord Injury.

Aging Dis 2020 May 9;11(3):603-617. Epub 2020 May 9.

1Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha, China.

The complex pathology of chronic thoracic spinal cord compression involves vascular and neuroarchitectural repair processes that are still largely unknown. In this study, we used synchrotron radiation microtomography (SRμCT) to quantitatively characterize the 3D temporal-spatial changes in the vascular and neuronal network after chronic thoracic spinal cord compression in order to obtain further insights into the pathogenesis of this disease and to elucidate its underlying mechanisms. Direct 3D characterization of the spinal cord microvasculature and neural microstructure of the thoracic spinal cord was successfully reconstructed. The significant reduction in vasculature and degeneration of neurons in the thoracic spinal cord visualized via SRμCT after chronic compression were consistent with the changes detected by immunofluorescence staining. The 3D morphological measurements revealed significant reductions of neurovascular parameters in the thoracic spinal cord after 1 month of compression and became even worse after 6 months without relief of compression. In addition, the distinct 3D morphological twist and the decrease in branches of the central sulcal artery after chronic compression vividly displayed that these could be the potential triggers leading to blood flow reduction and neural deficits of the thoracic spinal cord. Our findings propose a novel methodology for the 3D analysis of neurovascular repair in chronic spinal cord compression, both qualitatively and quantitatively. The results indicated that compression simultaneously caused vascular dysfunction and neuronal network impairment, which should be acknowledged as concurrent events after chronic thoracic spinal cord injury. Combining neuroprotection with vasoprotection may provide promising therapeutic targets for chronic thoracic spinal cord compression.
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http://dx.doi.org/10.14336/AD.2019.0529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220295PMC
May 2020

Sensory nerves regulate mesenchymal stromal cell lineage commitment by tuning sympathetic tones.

J Clin Invest 2020 07;130(7):3483-3498

Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, Maryland, USA.

The sensory nerve was recently identified as being involved in regulation of bone mass accrual. We previously discovered that prostaglandin E2 (PGE2) secreted by osteoblasts could activate sensory nerve EP4 receptor to promote bone formation by inhibiting sympathetic activity. However, the fundamental units of bone formation are active osteoblasts, which originate from mesenchymal stromal/stem cells (MSCs). Here, we found that after sensory denervation, knockout of the EP4 receptor in sensory nerves, or knockout of COX-2 in osteoblasts, could significantly promote adipogenesis and inhibit osteogenesis in adult mice. Furthermore, injection of SW033291 (a small molecule that locally increases the PGE2 level) or propranolol (a beta blocker) significantly promoted osteogenesis and inhibited adipogenesis. This effect of SW033291, but not propranolol, was abolished in conditional EP4-KO mice under normal conditions or in the bone repair process. We conclude that the PGE2/EP4 sensory nerve axis could regulate MSC differentiation in bone marrow of adult mice.
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http://dx.doi.org/10.1172/JCI131554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324175PMC
July 2020

Author Correction: Sensory innervation in porous endplates by Netrin-1 from osteoclasts mediates PGE2-induced spinal hypersensitivity in mice.

Nat Commun 2020 Jan 6;11(1):149. Epub 2020 Jan 6.

Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-019-13970-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944687PMC
January 2020

Sensory innervation in porous endplates by Netrin-1 from osteoclasts mediates PGE2-induced spinal hypersensitivity in mice.

Nat Commun 2019 12 10;10(1):5643. Epub 2019 Dec 10.

Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

Spinal pain is a major clinical problem, however, its origins and underlying mechanisms remain unclear. Here we report that in mice, osteoclasts induce sensory innervation in the porous endplates which contributes to spinal hypersensitivity in mice. Sensory innervation of the porous areas of sclerotic endplates in mice was confirmed. Lumbar spine instability (LSI), or aging, induces spinal hypersensitivity in mice. In these conditions, we show that there are elevated levels of PGE2 which activate sensory nerves, leading to sodium influx through Na 1.8 channels. We show that knockout of PGE2 receptor 4 in sensory nerves significantly reduces spinal hypersensitivity. Inhibition of osteoclast formation by knockout Rankl in the osteocytes significantly inhibits LSI-induced porosity of endplates, sensory innervation, and spinal hypersensitivity. Knockout of Netrin-1 in osteoclasts abrogates sensory innervation into porous endplates and spinal hypersensitivity. These findings suggest that osteoclast-initiated porosity of endplates and sensory innervation are potential therapeutic targets for spinal pain.
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http://dx.doi.org/10.1038/s41467-019-13476-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904550PMC
December 2019

UTX/KDM6A Deletion Promotes Recovery of Spinal Cord Injury by Epigenetically Regulating Vascular Regeneration.

Mol Ther 2019 12 22;27(12):2134-2146. Epub 2019 Aug 22.

