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Banerjee T, Pradeep K, Karar A, Pal B. Effect of cage surface geometry on load transfer and ranges of motion in a fused lumbar spine model: A comparative finite element analysis. Proc Inst Mech Eng H 2025; 239:423-435. [PMID: 40237621 DOI: 10.1177/09544119251332072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/18/2025]
Abstract
Lumbar degenerative disc diseases (DDDs) are the common causes of low back pain, leading to non-conservative treatments like fusion and non-fusion surgery as a last resort. Fusion surgery is the gold standard for addressing DDDs, where implants such as cages, pedicle screws and rods are used for posterior stabilization. Various finite element (FE) studies have reported using corrugated cage surface textures; some others have used flat textures for virtual implantation. No comparative studies have been reported on the biomechanical effects of fusion surgery under implantation with cages of varying surface textures. The present biomechanical study compares the mechanical behaviour of an L4-L5 segment implanted with cages of different surface textures. The surgical techniques used for implantation are posterior lumbar interbody fusion (PLIF) and transforaminal lumbar interbody fusion. The virtual surgical models were developed from a previously validated intact lumbar spine FE model and simulated for physiological loading conditions. Compared to the flat cage implantation, a higher magnitude of stress was experienced by the cages and pedicle screw-rod systems under corrugated cage implantation. The maximum von Mises stress generated in the PLIF corrugated cage was 80.69% more than that observed in the flat cage. The maximum stresses in the corrugated cage were higher than those of the flat cage by 38.43%-80.69%, considering all the applied loading conditions. The findings of the study suggest that corrugated cage surface texture and suitable material selection may help in improving the long-term stability of cages.
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Affiliation(s)
- Tirtharaj Banerjee
- Department of Mechanical Engineering, Indian Institute of Engineering Science and Technology (IIEST), Howrah, West Bengal, India
| | - Kishore Pradeep
- Department of Mechanical Engineering, Indian Institute of Engineering Science and Technology (IIEST), Howrah, West Bengal, India
| | - Aritra Karar
- Department of Mechanical Engineering, Kalyani Government Engineering College, Kalyani, West Bengal, India
| | - Bidyut Pal
- Department of Mechanical Engineering, Indian Institute of Engineering Science and Technology (IIEST), Howrah, West Bengal, India
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Wei Z, Athertya JS, Chung CB, Bydder GM, Chang EY, Du J, Yang W, Ma Y. Qualitative and Quantitative MR Imaging of the Cartilaginous Endplate: A Review. J Magn Reson Imaging 2025; 61:1552-1571. [PMID: 39165086 PMCID: PMC11839955 DOI: 10.1002/jmri.29562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 07/26/2024] [Accepted: 07/26/2024] [Indexed: 08/22/2024] Open
Abstract
The cartilaginous endplate (CEP) plays a pivotal role in facilitating the supply of nutrients and, transport of metabolic waste, as well as providing mechanical support for the intervertebral disc (IVD). Recent technological advances have led to a surge in MR imaging studies focused on the CEP. This article describes the anatomy and functions of the CEP as well as MRI techniques for both qualitative and quantitative assessment of the CEP. Effective CEP MR imaging sequences require two key features: high spatial resolution and relatively short echo time. High spatial resolution spoiled gradient echo (SPGR) and ultrashort echo time (UTE) sequences, fulfilling these requirements, are the basis for most of the sequences employed in CEP imaging. This article reviews existing sequences for qualitative CEP imaging, such as the fat-suppressed SPGR and UTE, dual-echo subtraction UTE, inversion recovery prepared and fat-suppressed UTE, and dual inversion recovery prepared UTE sequences. These sequences are employed together with other techniques for quantitative CEP imaging, including measurements of T2*, T2, T1, T1ρ, magnetization transfer, perfusion, and diffusion tensor parameters. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.
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Affiliation(s)
- Zhao Wei
- Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing, China
- Department of Radiology, University of California San Diego, CA, United States
| | - Jiyo S. Athertya
- Department of Radiology, University of California San Diego, CA, United States
| | - Christine B. Chung
- Department of Radiology, University of California San Diego, CA, United States
- Radiology Service, Veterans Affairs San Diego Healthcare System, CA, USA
| | - Graeme M. Bydder
- Department of Radiology, University of California San Diego, CA, United States
| | - Eric Y. Chang
- Department of Radiology, University of California San Diego, CA, United States
- Radiology Service, Veterans Affairs San Diego Healthcare System, CA, USA
| | - Jiang Du
- Department of Radiology, University of California San Diego, CA, United States
- Radiology Service, Veterans Affairs San Diego Healthcare System, CA, USA
- Department of Bioengineering, University of California San Diego, CA, USA
| | - Wenhui Yang
- Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yajun Ma
- Department of Radiology, University of California San Diego, CA, United States
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Sinopoli SI, Whittal MC, Briar KJ, Gregory DE. Does Annulus Fibrosus Lamellar Adhesion Testing Require Preconditioning? J Biomech Eng 2025; 147:024502. [PMID: 39665769 DOI: 10.1115/1.4067399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 12/09/2024] [Indexed: 12/13/2024]
Abstract
The interlamellar matrix (ILM), located between the annular layers of the intervertebral disc (IVD), is an adhesive component which acts to resist delamination. Investigating the mechanical properties of the ILM can provide us with valuable information regarding risk of disc injury; however given its viscoelastic nature, it may be necessary to conduct preconditioning on tissue samples before measuring these ILM properties. Therefore, the aim of this study was to optimize mechanical testing protocols of the ILM by examining the effect of preconditioning on stiffness and strength of this adhesive matrix. Eighty-eight annular samples were dissected from 22 porcine cervical discs and randomized into one of four testing conditions consisting of ten cycles of 15% strain followed by a 180 deg adhesive peel test. The four testing groups employed a different strain rate for the ten cycles of preconditioning: 0.01 mm/s (n = 23); 0.1 mm/s (n = 26); 1 mm/s (n = 23); and no preconditioning employed (n = 16). Samples preconditioned at 0.01 mm/s were significantly less stiff than those that had not received preconditioning (p = 0.014). No other results were found to be statistically significant. Given the lack of differences observed in this study, preconditioning is likely not necessary prior to conducting a 180 deg peel test. However, if preconditioning is employed, the findings from this study suggest avoiding preconditioning conducted at very slow rates (i.e., 0.01 mm/s) as the long testing time may negatively affect the tissue.
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Affiliation(s)
- Sabrina I Sinopoli
- Wilfrid Laurier University, 75 University Avenue West, Waterloo, ON N2L 3C5, Canada
| | - Mitchel C Whittal
- Wilfrid Laurier University, 75 University Avenue West, Waterloo, ON N2L 3C5, Canada
| | - K Josh Briar
- University of Guelph, 50 Stone Road East, Guelph, ON N1G 2W1, Canada
- University of Guelph
| | - Diane E Gregory
- Wilfrid Laurier University, 75 University Avenue West, Waterloo, ON N2L 3C5, Canada
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Sheng L, Xu H, Wang Y, Ni J, Xiang T, Xu H, Zhou X, Wei K, Dai J. Systematic analysis of lysine lactylation in nucleus pulposus cells. iScience 2024; 27:111157. [PMID: 39524337 PMCID: PMC11546124 DOI: 10.1016/j.isci.2024.111157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 05/28/2024] [Accepted: 10/09/2024] [Indexed: 11/16/2024] Open
Abstract
Nucleus pulposus (NP) resides in hypoxic microenvironment and NP cells (NPCs), primarily reply on glycolysis and producing high levels of lactate. Intracellular lactate drives lysine lactylation (Kla) as a newly epigenetic modification. However, the impact of Kla on NPCs remains unknown. Here, single-cell RNA sequencing (scRNA-seq) data suggested an altered balance between glycolysis and aerobic oxidation in intervertebral disc degeneration (IDD). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis displayed 3510 lactylation sites on 1052 non-histone proteins of NPCs isolated from rat cultured in normoxia and hypoxia. Moreover, there are 18 proteins with 129 Kla sites and 117 Kla sites in 27 proteins exclusively detected in normoxia and hypoxia group, respectively. Bioinformatics analysis displayed that these lactylated proteins are tightly related to ribosome, spliceosome and the VEGFA-VEGFA2 signaling pathway. Together, our study reveals that Kla may play an important role in regulating cellular metabolism of NPCs.