Department of Spine Surgery, Xiangya Hospital, Central South University, 410008 Changsha, China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, 410008 Changsha, China; Research Centre of Sports Medicine, Xiangya Hospital, Central South University, 410008 Changsha, China. Electronic address:

The regeneration of the blood vessel system post spinal cord injury (SCI) is essential for the repair of neurological function. As a significant means to regulate gene expression, epigenetic regulation of angiogenesis in SCI is still largely unknown. Here, we found that Ubiquitously Transcribed tetratricopeptide repeat on chromosome X (UTX), the histone H3K27 demethylase, increased significantly in endothelial cells post SCI. Knockdown of UTX can promote the migration and tube formation of endothelial cells. The specific knockout of UTX in endothelial cells enhanced angiogenesis post SCI accompanied with improved neurological function. In addition, we found regulation of UTX expression can change the level of microRNA 24 (miR-24) in vitro. The physical binding of UTX to the promotor of miR-24 was indicated by chromatin immunoprecipitation (ChIP) assay. Meanwhile, methylation sequencing of endothelial cells demonstrated that UTX could significantly decrease the level of methylation in the miR-24 promotor. Furthermore, miR-24 significantly abolished the promoting effect of UTX deletion on angiogenesis in vitro and in vivo. Finally, we predicted the potential target mRNAs of miR-24 related to angiogenesis. We indicate that UTX deletion can epigenetically promote the vascular regeneration and functional recovery post SCI by forming a regulatory network with miR-24.
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http://dx.doi.org/10.1016/j.ymthe.2019.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904668PMC
December 2019

Synchrotron radiation micro-tomography for high-resolution neurovascular network morphology investigation.

J Synchrotron Radiat 2019 May 15;26(Pt 3):607-618. Epub 2019 Apr 15.

Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China.

There has been increasing interest in using high-resolution micro-tomography to investigate the morphology of neurovascular networks in the central nervous system, which remain difficult to characterize due to their microscopic size as well as their delicate and complex 3D structure. Synchrotron radiation X-ray imaging, which has emerged as a cutting-edge imaging technology with a high spatial resolution, provides a novel platform for the non-destructive imaging of microvasculature networks at a sub-micrometre scale. When coupled with computed tomography, this technique allows the characterization of the 3D morphology of vasculature. The current review focuses on recent progress in developing synchrotron radiation methodology and its application in probing neurovascular networks, especially the pathological changes associated with vascular abnormalities in various model systems. Furthermore, this tool represents a powerful imaging modality that improves our understanding of the complex biological interactions between vascular function and neuronal activity in both physiological and pathological states.
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http://dx.doi.org/10.1107/S1600577519003060DOI Listing
May 2019

Macrophage-lineage TRAP+ cells recruit periosteum-derived cells for periosteal osteogenesis and regeneration.

J Clin Invest 2019 04 4;129(6):2578-2594. Epub 2019 Apr 4.

Department of Orthopaedic Surgery, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

The periosteum, a thin tissue that covers almost the entire bone surface, accounts for more than 80% of human bone mass and is essential for bone regeneration. Its osteogenic and bone regenerative abilities are well studied, but much is unknown about the periosteum. In this study, we found that macrophage-lineage cells recruit periosteum-derived cells (PDCs) for cortical bone formation. Knockout of colony stimulating factor-1 eliminated macrophage-lineage cells and resulted in loss of PDCs with impaired periosteal bone formation. Moreover, macrophage-lineage TRAP+ cells induced transcriptional expression of periostin and recruitment of PDCs to the periosteal surface through secretion of platelet-derived growth factor-BB (PDGF-BB), where the recruited PDCs underwent osteoblast differentiation coupled with type H vessel formation. We also found that subsets of Nestin+ and LepR+ PDCs possess multipotent and self-renewal abilities and contribute to cortical bone formation. Nestin+ PDCs are found primarily during bone development, whereas LepR+ PDCs are essential for bone homeostasis in adult mice. Importantly, conditional knockout of Pdgfrβ (platelet-derived growth factor receptor beta) in LepR+ cells impaired periosteal bone formation and regeneration. These findings uncover the essential role of periosteal macrophage-lineage cells in regulating periosteum homeostasis and regeneration.
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http://dx.doi.org/10.1172/JCI98857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538344PMC
April 2019

Unilateral Osteotomy of Lumbar Facet Joint Induces a Mouse Model of Lumbar Facet Joint Osteoarthritis.

Spine (Phila Pa 1976) 2019 Aug;44(16):E930-E938

Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha, People's Republic of China.

Study Design: The lumbar facet joint (LFJ) osteoarthritis (OA) model that highly mimics the clinical conditions was established and evaluated.

Objective: Here, we innovatively constructed and evaluated the aberrant mechanical loading-related LFJ OA model.

Summary Of Background Data: LFJ is the only true synovial joint in a functional spinal unit in mammals. The LFJ osteoarthritis is considered to contribute 15% to 45% of low back pain. The establish of animal models highly mimicking the clinical conditions is a useful tool for the investigation of LFJ OA. However, the previously established animal models damaged the LFJ structure directly, which did not demonstrate the effect of aberrant mechanical loading on the development of LFJ osteoarthritis.

Methods: In the present study, an animal model for LFJ degeneration was established by the unilateral osteotomy of LFJ (OLFJ) in L4/5 unit to induce the spine instability. Then, the change of contralateral LFJ was evaluated by morphological and molecular biological techniques.

Results: We showed that the OLFJ induced instability accelerated the cartilage degeneration of the contralateral LFJ. Importantly, the SRμCT elucidated that the three-dimensional structure of the subchondral bone changed in contralateral LFJ, indicated as the abnormity of bone volume/total volume ratio (BV/TV), trabecular pattern factor (Tb. Pf), and the trabecular thickness (Tb. Th). Immunostaining further demonstrated the uncoupled osteoclastic bone resorption, and bone formation in the subchondral bone of contralateral LFJ, indicated as increased activity of osteoclast, osteoblast, and Type H vessels.

Conclusion: We develop a novel LFJ OA model demonstrating the effect of abnormal mechanical instability on the degeneration of LFJ. This LFJ degeneration model that highly mimics the clinical conditions is a valuable tool to investigate the LFJ osteoarthritis.

Level Of Evidence: N/A.
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http://dx.doi.org/10.1097/BRS.0000000000003023DOI Listing
August 2019

Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis.

Nat Commun 2019 01 14;10(1):181. Epub 2019 Jan 14.

Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD, 21205, USA.

Whether sensory nerve can sense bone density or metabolic activity to control bone homeostasis is unknown. Here we found prostaglandin E2 (PGE2) secreted by osteoblastic cells activates PGE2 receptor 4 (EP4) in sensory nerves to regulate bone formation by inhibiting sympathetic activity through the central nervous system. PGE2 secreted by osteoblasts increases when bone density decreases as demonstrated in osteoporotic animal models. Ablation of sensory nerves erodes the skeletal integrity. Specifically, knockout of the EP4 gene in the sensory nerves or cyclooxygenase-2 (COX2) in the osteoblastic cells significantly reduces bone volume in adult mice. Sympathetic tone is increased in sensory denervation models, and propranolol, a β2-adrenergic antagonist, rescues bone loss. Furthermore, injection of SW033291, a small molecule to increase PGE2 level locally, significantly boostes bone formation, whereas the effect is obstructed in EP4 knockout mice. Thus, we show that PGE2 mediates sensory nerve to control bone homeostasis and promote regeneration.
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http://dx.doi.org/10.1038/s41467-018-08097-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331599PMC
January 2019

Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain.

J Clin Invest 2019 03 4;129(3):1076-1093. Epub 2019 Feb 4.

Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Joint pain is the defining symptom of osteoarthritis (OA) but its origin and mechanisms remain unclear. Here, we investigated an unprecedented role of osteoclast-initiated subchondral bone remodeling in sensory innervation for OA pain. We show that osteoclasts secrete netrin-1 to induce sensory nerve axonal growth in subchondral bone. Reduction of osteoclast formation by knockout of receptor activator of nuclear factor kappa-B ligand (Rankl) in osteocytes inhibited the growth of sensory nerves into subchondral bone, dorsal root ganglion neuron hyperexcitability, and behavioral measures of pain hypersensitivity in OA mice. Moreover, we demonstrated a possible role for netrin-1 secreted by osteoclasts during aberrant subchondral bone remodeling in inducing sensory innervation and OA pain through its receptor DCC (deleted in colorectal cancer). Importantly, knockout of Netrin1 in tartrate-resistant acid phosphatase-positive (TRAP-positive) osteoclasts or knockdown of Dcc reduces OA pain behavior. In particular, inhibition of osteoclast activity by alendronate modifies aberrant subchondral bone remodeling and reduces innervation and pain behavior at the early stage of OA. These results suggest that intervention of the axonal guidance molecules (e.g., netrin-1) derived from aberrant subchondral bone remodeling may have therapeutic potential for OA pain.
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http://dx.doi.org/10.1172/JCI121561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391093PMC
March 2019

The protective effect of microRNA-21 in neurons after spinal cord injury.

Spinal Cord 2019 Feb 8;57(2):141-149. Epub 2018 Aug 8.

Department of Sports Medicine, Research Center of Sports Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.

Study Design: Experimental animal study.

Objectives: To validate the anti-apoptosis effect of microRNA-21 in neurons after spinal cord injury (SCI) and explore the mechanism.

Setting: Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.

Methods: In situ hybridization was used to detect the expression of miR-21 in spinal cord neurons (n = 24). In a rat contusion SCI model (n = 48), we upregulated the miR-21 level around the injured area using miR-21 lentiviral vectors and evaluated the therapeutic effect with histology and behavioural scores. In neuronal cells, oxygen-glucose deprivation (OGD) was exerted to imitate SCI, and we explored the biomechanism using molecular biology and a dual-luciferase reporter assay.