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Affiliation(s)
- Lei Sheng
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Haoran Xu
- Department of Joint Surgery, Center for Orthopedic Surgery, Orthopedic Hospital of Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510000, China
| | - Yuexing Wang
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Jinhao Ni
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Taiyang Xiang
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Huanhuan Xu
- Department of Obstetrics and Gynecology, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, China
| | - Xiaozhong Zhou
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Kang Wei
- Department of Plastic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
| | - Jun Dai
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
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Li T, Liu Y, Cao J, Pan C, Ding R, Zhao J, Liu J, He D, Jia J, Cheng X. LTF ameliorates cartilage endplate degeneration by suppressing calcification, senescence and matrix degradation through the JAK2/STAT3 pathway. J Cell Mol Med 2024; 28:e18267. [PMID: 39392081 PMCID: PMC11467740 DOI: 10.1111/jcmm.18267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 02/16/2024] [Accepted: 03/11/2024] [Indexed: 10/12/2024] Open
Abstract
Intervertebral disc degeneration (IDD)-induced cervical and lumbar herniations are debilitating diseases. The function of intervertebral disc (IVD) mainly depends on the cartilage endplate (CEP), which provides support and waste removal. Therefore, IDD stems from the degeneration of CEP. Our study shows that the expression of lactotransferrin (LTF), an iron-binding protein, is significantly decreased in degenerated human and rat CEP tissues. In addition, we found that LTF knockdown promoted calcification, senescence, and extracellular matrix (ECM) degradation in human endplate chondrocytes. Furthermore, the in vivo experiment results confirmed that the JAK2/STAT3 pathway inhibitor AG490 significantly reversed these effects. In addition to investigating the role and mechanism of LTF in CEP degeneration, this study provides a theoretical basis and experimental evidence to improve IDD treatment.
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Affiliation(s)
- Tao Li
- Department of OrthopedicsThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Yuchi Liu
- Department of OrthopedicsThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Jian Cao
- Department of OrthopedicsThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
- Institute of Orthopedics of Jiangxi ProvinceThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Chongzhi Pan
- Department of OrthopedicsThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Rui Ding
- Department of OrthopedicsThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Jiangminghao Zhao
- Department of OrthopedicsThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Jiahao Liu
- Department of OrthopedicsThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Dingwen He
- Department of OrthopedicsThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
- Institute of Orthopedics of Jiangxi ProvinceThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
- Institute of Minimally Invasive OrthopedicsNanchang UniversityNanchangChina
| | - Jingyu Jia
- Department of OrthopedicsThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
- Institute of Orthopedics of Jiangxi ProvinceThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
- Institute of Minimally Invasive OrthopedicsNanchang UniversityNanchangChina
| | - Xigao Cheng
- Department of OrthopedicsThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
- Institute of Orthopedics of Jiangxi ProvinceThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
- Institute of Minimally Invasive OrthopedicsNanchang UniversityNanchangChina
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Xu T, Chen G, Li J, Zhang Y. Exploring causal correlations between inflammatory cytokines and intervertebral disc degeneration: A Mendelian randomization. JOR Spine 2024; 7:e1349. [PMID: 38993524 PMCID: PMC11237178 DOI: 10.1002/jsp2.1349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 06/18/2024] [Accepted: 06/20/2024] [Indexed: 07/13/2024] Open
Abstract
Background Inflammatory cytokines have been reported to be related to intervertebral disc degeneration (IVDD) in several previous studies. However, it remains unclear about the causal relationship between inflammatory cytokines and IVDD. This study employs Mendelian randomization (MR) to analyze the causal link between inflammatory cytokines and the risk of IVDD. Method We used genetic variants associated with inflammatory cytokines from a meta-analysis of genome-wide association study (GWAS) in 8293 Finns as instrumental variables and IVDD data were sourced from the FinnGen consortium. The main analytical approach utilized Inverse-Variance Weighting (IVW) with random effects to assess the causal relationship. Additionally, complementary methods such as MR-Egger, weighted median, simple mode, weighted mode, and MR pleiotropy residual sum and outlier were employed to enhance the robustness of the final results. Result We found interferon-gamma (IFN-γ, p = 2.14 × 10-6, OR = 0.870, 95% CI = 0.821-0.921), interleukin-1 beta (IL-1b, p = 0.012, OR = 0.951, 95% CI = 0.914-0.989), interleukin-4 (IL-4, p = 0.034, OR = 0.946, 95% CI = 0.899-0.996), interleukin-18 (IL-18, p = 0.028, OR = 0.964, 95% CI = 0.934-0.996), granulocyte colony-stimulating factor (GCSF, p = 0.010, OR = 0.919, 95% CI = 0.861-0.980), and Stromal cell-derived factor 1a (SDF1a, p = 0.014, OR = 1.072, 95% CI = 1.014-1.134) were causally associated with risk of IVDD. Conclusion Our MR analyses found a potential causal relationship between six inflammation cytokines (IFN-γ, IL-1b, IL-4, IL-18, SDF1a, and GCSF) and altered IVDD risk.
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Affiliation(s)
- Tao Xu
- Department of Orthopedics, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanPeople's Republic of China
| | - Guangzi Chen
- Department of Orthopedics, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanPeople's Republic of China
| | - Jian Li
- Department of OrthopaedicsThird Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi HospitalTaiyuanPeople's Republic of China
| | - Yingchi Zhang
- Department of Orthopedics, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanPeople's Republic of China
- Department of Traumatology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanPeople's Republic of China
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Yao H, Zhang Z, Cheng G, Chen X, He L, Wang W, Zhou S, Wang P. Automatic measurement of anatomical parameters of the lumbar vertebral body and the intervertebral disc on radiographs by deep learning. Quant Imaging Med Surg 2024; 14:5877-5890. [PMID: 39143991 PMCID: PMC11320507 DOI: 10.21037/qims-23-1859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 07/01/2024] [Indexed: 08/16/2024]
Abstract
Background Lumbar spine disorders are one of the common causes of low back pain (LBP). Objective and reliable measurement of anatomical parameters of the lumbar spine is essential in the clinical diagnosis and evaluation of lumbar disorders. However, manual measurements are time-consuming and laborious, with poor consistency and repeatability. Here, we aim to develop and evaluate an automatic measurement model for measuring the anatomical parameters of the vertebral body and intervertebral disc based on lateral lumbar radiographs and deep learning (DL). Methods A model based on DL was developed with a dataset consisting of 1,318 lateral lumbar radiographs for the prediction of anatomical parameters, including vertebral body heights (VBH), intervertebral disc heights (IDH), and intervertebral disc angles (IDA). The mean of the values obtained by 3 radiologists was used as a reference standard. Statistical analysis was performed in terms of standard deviation (SD), mean absolute error (MAE), Percentage of correct keypoints (PCK), intraclass correlation coefficient (ICC), regression analysis, and Bland-Altman plot to evaluate the performance of the model compared with the reference standard. Results The percentage of intra-observer landmark distance within the 3 mm threshold was 96%. The percentage of inter-observer landmark distance within the 3 mm threshold was 94% (R1 and R2), 92% (R1 and R3), and 93% (R2 and R3), respectively. The PCK of the model within the 3 mm distance threshold was 94-99%. The model-predicted values were 30.22±3.01 mm, 10.40±3.91 mm, and 10.63°±4.74° for VBH, IDH, and IDA, respectively. There were good correlation and consistency in anatomical parameters of the lumbar vertebral body and disc between the model and the reference standard in most cases (R2=0.89-0.95, ICC =0.93-0.98, MAE =0.61-1.15, and SD =0.89-1.64). Conclusions The newly proposed model based on a DL algorithm can accurately measure various anatomical parameters on lateral lumbar radiographs. This could provide an accurate and efficient measurement tool for the quantitative evaluation of spinal disorders.
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Affiliation(s)
- Hongyan Yao
- Department of Radiology, Gansu Provincial Hospital, Lanzhou, China
| | - Zhihong Zhang
- The First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou, China
| | - Guohua Cheng
- Hangzhou Jianpei Technology Co., Ltd., Hangzhou, China
| | - Xiaofei Chen
- Department of Radiology, Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, China
| | - Linyang He
- Hangzhou Jianpei Technology Co., Ltd., Hangzhou, China
| | - Wenqi Wang
- Department of Radiology, Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, China
| | - Sheng Zhou
- Department of Radiology, Gansu Provincial Hospital, Lanzhou, China
| | - Ping Wang
- Department of Radiology, Gansu Provincial Hospital, Lanzhou, China
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Shi P, Gao H, Cheng Z, Zhao K, Chen Y, Chen X, Gan W, Zhang A, Yang C, Zhang Y. Static magnetic field-modulated mesenchymal stem cell-derived mitochondria-containing microvesicles for enhanced intervertebral disc degeneration therapy. J Nanobiotechnology 2024; 22:457. [PMID: 39085827 PMCID: PMC11290117 DOI: 10.1186/s12951-024-02728-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 07/17/2024] [Indexed: 08/02/2024] Open
Abstract
Intervertebral disc degeneration (IVDD) is characterized by the senescence and declining vitality of nucleus pulposus cells (NPCs), often driven by mitochondrial dysfunction. This study elucidates that mesenchymal stem cells (MSCs) play a crucial role in attenuating NPC senescence by secreting mitochondria-containing microvesicles (mitoMVs). Moreover, it demonstrates that static magnetic fields (SMF) enhance the secretion of mitoMVs by MSCs. By distinguishing mitoMV generation from exosomes, this study shifts focus to understanding the molecular mechanisms of SMF intervention, emphasizing cargo transport and plasma membrane budding processes, with RNA sequencing indicating the potential involvement of the microtubule-based transport protein Kif5b. The study further confirms the interaction between Rab22a and Kif5b, revealing Rab22a's role in sorting mitoMVs into microvesicles (MVs) and potentially mediating subsequent plasma membrane budding. Subsequent construction of a gelatin methacrylate (GelMA) hydrogel delivery system further addresses the challenges of in vivo application and verifies the substantial potential of mitoMVs in delaying IVDD. This research not only sheds light on the molecular intricacies of SMF-enhanced mitoMV secretion but also provides innovative perspectives for future IVDD therapeutic strategies.
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Affiliation(s)
- Pengzhi Shi
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Haiyang Gao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zhangrong Cheng
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Kangcheng Zhao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yuhang Chen
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xianglong Chen
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Weikang Gan
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Anran Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Cao Yang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yukun Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Tang Y, Zhou Y, Zhang M. A Chitosan Scaffold Supports the Enhanced and Prolonged Differentiation of HiPSCs into Nucleus Pulposus-like Cells. ACS APPLIED MATERIALS & INTERFACES 2024; 16:28263-28275. [PMID: 38788694 DOI: 10.1021/acsami.4c06013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2024]
Abstract
Intervertebral disc degeneration (IDD) is a progressive condition and stands as one of the primary causes of low back pain. Cell therapy that uses nucleus pulposus (NP)-like cells derived from human induced pluripotent stem cells (hiPSCs) holds great promise as a treatment for IDD. However, the conventional two-dimensional (2D) monolayer cultures oversimplify cell-cell interactions, leading to suboptimal differentiation efficiency and potential loss of phenotype. While three-dimensional (3D) culture systems like Matrigel improve hiPSC differentiation efficiency, they are limited by animal-derived materials for translation, poorly defined composition, short-term degradation, and high cost. In this study, we introduce a new 3D scaffold fabricated using medical-grade chitosan with a high degree of deacetylation. The scaffold features a highly interconnected porous structure, near-neutral surface charge, and exceptional degradation stability, benefiting iPSC adhesion and proliferation. This scaffold remarkably enhances the differentiation efficiency and allows uninterrupted differentiation for up to 25 days without subculturing. Notably, cells differentiated on the chitosan scaffold exhibited increased cell survival rates and upregulated gene expression associated with extracellular matrix secretion under a chemically defined condition mimicking the challenging microenvironment of intervertebral discs. These characteristics qualify the chitosan scaffold-cell construct for direct implantation, serving as both a structural support and a cellular source for enhanced stem cell therapy for IDD.
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Affiliation(s)
- Yuanzhang Tang
- Department of Materials Science and Engineering, University of Washington, Seattle, Washington 98195, United States
| | - Yang Zhou
- Department of Materials Science and Engineering, University of Washington, Seattle, Washington 98195, United States
| | - Miqin Zhang
- Department of Materials Science and Engineering, University of Washington, Seattle, Washington 98195, United States
- Department of Neurological Surgery, University of Washington, Seattle, Washington 98195, United States
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Cho PG, Yoon SJ, Shin DA, Chang MC. Finite Element Analysis of Stress Distribution and Range of Motion in Discogenic Back Pain. Neurospine 2024; 21:536-543. [PMID: 38317545 PMCID: PMC11224725 DOI: 10.14245/ns.2347216.608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 01/08/2024] [Accepted: 01/09/2024] [Indexed: 02/07/2024] Open
Abstract
OBJECTIVE Precise knowledge regarding the mechanical stress applied to the intervertebral disc following each individual spine motion enables physicians and patients to understand how people with discogenic back pain should be guided in their exercises and which spine motions to specifically avoid. We created an intervertebral disc degeneration model and conducted a finite element (FE) analysis of loaded stresses following each spinal posture or motion. METHODS A 3-dimensional FE model of intervertebral disc degeneration at L4-5 was constructed. The intervertebral disc degeneration model was created according to the modified Dallas discogram scale. The von Mises stress and range of motion (ROM) regarding the intervertebral discs and the endplates were analyzed. RESULTS We observed that mechanical stresses loaded onto the intervertebral discs were similar during flexion, extension, and lateral bending, which were greater than those occurring during torsion. Based on the comparison among the grades divided by the modified Dallas discogram scale, the mechanical stress during extension was greater in grades 3-5 than it was during the others. During extension, the mechanical stress loaded onto the intervertebral disc and endplate was greatest in the posterior portion. Mechanical stresses loaded onto the intervertebral disc were greater in grades 3-5 compared to those in grades 0-2. CONCLUSION Our findings suggest that it might be beneficial for patients experiencing discogenic back pain to maintain a neutral posture in their lumbar spine when engaging in daily activities and exercises, especially those suffering from significant intravertebral disc degeneration.
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Affiliation(s)
- Pyung-Goo Cho
- Department of Neurosurgery, Ajou University Medical Center, Suwon, Korea
| | - Seon-Jin Yoon
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea
| | - Dong Ah Shin
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea
| | - Min Cheol Chang
- Department of Physical Medicine & Rehabilitation, Yeungnam University College of Medicine, Daegu, Korea
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Athertya JS, Lo J, Chen X, Shin SH, Malhi BS, Jerban S, Ji Y, Sedaghat S, Yoshioka H, Du J, Guma M, Chang EY, Ma Y. High contrast cartilaginous endplate imaging in spine using three dimensional dual-inversion recovery prepared ultrashort echo time (3D DIR-UTE) sequence. Skeletal Radiol 2024; 53:881-890. [PMID: 37935923 PMCID: PMC10973042 DOI: 10.1007/s00256-023-04503-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 10/14/2023] [Accepted: 10/29/2023] [Indexed: 11/09/2023]
Abstract
PURPOSE To investigate the feasibility and application of a novel imaging technique, a three-dimensional dual adiabatic inversion recovery prepared ultrashort echo time (3D DIR-UTE) sequence, for high contrast assessment of cartilaginous endplate (CEP) imaging with head-to-head comparisons between other UTE imaging techniques. METHOD The DIR-UTE sequence employs two narrow-band adiabatic full passage (AFP) pulses to suppress signals from long T2 water (e.g., nucleus pulposus (NP)) and bone marrow fat (BMF) independently, followed by multispoke UTE acquisition to detect signals from the CEP with short T2 relaxation times. The DIR-UTE sequence, in addition to three other UTE sequences namely, an IR-prepared and fat-saturated UTE (IR-FS-UTE), a T1-weighted and fat-saturated UTE sequence (T1w-FS-UTE), and a fat-saturated UTE (FS-UTE) was used for MR imaging on a 3 T scanner to image six asymptomatic volunteers, six patients with low back pain, as well as a human cadaveric specimen. The contrast-to-noise ratio of the CEP relative to the adjacent structures-specifically the NP and BMF-was then compared from the acquired images across the different UTE sequences. RESULTS For asymptomatic volunteers, the DIR-UTE sequence showed significantly higher contrast-to-noise ratio values between the CEP and BMF (CNRCEP-BMF) (19.9 ± 3.0) and between the CEP and NP (CNRCEP-NP) (23.1 ± 1.7) compared to IR-FS-UTE (CNRCEP-BMF: 17.3 ± 1.2 and CNRCEP-NP: 19.1 ± 1.8), T1w-FS-UTE (CNRCEP-BMF: 9.0 ± 2.7 and CNRCEP-NP: 10.4 ± 3.5), and FS-UTE (CNRCEP-BMF: 7.7 ± 2.2 and CNRCEP-NP: 5.8 ± 2.4) for asymptomatic volunteers (all P-values < 0.001). For the spine sample and patients with low back pain, the DIR-UTE technique detected abnormalities such as irregularities and focal defects in the CEP regions. CONCLUSION The 3D DIR-UTE sequence is able to provide high-contrast volumetric CEP imaging for human spines on a clinical 3 T scanner.