Results: miR-21 was expressed in spinal cord neurons and was found to improve neuronal survival and promote functional recovery in rat SCI models. The in vitro results in PC-12 cells revealed that the augmentation of endogenous miR-21 was able to reduce neuronal cell death after OGD. In addition, overexpression of miR-21 was able to reduce cellular apoptosis via decreasing PDCD4 protein levels, and caspase-3 activity was also influenced. Transfection of miR-21 into 293T cells was able to decrease luciferase activity in a reporter assay system, including the 3' untranslated region of PDCD4.

Conclusions: miR-21 may have a protective role in neuronal apoptosis after SCI. PDCD4 may be a functional target gene involved in the miR-21-mediated anti-apoptotic effect through an miR-21/PDCD4/caspase-3 pathway.
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http://dx.doi.org/10.1038/s41393-018-0180-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358587PMC
February 2019

Ciliary parathyroid hormone signaling activates transforming growth factor-β to maintain intervertebral disc homeostasis during aging.

Bone Res 2018 18;6:21. Epub 2018 Jul 18.

1Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Ross Building, Room 229, 720 Rutland Ave, Baltimore, MD USA.

Degenerative disc disease (DDD) is associated with intervertebral disc degeneration of spinal instability. Here, we report that the cilia of nucleus pulposus (NP) cells mediate mechanotransduction to maintain anabolic activity in the discs. We found that mechanical stress promotes transport of parathyroid hormone 1 receptor (PTH1R) to the cilia and enhances parathyroid hormone (PTH) signaling in NP cells. PTH induces transcription of integrin αβ to activate the transforming growth factor (TGF)-β-connective tissue growth factor (CCN2)-matrix proteins signaling cascade. Intermittent injection of PTH (iPTH) effectively attenuates disc degeneration of aged mice by direct signaling through NP cells, specifically improving intervertebral disc height and volume by increasing levels of TGF-β activity, CCN2, and aggrecan. PTH1R is expressed in both mouse and human NP cells. Importantly, knockout PTH1R or cilia in the NP cells results in significant disc degeneration and blunts the effect of PTH on attenuation of aged discs. Thus, mechanical stress-induced transport of PTH1R to the cilia enhances PTH signaling, which helps maintain intervertebral disc homeostasis, particularly during aging, indicating therapeutic potential of iPTH for DDD.
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http://dx.doi.org/10.1038/s41413-018-0022-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050246PMC
July 2018

One-stage posterior debridement and fusion combined with irrigation and drainage for the treatment of postoperative lumbar spondylodiscitis.

Acta Orthop Traumatol Turc 2018 Jul 18;52(4):277-282. Epub 2018 May 18.

Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Research Center of Sports Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, PR China. Electronic address:

Objective: The aim of this study was to evaluate the clinical outcomes of one-stage posterior debridement, interbody fusion, and instrumentation, combined with irrigation and drainage, for treating lumbar spondylodiscitis.

Methods: The study included 23 patients (13 male and 10 female, mean age: 45 years) who had posterior debridement, interbody fusion, and instrumentation, followed by continuous closed irrigation and drainage for lumbar postoperative spondylodiscitis. The visual analog scale, Oswestry disability index, and lumbar lordosis angle were assessed before and after surgery to evaluate the clinical outcome.

Results: The mean follow-up time was 27 (24-36) months. All patients tolerated the procedure well, and there were no instances of spondylodiscitis recurrence, though a dorsal dermal sinus developed in one patient after surgery. Infection was eliminated, as evidenced by the normalization of the erythrocyte sedimentation rates and C-reactive protein levels. The mean visual analog scale scores were significantly decreased after the operation. The mean lumbar lordosis angle before surgery was 21.61 ± 6.88° and the angle at the final follow-up was 31.61 ± 4.24°. The mean Oswestry disability index scores improved significantly both after the operation and at the follow-up visits (p < 0.05). Bone union was confirmed in all patients at a mean of 8.6 months post-operation, though this was not achieved until 2 years post-operation in one patient. All 3 patients who had neurological deficits showed great improvement at the last follow-up.

Conclusion: Surgical management using one-stage posterior debridement, interbody fusion, and instrumentation, followed by continuous closed irrigation and drainage, might be an effective treatment option for lumbar postoperative spondylodiscitis.

Level Of Evidence: Level IV, Therapeutic study.
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http://dx.doi.org/10.1016/j.aott.2018.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150443PMC
July 2018

Synchrotron Radiation Imaging Reveals the Role of Estrogen in Promoting Angiogenesis After Acute Spinal Cord Injury in Rats.

Spine (Phila Pa 1976) 2018 09;43(18):1241-1249

Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha, PR China.