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Affiliation(s)
- Jiyo S Athertya
- Department of Radiology, University of California San Diego, San Diego, CA, USA
| | - James Lo
- Department of Radiology, University of California San Diego, San Diego, CA, USA
- Department of Bioengineering, University of California San Diego, San Diego, CA, USA
| | - Xiaojun Chen
- Department of Radiology, University of California San Diego, San Diego, CA, USA
| | - Soo Hyun Shin
- Department of Radiology, University of California San Diego, San Diego, CA, USA
| | | | - Saeed Jerban
- Department of Radiology, University of California San Diego, San Diego, CA, USA
| | - Yang Ji
- Department of Radiology, University of California San Diego, San Diego, CA, USA
| | - Sam Sedaghat
- Department of Radiology, University of California San Diego, San Diego, CA, USA
| | - Hiroshi Yoshioka
- Department of Radiological Sciences, University of California Irvine, Irvine, CA, USA
| | - Jiang Du
- Department of Radiology, University of California San Diego, San Diego, CA, USA
- Department of Bioengineering, University of California San Diego, San Diego, CA, USA
- Radiology Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
| | - Monica Guma
- Department of Medicine, University of California San Diego, San Diego, CA, USA
- Medicine Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
| | - Eric Y Chang
- Department of Radiology, University of California San Diego, San Diego, CA, USA
- Radiology Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
| | - Yajun Ma
- Department of Radiology, University of California San Diego, San Diego, CA, USA.
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Raftery K, Rahman T, Smith N, Schaer T, Newell N. The role of the nucleus pulposus in intervertebral disc recovery: Towards improved specifications for nucleus replacement devices. J Biomech 2024; 166:111990. [PMID: 38383232 DOI: 10.1016/j.jbiomech.2024.111990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 01/26/2024] [Accepted: 02/07/2024] [Indexed: 02/23/2024]
Abstract
Nucleus replacement devices (NRDs) have potential to treat degenerated or herniated intervertebral discs (IVDs). However, IVD height loss is a post-treatment complication. IVD height recovery involves the nucleus pulposus (NP), but the mechanism of this in response to physiological loads is not fully elucidated. This study aimed to characterise the non-linear recovery behaviour of the IVD in intact, post-nuclectomy, and post-NRD treatment states, under physiological loading. 36 bovine IVDs (12 intact, 12 post-nuclectomy, 12 post-treatment) underwent creep-recovery protocols simulating Sitting, Walking or Running, followed by 12 h of recovery. A rheological model decoupled the fluid-independent (elastic, fast) and fluid-dependent (slow) recovery phases. In post-nuclectomy and post-treatment groups, nuclectomy efficiency (ratio of NP removed to remaining NP) was quantified following post-test sectioning. Relative to intact, post-nuclectomy recovery significantly decreased in Sitting (-0.3 ± 0.4 mm, p < 0.05) and Walking (-0.6 ± 0.3 mm, p < 0.001) coupled with significant decreases to the slow response (p < 0.05). Post-nuclectomy, the fast and slow responses negatively correlated with nuclectomy efficiency (p < 0.05). In all protocols, the post-treatment group performed significantly worse in recovery (-0.5 ± 0.3 mm, p < 0.01) and the slow response (p < 0.05). Results suggest the NP mainly facilitates slow-phase recovery, linearly dependent on the amount of NP present. Failure of this NRD to recover is attributed to poor fluid imbibition. Additionally, unconfined NRD performance cannot be extrapolated to the in vitro response. This knowledge informs NRD design criteria to provide high osmotic pressure, and encourages testing standards to incorporate long-term recovery protocols.
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Affiliation(s)
- K Raftery
- Department of Bioengineering, Imperial College London, London, UK
| | - T Rahman
- Department of Bioengineering, Imperial College London, London, UK; Biomechanics Group, Department of Mechanical Engineering, Imperial College London, London, UK
| | - N Smith
- Division of Surgery and Interventional Science, University College London, Stanmore, UK
| | - T Schaer
- Department of Clinical Studies New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Kennett Square, PA, USA
| | - N Newell
- Department of Bioengineering, Imperial College London, London, UK.
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13
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Li Y, Zhang H, Zhu D, Yang F, Wang Z, Wei Z, Yang Z, Jia J, Kang X. Notochordal cells: A potential therapeutic option for intervertebral disc degeneration. Cell Prolif 2024; 57:e13541. [PMID: 37697480 PMCID: PMC10849793 DOI: 10.1111/cpr.13541] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 08/08/2023] [Accepted: 08/21/2023] [Indexed: 09/13/2023] Open
Abstract
Intervertebral disc degeneration (IDD) is a prevalent musculoskeletal degenerative disorder worldwide, and ~40% of chronic low back pain cases are associated with IDD. Although the pathogenesis of IDD remains unclear, the reduction in nucleus pulposus cells (NPCs) and degradation of the extracellular matrix (ECM) are critical factors contributing to IDD. Notochordal cells (NCs), derived from the notochord, which rapidly degrades after birth and is eventually replaced by NPCs, play a crucial role in maintaining ECM homeostasis and preventing NPCs apoptosis. Current treatments for IDD only provide symptomatic relief, while lacking the ability to inhibit or reverse its progression. However, NCs and their secretions possess anti-inflammatory properties and promote NPCs proliferation, leading to ECM formation. Therefore, in recent years, NCs therapy targeting the underlying cause of IDD has emerged as a novel treatment strategy. This article provides a comprehensive review of the latest research progress on NCs for IDD, covering their biological characteristics, specific markers, possible mechanisms involved in IDD and therapeutic effects. It also highlights significant future directions in this field to facilitate further exploration of the pathogenesis of IDD and the development of new therapies based on NCs strategies.
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Affiliation(s)
- Yanhu Li
- Lanzhou University Second HospitalLanzhouPeople's Republic of China
- Orthopaedics Key Laboratory of Gansu ProvinceLanzhouPeople's Republic of China
| | - Haijun Zhang
- Lanzhou University Second HospitalLanzhouPeople's Republic of China
- Orthopaedics Key Laboratory of Gansu ProvinceLanzhouPeople's Republic of China
- The Second People's Hospital of Gansu ProvinceLanzhouPeople's Republic of China
| | - Daxue Zhu
- Lanzhou University Second HospitalLanzhouPeople's Republic of China
- Orthopaedics Key Laboratory of Gansu ProvinceLanzhouPeople's Republic of China
| | - Fengguang Yang
- Lanzhou University Second HospitalLanzhouPeople's Republic of China
- Orthopaedics Key Laboratory of Gansu ProvinceLanzhouPeople's Republic of China
| | - Zhaoheng Wang
- Lanzhou University Second HospitalLanzhouPeople's Republic of China
- Orthopaedics Key Laboratory of Gansu ProvinceLanzhouPeople's Republic of China
| | - Ziyan Wei
- Lanzhou University Second HospitalLanzhouPeople's Republic of China
- Orthopaedics Key Laboratory of Gansu ProvinceLanzhouPeople's Republic of China
| | - Zhili Yang
- Lanzhou University Second HospitalLanzhouPeople's Republic of China
- Orthopaedics Key Laboratory of Gansu ProvinceLanzhouPeople's Republic of China
| | - Jingwen Jia
- Lanzhou University Second HospitalLanzhouPeople's Republic of China
- Orthopaedics Key Laboratory of Gansu ProvinceLanzhouPeople's Republic of China
| | - Xuewen Kang
- Lanzhou University Second HospitalLanzhouPeople's Republic of China
- Orthopaedics Key Laboratory of Gansu ProvinceLanzhouPeople's Republic of China
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Hanidu I, Johnson R, Ahorukomeye P, Ahn NU. Association Between Hypercholesterolemia and Lumbar Degenerative Back Pain: A Medicare Expenditure Panel Survey (MEPS) Study. Cureus 2023; 15:e47930. [PMID: 38034239 PMCID: PMC10684830 DOI: 10.7759/cureus.47930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/29/2023] [Indexed: 12/02/2023] Open
Abstract
Introduction Hypercholesterolemia is known to be a major contributor to the morbidity associated with cardiovascular disease and has been hypothesized to result in degenerative changes to the spine through atherosclerosis of segmental lumbar vessels. The purpose of this study is to determine the relationship between hypercholesterolemia and degenerative lumbar spine conditions in a U.S. cohort. Methods A total of 30,461 participated in the 2018 Medicare Expenditure Panel Survey (MEPS). Of those, 1,063 subjects responded to whether a diagnosis of lumbar disorders with low back pain was present. Odds ratios (OR) were calculated, and logistic regression analyses were adjusted for demographic, education, occupation, cardiovascular and mental health conditions. Results Of the 1,063 respondents, 455 (43%) reported back pain. Mean age of the respondents was 62.7±16.1. Men and women reported back pain at similar rates (43% vs 45%, p=0.664). Age, race, education level and occupation were similar between those with and without back pain (p>0.05). Those with a diagnosis of depression had higher odds of having back pain (p<0.05). Prevalence of back pain in subjects who responded to the back pain diagnosis item on the survey was 42.6%. On univariate analysis, diagnosis of total cholesterol levels was significantly higher in those with a diagnosis of back pain (OR 1.36, 95% CI [1.20-1.54], p<.0001). Multivariable analysis showed that hypercholesterolemia was independently associated with back pain (adjusted OR 1.32, 95% CI [1.04-1.68], p=0.021) after controlling for covariates. Conclusions In this study, subjects with hypercholesterolemia were 34% more likely to have back pain after controlling for confounders which presents as a recent discovery amongst U.S. populations. Further studies should be performed to investigate the management of hypercholesterolemia in the development and progression of degenerative lumbar back pain.