Study Design: The efficacy of estrogen on vessel angiogenesis in acute spinal cord injury (SCI) in a rat model was evaluated by synchrotron radiation.

Objective: Here, we investigate the change in injured spinal cord vessels and used the synchrotron radiation to investigate the effect of estrogen on vessel angiogenesis and functional recovery in a rat model of SCI.

Summary Of Background Data: The promotion of angiogenesis after SCI may be a therapeutic target in the treatment of SCI. Estrogen has been reported to improve locomotor recovery after SCI. However, how estrogen regulates angiogenesis in acute SCI and enhances neurological functional recovery has not been fully characterized.

Methods: Synchrotron radiation imaging combined with histological methods was used to image angiogenesis in acute spinal cord treatment with estrogen in rats.

Results: Synchrotron radiation imaging vividly demonstrated three-dimensional vessel changes in the spinal cord after injury. The imaging showed that vessel number, vessel volume fraction, and vessel connectivity value in the groups treated with estrogen after SCI were significantly increased compared to control groups (P < 0.05). Vessel angiogenesis increased in groups treated with estrogen compared with control rats, which was confirmed with histological staining. Estrogen treatment also attenuated the injury-induced lesion area compared with control groups and improved locomotor functional recovery after SCI.

Conclusion: The results indicated that synchrotron radiation is a powerful imaging tool for visualizing angiogenesis after acute SCI. Estrogen treatment exerted a neuroprotective effect on acute SCI treatment by promoting angiogenesis and reducing the injury-induced lesion area could be recommended as a potential preclinical treatment approach for acute SCI.

Level Of Evidence: N/A.
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http://dx.doi.org/10.1097/BRS.0000000000002629DOI Listing
September 2018

Three-dimensional visualization and pathologic characteristics of cartilage and subchondral bone changes in the lumbar facet joint of an ovariectomized mouse model.

Spine J 2018 04 15;18(4):663-673. Epub 2017 Nov 15.

Department of Spine Surgery, Xiangya Hospital, Central South University, Xiangya Rd No.87, Changsha, 410008, China; The Key Laboratory of Organ Damage, Aging and Reproductive Medicine of Hunan Province, Xiangya Rd No.87, Changsha, Hunan, China. Electronic address:

Background Context: Low back pain (LBP) is more prevalent among postmenopausal women than men. Ovariectomy (OVX) is an established animal model that mimics the estrogen deficiency of postmenopausal women. Little is known about the three-dimensional (3D) morphologic properties of cartilage and subchondral bone changes in the lumbar facet joint (LFJ) of an OVX mouse model.

Purpose: The purpose of this study was to characterize the 3D morphologic change of cartilage and subchondral bone in the LFJ of an OVX mouse model.

Study Design: Three-dimensional visualization and a histologic study on degenerative changes in cartilage and subchondral bone in the LFJ of an OVX mouse model were conducted.

Materials And Methods: Ovariectomy is performed to mimic postmenopausal changes in adult female mice. We present an imaging tool for 3D visualization of the pathologic characteristics of cartilage and subchondral bone changes LFJ degradation using propagation-based phase-contrast computed tomography (PPCT). The samples were further dissected, fixed, and stained for histologic examination.

Results: Propagation-based phase-contrast computed tomography imaging provides a 3D visualization of altered cartilage with a simultaneous high detail of the subchondral bone abnormalities in an OVX LFJ model. A quantitative analysis demonstrated that the cartilage volume, the surface area, and thickness were decreased in the OVX group compared with the control group (p<.05). Meanwhile, these decreases were accompanied by an obvious destruction of the subchondral bone surface and a loss of trabecular bone in the OVX group (p<.05). The delineation of the 3D pathologic changes in the PPCT imaging was confirmed by a histopathologic method with Safranin-O staining. Tartrate-resistant acid phosphatase staining revealed an increased number of osteoclasts in the subchondral bone of the OVX mice compared with that of the control group.

Conclusions: These results demonstrated that a mouse model of OVX-induced LFJ osteoarthritis (OA)-like changes was successfully established and showed a good resemblance to the human OA pathology. Propagation-based phase-contrast computed tomography has great potential to becomea powerful 3D imaging method to comprehensively characterize LFJ OA and to effectively monitor therapeutics. Moreover, degenerative LFJ possesses a severe morphologic change in the subchondral bone, may be the source of postmenopausal LBP, and has the potential to be a novel therapeutic target for LBP treatment.
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http://dx.doi.org/10.1016/j.spinee.2017.11.009DOI Listing
April 2018

The 3D characteristics of post-traumatic syringomyelia in a rat model: a propagation-based synchrotron radiation microtomography study.

J Synchrotron Radiat 2017 Nov 4;24(Pt 6):1218-1225. Epub 2017 Oct 4.

Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China.

Many published literature sources have described the histopathological characteristics of post-traumatic syringomyelia (PTS). However, three-dimensional (3D) visualization studies of PTS have been limited due to the lack of reliable 3D imaging techniques. In this study, the imaging efficiency of propagation-based synchrotron radiation microtomography (PB-SRµCT) was determined to detect the 3D morphology of the cavity and surrounding microvasculature network in a rat model of PTS. The rat model of PTS was established using the infinite horizon impactor to produce spinal cord injury (SCI), followed by a subarachnoid injection of kaolin to produce arachnoiditis. PB-SRµCT imaging and histological examination, as well as fluorescence staining, were conducted on the animals at the tenth week after SCI. The 3D morphology of the cystic cavity was vividly visualized using PB-SRµCT imaging. The quantitative parameters analyzed by PB-SRµCT, including the lesion and spared spinal cord tissue area, the minimum and maximum diameters in the cystic cavity, and cavity volume, were largely consistent with the results of the histological assessment. Moreover, the 3D morphology of the cavity and surrounding angioarchitecture could be simultaneously detected on the PB-SRµCT images. This study demonstrated that high-resolution PB-SRµCT could be used for the 3D visualization of trauma-induced spinal cord cavities and provides valuable quantitative data for cavity characterization. PB-SRµCT could be used as a reliable imaging technique and offers a novel platform for tracking cavity formation and morphological changes in an experimental animal model of PTS.
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http://dx.doi.org/10.1107/S1600577517011201DOI Listing
November 2017

Morphometric Analysis of Rat Spinal Cord Angioarchitecture by Phase Contrast Radiography: From 2D to 3D Visualization.

Spine (Phila Pa 1976) 2018 05;43(9):E504-E511

Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha, China.

Study Design: An advanced imaging of vasculature with synchrotron radiation X-ray in a rat model.

Objective: To develop the potential for quantitative assessment of vessel network from two-dimensional (2D) to 3D visualization by synchrotron radiation X-ray phase contrast tomography (XPCT) in rat spinal cord model.

Summary Of Background Data: Investigation of microvasculature contributes to the understanding of pathological development of spinal cord injury. A few of X-ray imaging is available to visualize vascular architecture without usage of angiography or invasive casting preparation.

Methods: A rat spinal cord injury model was produced by modified Allen method. Histomorphometric detection was simultaneously analyzed by both histology and XPCT from 2D to 3D visualization. The parameters including tissue lesion area, microvessel density, vessel diameter, and frequency distribution of vessel diameter were evaluated.

Results: XPCT rendered the microvessels as small as capillary scale with a pixel size of 3.7 μm. It presented a high linear concordance for characterizing the 2D vascular morphometry compared with the histological staining (r = 0.8438). In the presence of spinal cord injury model, 3D construction quantified the significant angioarchitectural deficiency in the injury epicenter of cord lesion (P<0.01).

Conclusion: XPCT has a great potential to detect the smallest vascular network with pixel size up to micron dimension. It is inferred that the loss of abundant microvessels (≤40 μm) is responsible for local ischemia and neural dysfunction. XPCT holds a promise for morphometric analysis from 2D to 3D imaging in experimental model of neurovascular disorders.

Level Of Evidence: N/A.
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http://dx.doi.org/10.1097/BRS.0000000000002408DOI Listing
May 2018

WITHDRAWN: 3D visualization and pathological characteristics of cartilage and subchondral bone changes in the lumbar facet joint of an Ovariectomized mouse model.

Spine J 2017 Jul 13. Epub 2017 Jul 13.

Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China; The Key Laboratory of Organ Damage, Aging and Reproductive Medicine of Hunan Province, Changsha, Hunan, PR China.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.spinee.2017.11.009. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
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http://dx.doi.org/10.1016/j.spinee.2017.07.004DOI Listing
July 2017

3D characterization of morphological changes in the intervertebral disc and endplate during aging: A propagation phase contrast synchrotron micro-tomography study.

Sci Rep 2017 03 7;7:43094. Epub 2017 Mar 7.

Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China.

A better understanding of functional changes in the intervertebral disc (IVD) and interaction with endplate is essential to elucidate the pathogenesis of IVD degeneration disease (IDDD). To date, the simultaneous depiction of 3D micro-architectural changes of endplate with aging and interaction with IVD remains a technical challenge. We aim to characterize the 3D morphology changes of endplate and IVD during aging using PPCST. The lumbar vertebral level 4/5 IVDs harvested from 15-day-, 4- and 24-month-old mice were initially evaluated by PPCST with histological sections subsequently analyzed to confirm the imaging efficiency. Quantitative assessments of age-related trends after aging, including mean diameter, volume fraction and connectivity of the canals, and endplate porosity and thickness, reached a peak at 4 months and significantly decreased at 24 months. The IVD volume consistently exhibited same trend of variation with the endplate after aging. In this study, PPCST simultaneously provided comprehensive details of 3D morphological changes of the IVD and canal network in the endplate and the interaction after aging. The results suggest that PPCST has the potential to provide a new platform for attaining a deeper insight into the pathogenesis of IDDD, providing potential therapeutic targets.
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http://dx.doi.org/10.1038/srep43094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339826PMC
March 2017

Comparison of Synchrotron Radiation-based Propagation Phase Contrast Imaging and Conventional Micro-computed Tomography for Assessing Intervertebral Discs and Endplates in a Murine Model.