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Affiliation(s)
- Idris Hanidu
- Orthopedic Surgery, University of Illinois at Chicago, Chicago, USA
| | - Ryan Johnson
- Orthopedic Surgery, Meharry Medical College School of Medicine, Atlanta, USA
| | - Peter Ahorukomeye
- Orthopedic Surgery, Case Western Reserve University School of Medicine, Cleveland, USA
| | - Nicholas U Ahn
- Orthopedic Surgery, University Hospitals Cleveland Medical Center, Cleveland, USA
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Wang J, Xia Z, Su Z, Xue H, Huang C, Su M. Knockdown of microRNA-96-5p resists oxidative stress-induced apoptosis in nucleus pulposus cells. Am J Transl Res 2023; 15:4912-4921. [PMID: 37560214 PMCID: PMC10408537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 06/13/2023] [Indexed: 08/11/2023]
Abstract
BACKGROUND Intervertebral disc degeneration (IVDD) often leads to low back pain, which severely affects people's quality of life. Oxidative stress (OS) can accelerate nucleus pulposus cell (NPCs) senescence and apoptosis. Exploring the mechanism underlying OS-induced apoptosis is of utmost importance to aid in the development of IVDD treatment. METHODS In the current study, we tested the function of microRNA-96-5p in H2O2-treated NPCs. Apoptosis and mitophagy-related proteins were examined by western blot. Reactive oxygen species (ROS) generation, mitochondrial membrane potential, and apoptosis of NPCs were evaluated by flow cytometry. A luciferase reporter assay was conducted to confirm the interaction between microRNA-96-5p and Forkhead Box Protein O1 (FOXO1). RESULTS H2O2 treatment enhanced apoptosis in NPCs and upregulated the microRNA-96-5p expression. It was shown that knockdown of microRNA-96-5p attenuated H2O2-induced OS and apoptosis. FOXO1 is a direct target of microRNA-96-5p, and knockdown of microRNA-96-5p enhanced PINK1/Parkin-mediated mitophagy by up-regulating FOXO1. CONCLUSIONS Collectively, knockdown of microRNA-96-5p enhanced PINK1/Parkin-mediated mitophagy by up-regulating FOXO1. Our results facilitate the understanding of the role of microRNA-96-5p in IVDD and the mechanism of H2O2-induced oxidative damage.
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Affiliation(s)
- Ji Wang
- Department of Orthopedics, Liuzhou Traditional Chinese Medical Hospital of Guangxi University of Chinese MedicineLiuzhou, Guangxi, P. R. China
| | - Ziming Xia
- Department of Orthopedics, Liuzhou Traditional Chinese Medical Hospital of Guangxi University of Chinese MedicineLiuzhou, Guangxi, P. R. China
| | - Zhengyi Su
- Department of Orthopedics, Liuzhou Traditional Chinese Medical Hospital of Guangxi University of Chinese MedicineLiuzhou, Guangxi, P. R. China
| | - Hong Xue
- Department of Orthopedics, Liuzhou Traditional Chinese Medical Hospital of Guangxi University of Chinese MedicineLiuzhou, Guangxi, P. R. China
| | - Chengjun Huang
- Department of Orthopedics, Liuzhou Traditional Chinese Medical Hospital of Guangxi University of Chinese MedicineLiuzhou, Guangxi, P. R. China
| | - Ming Su
- Department of Pain, Liuzhou Traditional Chinese Medical Hospital of Guangxi University of Chinese MedicineLiuzhou, Guangxi, P. R. China
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Fujii T, Daimon K, Ozaki M, Suzuki S, Takahashi Y, Tsuji O, Nagoshi N, Yagi M, Michikawa T, Matsumoto M, Nakamura M, Watanabe K. 10-year Longitudinal MRI Study of Intervertebral Disk Degeneration in Patients With Lumbar Spinal Canal Stenosis After Posterior Lumbar Decompression Surgery. Spine (Phila Pa 1976) 2023; 48:815-824. [PMID: 37026757 DOI: 10.1097/brs.0000000000004671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 03/25/2023] [Indexed: 04/08/2023]
Abstract
STUDY DESIGN A prospective longitudinal magnetic resonance imaging (MRI) study. OBJECTIVE The objective of this study was to describe the progression of intervertebral disk (IVD) degeneration in patients who underwent posterior decompression surgery for lumbar spinal canal stenosis (LSS). SUMMARY OF BACKGROUND DATA IVD degeneration contributes to the pathogenesis of LSS; however, the long-term consequences of degenerative changes after decompression surgery remain unknown. MATERIALS AND METHODS Of 258 consecutive patients who underwent posterior lumbar decompression surgery for LSS, 62 who underwent MRI at their 10-year follow-up were included; 17 age-matched asymptomatic volunteers were analyzed as controls. Three MRI findings representing IVD degeneration were graded on their severity: decrease in signal intensity, posterior disk protrusion (PDP), and disk space narrowing (DSN). Clinical outcome was assessed using the low back pain (LBP) score from the Japanese Orthopaedic Association scoring system. We examined the association between the progression of degenerative changes on MRI and LBP/associated factors using logistic regression adjusting for age at baseline and sex. RESULTS The severity of IVD degeneration tended to be higher in patients with LSS than asymptomatic volunteers at both baseline and follow-up. IVD degeneration progressed in all patients during the 10-year follow-up period. Progression of decrease in signal intensity and PDP was observed at L1/2 in 73% and at L2/3 in 34%, respectively (the highest frequencies in the lumbar spine). Progression of DSN was highest at L4/5 in 42%. The rates of PDP and DSN progression during the 10-year follow-up period tended to be greater in patients with LSS than in asymptomatic volunteers. No significant difference in the proportion of LBP deterioration was evident for individuals with and without MRI findings of progression. CONCLUSIONS Our study reveals a natural history of the long-term postoperative course of IVD degeneration after posterior decompression surgery for LSS. Compared with healthy controls, patients with LSS seemed to be predisposed to IVD degeneration. Lumbar decompression surgery may promote the progression of DSN; however, progression of IVD degeneration after lumbar decompression surgery was not associated with worsening LBP scores.
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Affiliation(s)
- Takeshi Fujii
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
- Department of Orthopaedic Surgery, Tokyo Saiseikai Central Hospital, Tokyo, Japan
| | - Kenshi Daimon
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Masahiro Ozaki
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Satoshi Suzuki
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yohei Takahashi
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Osahiko Tsuji
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Narihito Nagoshi
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Mitsuru Yagi
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Takehiro Michikawa
- Department of Environmental and Occupational Health, School of Medicine, Toho University, Tokyo, Japan
| | - Morio Matsumoto
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Masaya Nakamura
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Kota Watanabe
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
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Höflsauer S, Bonnaire FC, Bamberger CE, Danalache M, Feierabend M, Hofmann UK. Changes in stiffness of the extracellular and pericellular matrix in the anulus fibrosus of lumbar intervertebral discs over the course of degeneration. Front Bioeng Biotechnol 2022; 10:1006615. [PMID: 36619385 PMCID: PMC9816436 DOI: 10.3389/fbioe.2022.1006615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 11/08/2022] [Indexed: 12/24/2022] Open
Abstract
Analogous to articular cartilage, changes in spatial chondrocyte organisation have been proposed to be a strong indicator for local tissue degeneration in the intervertebral disc (IVD). While a progressive structural and functional degradation of the extracellular (ECM) and pericellular (PCM) matrix occurs in osteoarthritic cartilage, these processes have not yet been biomechanically elucidated in the IVD. We aimed to evaluate the local stiffness of the ECM and PCM in the anulus fibrosus of the IVD on the basis of local chondrocyte spatial organisation. Using atomic force microscopy, we measured the Young's modulus of the local ECM and PCM in human and bovine disc samples using the spatial chondrocyte patterns as an image-based biomarker. By measuring tissue from 31 patients and six bovine samples, we found a significant difference in the elastic moduli (E) of the PCM in clusters when compared to the healthy patterns single cells (p = 0.029), pairs (p = 0.016), and string-formations (p = 0.010). The ECM/PCM ratio ranged from 0.62-0.89. Interestingly, in the bovine IVD, the ECM/PCM ratio of the E significantly varied (p = 0.002) depending on the tissue origin. Overall the reduced E in clusters demonstrates that cluster formation is not only a morphological phenomenon describing disc degeneration, but it marks a compromised biomechanical functioning. Immunohistochemical analyses indicate that collagen type III degradation might be involved. This study is the first to describe and quantify the differences in the E of the ECM in relation to the PCM in the anulus fibrosus of the IVD by means of atomic force microscopy on the basis of spatial chondrocyte organisation.
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Affiliation(s)
- Sebastian Höflsauer
- Laboratory of Cell Biology, Department of Orthopaedic Surgery, University Hospital of Tübingen, Tübingen, Germany,Medical Faculty of the University of Tübingen, Tübingen, Germany
| | - Florian Christof Bonnaire
- Laboratory of Cell Biology, Department of Orthopaedic Surgery, University Hospital of Tübingen, Tübingen, Germany,Department of Orthopaedic Surgery, University Hospital of Tübingen, Tübingen, Germany
| | - Charlotte Emma Bamberger
- Laboratory of Cell Biology, Department of Orthopaedic Surgery, University Hospital of Tübingen, Tübingen, Germany,Medical Faculty of the University of Tübingen, Tübingen, Germany
| | - Marina Danalache
- Laboratory of Cell Biology, Department of Orthopaedic Surgery, University Hospital of Tübingen, Tübingen, Germany,Medical Faculty of the University of Tübingen, Tübingen, Germany
| | - Martina Feierabend
- Institute for Bioinformatics and Medical Informatics, Faculty of Science of the University of Tübingen, Tübingen, Germany,*Correspondence: Martina Feierabend,
| | - Ulf Krister Hofmann
- Department of Orthopaedic Surgery, University Hospital of Tübingen, Tübingen, Germany,Department of Orthopaedic Trauma and Reconstructive Surgery, RWTH Aachen University Hospital, Aachen, Germany
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Ahorukomeye P, Weinberg DS, Du JY, Bhandutia AK, Yu CC, Ahn NU. Association between angina pectoris and back pain in a cross-sectional population-based study. INTERDISCIPLINARY NEUROSURGERY 2022. [DOI: 10.1016/j.inat.2022.101630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022] Open
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Liebsch C, Wilke HJ. Even mild intervertebral disc degeneration reduces the flexibility of the thoracic spine: an experimental study on 95 human specimens. Spine J 2022; 22:1913-1921. [PMID: 35779838 DOI: 10.1016/j.spinee.2022.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/31/2022] [Accepted: 06/17/2022] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Intervertebral disc degeneration represents one of multiple potential trigger factors for reduced passive spinal mobility and back pain. The effects of age-related degenerative intervertebral disc changes on spinal flexibility were however mainly investigated for the lumbar spine in the past, while intervertebral disc degeneration is also highly prevalent in the thoracic spine. PURPOSE To evaluate the effect of the degeneration grade on the range of motion and neutral zone of the thoracic spine. STUDY DESIGN Experimental study including combined radiological grading of intervertebral disc degeneration and biomechanical testing of 95 human thoracic functional spinal units (min. n=4 per level from T1-T2 to T11-T12) from 33 donors (15 female / 18 male, mean age 56 years, age range 37-80 years). METHODS Degeneration grades of the intervertebral discs were assessed using the validated x-ray grading scheme of Liebsch et al. (0=no, 1=mild, 2=moderate, 3=severe degeneration). Motion segments were loaded with pure moments in flexion/extension, lateral bending, and axial rotation to determine range of motion and neutral zone at 5 Nm. RESULTS All tested specimens exhibited degeneration grades between zero and two. Range of motion significantly decreased for grades one and two compared with grade zero in any motion direction (p<.05), showing the strongest decrease in extension comparing grade two with grade zero (-42%), while no significant differences were detected between grades one and two. Similar trends were found for the neutral zone with the strongest decrease in extension also comparing grade two with grade zero (-47%). Donor age did not significantly affect the range of motion, whereas the range of motion was significantly reduced in specimens from male donors due to the significantly higher degeneration grade in this study. CONCLUSIONS Even mild intervertebral disc degeneration reduces the range of motion and neutral zone of the thoracic spine in any motion plane, whereas progressing degeneration does not further affect its flexibility. This is in contrast to the lumbar spine, where a more gradual decrease of flexibility was found in prior studies, which might be explained by differences between thoracic and lumbar intervertebral disc morphologies. CLINICAL SIGNIFICANCE Thoracic intervertebral disc degeneration should be considered as one of multiple potential causal factors in patients showing reduced passive mobility and middle back pain.
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Affiliation(s)
- Christian Liebsch
- Institute of Orthopaedic Research and Biomechanics, Trauma Research Centre Ulm, Ulm University, Helmholtzstr. 14, 89081 Ulm, Baden-Wuerttemberg, Germany
| | - Hans-Joachim Wilke
- Institute of Orthopaedic Research and Biomechanics, Trauma Research Centre Ulm, Ulm University, Helmholtzstr. 14, 89081 Ulm, Baden-Wuerttemberg, Germany.
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Selective Nerve Root Block in Treatment of Lumbar Radiculopathy: A Narrative Review. SURGERIES 2022. [DOI: 10.3390/surgeries3030028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Selective Nerve Root Block (SNRB) is a precise local injection technique that can be utilised to target a particular inflamed nerve root causing lumbar radiculopathy for both diagnostic and therapeutic purposes. Usually, for SNRB to be therapeutic, a combination of a local anaesthetic agent and a steroid is injected under imaging guidance, whereas for diagnostic purposes, just the local anaesthetic agent is injected. While the ideal treatment strategy is to relieve the nerve root from its compressing pathology, local injection of steroids targeted at the affected nerve root can also be attempted to reduce inflammation and thus achieve pain relief. Although the general principle for administering an SNRB remains largely the same across the field, there are differences in techniques depending on the region and level of the spine that is targeted. Moreover, drug combinations utilised by clinicians vary based on preference. The proven benefits of SNRBs largely outweigh their risks, and the procedure is deemed safe and well tolerated in a majority of patients. In this narrative, we explore the existing literature and seek to provide a comprehensive understanding of SNRB as a treatment for lumbar radiculopathy, its indications, techniques, outcomes, and complications.
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Bhujel B, Shin HE, Choi DJ, Han I. Mesenchymal Stem Cell-Derived Exosomes and Intervertebral Disc Regeneration: Review. Int J Mol Sci 2022; 23:7306. [PMID: 35806304 PMCID: PMC9267028 DOI: 10.3390/ijms23137306] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 02/07/2023] Open
Abstract
Intervertebral disc degeneration (IVDD) is a common cause of lower back pain (LBP), which burdens individuals and society as a whole. IVDD occurs as a result of aging, mechanical trauma, lifestyle factors, and certain genetic abnormalities, leads to loss of nucleus pulposus, alteration in the composition of the extracellular matrix, excessive oxidative stress, and inflammation in the intervertebral disc. Pharmacological and surgical interventions are considered a boon for the treatment of IVDD, but the effectiveness of those strategies is limited. Mesenchymal stem cells (MSCs) have recently emerged as a possible promising regenerative therapy for IVDD due to their paracrine effect, restoration of the degenerated cells, and capacity for differentiation into disc cells. Recent investigations have shown that the pleiotropic effect of MSCs is not related to differentiation capacity but is mediated by the secretion of soluble paracrine factors. Early studies have demonstrated that MSC-derived exosomes have therapeutic potential for treating IVDD by promoting cell proliferation, tissue regeneration, modulation of the inflammatory response, and reduced apoptosis. This paper highlights the current state of MSC-derived exosomes in the field of treatment of IVDD with further possible future developments, applications, and challenges.