Spine (Phila Pa 1976) 2017 Aug;42(15):E883-E889

Department of Sports Medicine, Research Center of Sports Medicine, Xiangya Hospital, Central South University, Changsha, PR China.

Study Design: The synchrotron radiation-based micro-computed tomography (SRμCT) and micro-CT (μCT) were applied to comparatively assess the intervertebral disc (IVD) and endplate (EP).

Objective: To explore a new approach to evaluate the detailed structure of the IVD and EP during maturation and aging in a murine model.

Summary Of Background Data: Till date, methods to observe the morphological changes in the IVD and EP from rodents have been relatively limited. SRμCT has been recognized as a potential way to visualize the structures containing sclerous and soft tissue. Our study focused on comparing the capacity of SRμCT and μCT in evaluating the detailed structure of the IVD and EP.

Methods: Both SRμCT and μCT were performed to depict the structure of spinal tissue from 4-month-old mice. Then, the imaging quality was evaluated in the three-dimensional (3D) reconstructed model. Further, the changes in the EP and IVD during the maturation and aging process were assessed morphologically and quantitatively using SRμCT.

Results: The 3D reconstructed model of the EP from both μCT and SRμCT provided detailed information on its inner structure. However, the IVD was only depicted using SRμCT. Multi-angle observations of the 3D structure of EP and IVD from mice of different ages (15 days, 2 months, 4 months, and 18 months) were dynamically performed by SRμCT. Quantitative evaluations indicated that the total volume of EP and IVD, the average height of IVD and the canal-total volume ratio of EP increased from 15-day-old mice to 4-month-old mice and decreased in 18-month-old mice.

Conclusion: The EP and IVD were clearly visualized using SRμCT. Compared with μCT, SRμCT provided a better ultrahigh resolution image of soft tissue and hard tissue simultaneously, which makes it a promising approach for the noninvasive study of disc degeneration.

Level Of Evidence: N /A.
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http://dx.doi.org/10.1097/BRS.0000000000002110DOI Listing
August 2017

Three Dimensional Quantification of Microarchitecture and Vessel Regeneration by Synchrotron Radiation Microcomputed Tomography in a Rat Model of Spinal Cord Injury.

J Neurotrauma 2017 03 2;34(6):1187-1199. Epub 2016 Dec 2.

4 Department of Sports Medicine, Research Centre of Sports Medicine, Xiangya Hospital, Central South University , Changsha, China .

A full understanding of the mechanisms behind spinal cord injury (SCI) processes requires reliable three-dimensional (3D) imaging tools for a thorough analysis of changes in angiospatial architecture. We aimed to use synchrotron radiation μCT (SRμCT) to characterize 3D temporal-spatial changes in microvasculature post-SCI. Morphometrical measurements revealed a significant decrease in vascular volume fraction, vascular bifurcation density, vascular segment density, and vascular connectivity density 1 day post-injury, followed by a gradual increase at 3, 7, and 14 days. At 1 day post-injury, SRμCT revealed an increase in vascular tortuosity (VT), which reached a plateau after 7 days and decreased slightly during the healing process. In addition, SRμCT images showed that vessels were largely concentrated in the gray matter 1 day post-injury. The maximal endothelial cell proliferation rate was detected at 7 days post-injury. The 3D morphology of the cavity appears in the spinal cord at 28 days post-injury. We describe a methodology for 3D analysis of vascular repair in SCI and reveal that endogenous revascularization occurs during the healing process. The spinal cord microvasculature configuration undergoes 3D remodeling and modification during the post-injury repair process. Examination of these processes might contribute to a full understanding of the compensatory vascular mechanisms after injury and aid in the development of novel and effective treatment for SCI.
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http://dx.doi.org/10.1089/neu.2016.4697DOI Listing
March 2017

Lentivirus-mediated PGC-1α overexpression protects against traumatic spinal cord injury in rats.

Neuroscience 2016 07 27;328:40-9. Epub 2016 Apr 27.