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Affiliation(s)
- Basanta Bhujel
- Department of Biomedical Science, College of Life Sciences, CHA University, Seongnam-si 13496, Korea; (B.B.); (H.-E.S.)
| | - Hae-Eun Shin
- Department of Biomedical Science, College of Life Sciences, CHA University, Seongnam-si 13496, Korea; (B.B.); (H.-E.S.)
| | - Dong-Jun Choi
- Department of Medicine, CHA Univerity School of Medicine, Seongnam-si 13496, Korea;
| | - Inbo Han
- Department of Neurosurgery, CHA University School of Medicine, CHA Bundang Medical Center, Seongnam-si 13496, Korea
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22
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The Genetic Association Identified Between Intervertebral Disc Degeneration and Associated Risk Factors Based on a Systems Biology Approach. Spine (Phila Pa 1976) 2022; 47:E370-E384. [PMID: 34919076 DOI: 10.1097/brs.0000000000004312] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN Genetic cross-over study of intervertebral disc degeneration (IDD) and its associated risk factors. OBJECTIVE The purpose is to identify molecular biomarkers that may be involved in the IDD process and to provide effective recommendations in combination with drug analysis via systems biology methods. SUMMARY OF BACKGROUND DATA The pathogenesis and genetic links of IDD are still unclear. Related research is mainly based on a single data set or gene, and the impact of related risk factors on IDD is often ignored. METHODS Identifying disease-associated biomarkers and therapeutic targets through a systems biology approach that Integrative network-based gene and multi-omics analysis. In this study, the differential expression of genes was analyzed through NCBI datasets, followed by enrichment analysis. The central protein was identified through the establishment of protein-protein interaction (PPI) network. Key genes were screened out by VENN diagram and reasonable suggestions were put forward based on gene-chemical drug analysis. RESULTS The IDD database analysis revealed 669 differentially expressed genes (DEGs) which were 22, 26, 168, 5, 38, 36, and 16 common DEGs with AG, SM, DEP, NAD, CED, OB, and HFD, respectively. GO and KEGG enrichment analysis may reveal the pathway by which these DEGs were involved. PPI network identified 10 central proteins including CCNB1, RETN, HMMR, BUB1, MPO, OIP5, HP, KIF11, BUB1B, and CDC25A. Three key genes BUB1, BUB1B, and CCNB1 were screened out and their expression might be related to the pathogenesis of IDD. According to the three chemical Dexamethasone, Nicotine, and Resvera-trol obtained from the analysis of genes-chemical drugs, reasonable treatment suggestions were put forward. CONCLUSION Genetic association between IDD and risk factors in the general population was revealed by association network. Important gene-related molecular pathways and chemical drugs closely related to IDD have been found. Further study can provide guidance for the treatment and prognosis of IDD.Level of Evidence: N/A.
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23
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Heo M, Yun J, Kim H, Lee SS, Park S. Optimization of a lumbar interspinous fixation device for the lumbar spine with degenerative disc disease. PLoS One 2022; 17:e0265926. [PMID: 35390024 PMCID: PMC8989208 DOI: 10.1371/journal.pone.0265926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 03/10/2022] [Indexed: 11/19/2022] Open
Abstract
Interspinous spacer devices used in interspinous fixation surgery remove soft tissues in the lumbar spine, such as ligaments and muscles and may cause degenerative diseases in adjacent segments its stiffness is higher than that of the lumbar spine. Therefore, this study aimed to structurally and kinematically optimize a lumbar interspinous fixation device (LIFD) using a full lumbar finite element model that allows for minimally invasive surgery, after which the normal behavior of the lumbar spine is not affected. The proposed healthy and degenerative lumbar spine models reflect the physiological characteristics of the lumbar spine in the human body. The optimum number of spring turns and spring wire diameter in the LIFD were selected as 3 mm and 2 turns, respectively—from a dynamic range of motion (ROM) perspective rather than a structural maximum stress perspective—by applying a 7.5 N∙m extension moment and 500 N follower load to the LIFD-inserted lumbar spine model. As the spring wire diameter in the LIFD increased, the maximum stress generated in the LIFD increased, and the ROM decreased. Further, as the number of spring turns decreased, both the maximum stress and ROM of the LIFD increased. When the optimized LIFD was inserted into a degenerative lumbar spine model with a degenerative disc, the facet joint force of the L3-L4 lumbar segment was reduced by 56%–98% in extension, lateral bending, and axial rotation. These results suggest that the optimized device can strengthen the stability of the lumbar spine that has undergone interspinous fixation surgery and reduce the risk of degenerative diseases at the adjacent lumbar segments.
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Affiliation(s)
- Minhyeok Heo
- School of Mechanical Engineering, Pusan National University, Busan, Republic of Korea (South Korea)
| | - Jihwan Yun
- School of Mechanical Engineering, Pusan National University, Busan, Republic of Korea (South Korea)
| | - Hanjong Kim
- School of Mechanical Engineering, Pusan National University, Busan, Republic of Korea (South Korea)
| | - Sang-Soo Lee
- Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, Republic of Korea (South Korea)
| | - Seonghun Park
- School of Mechanical Engineering, Pusan National University, Busan, Republic of Korea (South Korea)
- * E-mail:
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Ionizing Radiation Induces Disc Annulus Fibrosus Senescence and Matrix Catabolism via MMP-Mediated Pathways. Int J Mol Sci 2022; 23:ijms23074014. [PMID: 35409374 PMCID: PMC8999232 DOI: 10.3390/ijms23074014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 03/31/2022] [Accepted: 04/02/2022] [Indexed: 01/01/2023] Open
Abstract
Previous research has identified an association between external radiation and disc degeneration, but the mechanism was poorly understood. This study explores the effects of ionizing radiation (IR) on inducing cellular senescence of annulus fibrosus (AF) in cell culture and in an in vivo mouse model. Exposure of AF cell culture to 10–15 Gy IR for 5 min followed by 5 days of culture incubation resulted in almost complete senescence induction as evidenced by SA-βgal positive staining of cells and elevated mRNA expression of the p16 and p21 senescent markers. IR-induced senescent AF cells exhibited increased matrix catabolism, including elevated matrix metalloproteinase (MMP)-1 and -3 protein expression and aggrecanolysis. Analogous results were seen with whole body IR-exposed mice, demonstrating that genotoxic stress also drives disc cellular senescence and matrix catabolism in vivo. These results have important clinical implications in the potential adverse effects of ionizing radiation on spinal health.
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25
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Zhou L, Li C, Zhang H. Correlation between bone mineral density of different sites and lumbar disc degeneration in postmenopausal women. Medicine (Baltimore) 2022; 101:e28947. [PMID: 35421060 PMCID: PMC9276261 DOI: 10.1097/md.0000000000028947] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 02/09/2022] [Indexed: 01/04/2023] Open
Abstract
Osteoporosis and lumbar disc degeneration (LDD) have been common causes that make increasing patients suffer from different degrees of low back pain. At present, whether osteoporosis degenerates or protects disc is still controversial, and the correlation between hip bone mineral density (BMD) and LDD still remains unclear. Our study aims to analyze the correlation between BMD of different sites and LDD in postmenopausal women, and explore the potential pathophysiological mechanism of them.One hundred ninety-five postmenopausal female patients were enrolled and divided into osteoporosis, osteopenia, and normal bone mass groups. Their BMD and lumbar spine magnetic resonance imaging were retrospectively analyzed. Two spine surgeons were selected to assess LDD according to Pfirrmann grading system.Based on lumbar BMD, LDD of normal bone mass group was more severe than the other 2 groups in L1/2 and L2/3 segments (P < .05). Based on hip BMD, LDD of each disc from L1/2 to L5/S1 had no significant difference among the 3 groups (P > .05). Lumbar BMD (L1-L4) was positively correlated with corresponding degree of LDD (L1/2-L4/5) (P < .05), whereas there was no correlation between hip BMD and degree of LDD (P = .328).There is a positive correlation between lumbar BMD and LDD in postmenopausal women, which is more obvious in the upper lumbar spinal segments (L1, L2). However, there is no correlation between hip BMD and LDD, suggesting that in postmenopausal women with lumbar degenerative disease, hip BMD is more suitable for the diagnosis of osteoporosis.
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Wang D, He X, Zheng C, Wang C, Peng P, Gao C, Xu X, Ma Y, Liu M, Yang L, Luo Z. Endoplasmic Reticulum Stress: An Emerging Therapeutic Target for Intervertebral Disc Degeneration. Front Cell Dev Biol 2022; 9:819139. [PMID: 35178406 PMCID: PMC8843852 DOI: 10.3389/fcell.2021.819139] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 12/24/2021] [Indexed: 12/22/2022] Open
Abstract
Low back pain (LBP) is a global health issue. Intervertebral disc degeneration (IDD) is a major cause of LBP. Although the explicit mechanisms underpinning IDD are unclear, endoplasmic reticulum (ER) stress caused by aberrant unfolded or misfolded proteins may be involved. The accumulation of unfolded/misfolded proteins may result in reduced protein synthesis and promote aberrant protein degradation to recover ER function, a response termed the unfolded protein response. A growing body of literature has demonstrated the potential relationships between ER stress and the pathogenesis of IDD, indicating some promising therapeutic targets. In this review, we summarize the current knowledge regarding the impact of ER stress on the process of IDD, as well as some potential therapeutic strategies for alleviating disc degeneration by targeting different pathways to inhibit ER stress. This review will facilitate understanding the pathogenesis and progress of IDD and highlights potential therapeutic targets for treating this condition.