Department of Sports Medicine, Research Center of Sports Medicine, Xiangya Hospital, Central South University, Changsha 410008, China. Electronic address:

Peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α) is a crucial neuronal regulator in the brain. However, its role in the spinal cord and the underlying regulating mechanisms remain poorly understood. Our previous study demonstrated that PGC-1α is significantly down-regulated following acute spinal cord injury (SCI) in rats. The current study aimed to explore the effects of PGC-1α overexpression on the injured spinal cord by establishing a contusive SCI model in adult Sprague-Dawley rats, followed by immediate intraspinal injection of lentiviral vectors at rostral and caudal sites 3mm from the lesion epicenter. Hindlimb motor function was monitored using the Basso-Beattie-Bresnahan Locomotor Rating Scale (BBB scores), and cords were collected. Transfection efficiency analysis showed that lentivirus successfully induced enhanced PGC-1α expression. This resulted in attenuated apoptotic changes and a greater number of surviving spinal neurons, as determined by transmission electron microscopy and Nissl staining, respectively. Western blot and immunofluorescence analyses revealed increased growth-associated protein 43 and 5-hydroxytryptamine expression, two key markers of axonal regeneration. Importantly, BBB scores showed improved hindlimb motor functional recovery. Moreover, quantitative real-time polymerase chain reaction analysis demonstrated significantly inhibited RhoA, ROCK1, and ROCK2 mRNA expression, revealing a potential mechanism of PGC-1α overexpression following traumatic SCI. Altogether, these results suggest that gene delivery of PGC-1α exerts a significant neuroprotective effect following traumatic SCI, which could serve as a promising treatment for repair of the injured cord, and RhoA-ROCK pathway inhibition may partially underlie this neuroprotection.
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http://dx.doi.org/10.1016/j.neuroscience.2016.04.031DOI Listing
July 2016

The Angiogenic Effect of microRNA-21 Targeting TIMP3 through the Regulation of MMP2 and MMP9.

PLoS One 2016 12;11(2):e0149537. Epub 2016 Feb 12.

Department of Sports Medicine, Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, 410008, PR China.

microRNAs are a novel set of small, non-protein-coding nucleotide RNAs that negatively regulate the expression of target mRNAs. miRNA-21 is a microRNA that is highly enriched in endothelial cells. miRNA-21 has been shown to be a potential pro-angiogenic factor in some biological systems. Our previous study showed that the expression of miRNA-21 was up-regulated after spinal cord injury. However, the effect of miRNA-21 on angiogenesis in the spinal cord was unclear. In this study, to understand the role of miRNA-21 on injured endothelial cells exclusively, an oxygen and glucose deprivation model of endothelial cells was constructed, and the up-regulation of miRNA-21 was discovered in this model. An increased level of miRNA-21 by mimics promoted the survival, migration and tube formation of endothelial cells, which simultaneously inhibited tissue inhibitor of metalloproteinase-3 (TIMP3) expression and promoted matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-9 (MMP9) expression and secretion. A decreased level of miRNA-21 by antagomir exerted an opposite effect. As is well known, survival, migration and tube formation of endothelial cells are necessary prerequisites for angiogenesis after injury. TIMP3 was validated as a direct target of miRNA-21 by dual-luciferase reporter assay. Silencing with small interfering RNA against TIMP3 promoted tube formation and increased MMP2 and MMP9 expression at the protein level. In vivo, we found that decreased levels of miRNA-21 inhibited angiogenesis after spinal cord injury in rats using synchrotron radiation micro-computed tomography. In summary, these findings suggest that miRNA-21 has a protective effect on angiogenesis by reducing cell death and promoting cell survival, migration and tube formation via partially targeting the TIMP3 by potentially regulating MMP2 and MMP9. TIMP3 is a functional target gene. Identifying the role of miRNA-21 in the protection of angiogenesis might offer a novel therapeutic target for secondary spinal cord injury, in which angiogenesis is indispensable.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149537PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752282PMC
July 2016

Three-dimensional imaging of microvasculature in the rat spinal cord following injury.

Sci Rep 2015 Jul 29;5:12643. Epub 2015 Jul 29.

Department of Sports Medicine, Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.

Research studies on the three-dimensional (3D) morphological alterations of the spinal cord microvasculature after injury provide insight into the pathology of spinal cord injury (SCI). Knowledge in this field has been hampered in the past by imaging technologies that provided only two-dimensional (2D) information on the vascular reactions to trauma. The aim of our study is to investigate the 3D microstructural changes of the rat spinal cord microvasculature on day 1 post-injury using synchrotron radiation micro-tomography (SRμCT). This technology provides high-resolution 3D images of microvasculature in both normal and injured spinal cords, and the smallest vessel detected is approximately 7.4 μm. Moreover, we optimized the 3D vascular visualization with color coding and accurately calculated quantitative changes in vascular architecture after SCI. Compared to the control spinal cord, the damaged spinal cord vessel numbers decreased significantly following injury. Furthermore, the area of injury did not remain concentrated at the epicenter; rather, the signs of damage expanded rostrally and caudally along the spinal cord in 3D. The observed pathological changes were also confirmed by histological tests. These results demonstrate that SRμCT is an effective technology platform for imaging pathological changes in small arteries in neurovascular disease and for evaluating therapeutic interventions.
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http://dx.doi.org/10.1038/srep12643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518284PMC
July 2015
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