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Affiliation(s)
- Dong Wang
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Xin He
- Pharmacy Department, Air Force Hospital of Eastern Theater Command, Nanjing, China
| | - Chao Zheng
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Chengzhe Wang
- Rehabilitation Department, Dongchangfu Traditional Chinese Medicine Hospital, Liaocheng, China
| | - Pandi Peng
- Institute of Flexible Electronics, Northwestern Polytechnical University, Xi'an, China
| | - Chu Gao
- Medical Research Institute, Northwestern Polytechnical University, Xi'an, China
| | - Xiaolong Xu
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yachao Ma
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Mei Liu
- Pharmacy Department, Air Force Hospital of Eastern Theater Command, Nanjing, China
| | - Liu Yang
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.,Medical Research Institute, Northwestern Polytechnical University, Xi'an, China
| | - Zhuojing Luo
- Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.,Medical Research Institute, Northwestern Polytechnical University, Xi'an, China
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Comprehensive Network Analysis Identified SIRT7, NTRK2, and CHI3L1 as New Potential Markers for Intervertebral Disc Degeneration. JOURNAL OF ONCOLOGY 2022; 2022:4407541. [PMID: 35190738 PMCID: PMC8858045 DOI: 10.1155/2022/4407541] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/28/2021] [Accepted: 12/31/2021] [Indexed: 12/19/2022]
Abstract
Intervertebral disc degeneration (IDD) is considered the basis of serious clinical symptoms, especially for low back pain (LBP). Therefore, it is essential to explore the regulatory role and diagnostic performance of dysregulated genes and potential drugs in IDD. Through WGCNA co-expression analysis, 36 co-expression modules were obtained. Among them, MidnightBlue and Red modules were the most related to IDD. Functional enrichment analysis showed that the Red module was mainly related to neutrophil activation and regulation of cytokine-mediated signaling pathway and apoptosis, whereas the MidnightBlue module was mainly related to extracellular matrix organization, bone development, extracellular matrix, extracellular matrix component, and other extracellular matrices. Furthermore, 356 genes highly related to the module were screened to construct a protein interaction network. Network degree distribution analysis showed that the known IDD-related genes had a higher degree of distribution. Enrichment analysis demonstrated that these genes were enriched in MAPK_SIGNALING_PATHWAY (FDR = 0.012), CHEMOKINE_SIGNALING_PATHWAY, and some other pathways. By constructing a disease-gene interaction network, three disease-specific genes were finally identified. Through combining with the drug-target gene interaction network, two potential therapeutic drugs, entrectinib and larotrectinib, were determined. Finally, based on these genes, the diagnostic model in the training dataset, test dataset, and verification dataset all showed a high diagnostic performance. The findings of this study contributed to the diagnosis of IDD and personalized treatment of IDD.
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Salo S, Hurri H, Rikkonen T, Sund R, Kröger H, Sirola J. Association between severe lumbar disc degeneration and self-reported occupational physical loading. J Occup Health 2022; 64:e12316. [PMID: 35084078 PMCID: PMC8793002 DOI: 10.1002/1348-9585.12316] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 01/07/2022] [Accepted: 01/12/2022] [Indexed: 11/16/2022] Open
Abstract
Objectives Occupational physical loading has been reported to be associated with intervertebral disc degeneration. However, previous literature reports inconsistent results for different vertebral levels. The aim of our study was to investigate the association between lumbar disc degeneration (LDD) at different vertebral levels and the self‐reported physical loading of occupation. Methods The study population consisted of 1,022 postmenopausal women and was based on the prospective Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study cohort. The severity of LDD was graded from T2‐weighted MRI images using the five‐grade Pfirrmann classification. Five intervertebral levels (L1–L2 to L5–S1) were studied (total 5110 discs). The self‐rated occupational physical loading contained four groups: sedentary, light, moderate, and heavy. Results The heavy occupational physical loading group had higher odds for severe LDD at the L5–S1 vertebral level (OR 1.86, 95% CI: 1.19–2.92, p = .006) in comparison with the sedentary work group. A clear trend of increasing disc degeneration with heavier occupational loading was also observed at the L5–S1 level. Age, smoking, and higher body mass index (BMI) were associated with more severe LDD. Leisure‐time physical activity at the age of 11–17 years was associated with less severe LDD. Controlling for confounding factors did not alter the results. Conclusions There appears to be an association between occupational physical loading and severe disc degeneration at the lower lumbar spine in postmenopausal women. Individuals in occupations with heavy physical loading may have an increased risk for work‐related disability due to more severe disc degeneration.
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Affiliation(s)
- Sami Salo
- Kuopio musculoskeletal research unit (KMRU), Surgery, Institute of Clinical Medicine, University of Eastern Finland (UEF), Kuopio, Finland
| | - Heidi Hurri
- Kuopio musculoskeletal research unit (KMRU), Surgery, Institute of Clinical Medicine, University of Eastern Finland (UEF), Kuopio, Finland
| | - Toni Rikkonen
- Kuopio musculoskeletal research unit (KMRU), Surgery, Institute of Clinical Medicine, University of Eastern Finland (UEF), Kuopio, Finland
| | - Reijo Sund
- Kuopio musculoskeletal research unit (KMRU), Surgery, Institute of Clinical Medicine, University of Eastern Finland (UEF), Kuopio, Finland
| | - Heikki Kröger
- Kuopio musculoskeletal research unit (KMRU), Surgery, Institute of Clinical Medicine, University of Eastern Finland (UEF), Kuopio, Finland.,Department of Orthopaedics, Traumatology and Hand Surgery, Kuopio University Hospital, Kuopio, Finland
| | - Joonas Sirola
- Kuopio musculoskeletal research unit (KMRU), Surgery, Institute of Clinical Medicine, University of Eastern Finland (UEF), Kuopio, Finland.,Department of Orthopaedics, Traumatology and Hand Surgery, Kuopio University Hospital, Kuopio, Finland
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29
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Karaca R, Kacar E, Gunduz D, Korfali E. Vertebral end-plate changes: Are they clinically significant for postoperative low back pain? WEST AFRICAN JOURNAL OF RADIOLOGY 2022. [DOI: 10.4103/wajr.wajr_31_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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30
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Shi PZ, Wang JW, Wang PC, Han B, Lu XH, Ren YX, Feng XM, Cheng XF, Zhang L. Urolithin a alleviates oxidative stress-induced senescence in nucleus pulposus-derived mesenchymal stem cells through SIRT1/PGC-1α pathway. World J Stem Cells 2021; 13:1928-1946. [PMID: 35069991 PMCID: PMC8727228 DOI: 10.4252/wjsc.v13.i12.1928] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/12/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In degenerative intervertebral disc (IVD), an unfavorable IVD environment leads to increased senescence of nucleus pulposus (NP)-derived mesenchymal stem cells (NPMSCs) and the inability to complete the differentiation from NPMSCs to NP cells, leading to further aggravation of IVD degeneration (IDD). Urolithin A (UA) has been proven to have obvious effects in delaying cell senescence and resisting oxidative stress.
AIM To explore whether UA can alleviate NPMSCs senescence and to elucidate the underlying mechanism.
METHODS In vitro, we harvested NPMSCs from rat tails, and divided NPMSCs into four groups: the control group, H2O2 group, H2O2 + UA group, and H2O2 + UA + SR-18292 group. Senescence-associated β-Galactosidase (SA-β-Gal) activity, cell cycle, cell proliferation ability, and the expression of senescence-related and silent information regulator of transcription 1/PPAR gamma coactivator-1α (SIRT1/ PGC-1α) pathway-related proteins and mRNA were used to evaluate the protective effects of UA. In vivo, an animal model of IDD was constructed, and X-rays, magnetic resonance imaging, and histological analysis were used to assess whether UA could alleviate IDD in vivo.
RESULTS We found that H2O2 can cause NPMSCs senescence changes, such as cell cycle arrest, reduced cell proliferation ability, increased SA-β-Gal activity, and increased expression of senescence-related proteins and mRNA. After UA pretreatment, the abovementioned senescence indicators were significantly alleviated. To further demonstrate the mechanism of UA, we evaluated the mitochondrial membrane potential and the SIRT1/PGC-1α pathway that regulates mitochondrial function. UA protected mitochondrial function and delayed NPMSCs senescence by activating the SIRT1/PGC-1α pathway. In vivo, we found that UA treatment alleviated an animal model of IDD by assessing the disc height index, Pfirrmann grade and the histological score.
CONCLUSION In summary, UA could activate the SIRT1/PGC-1α signaling pathway to protect mitochondrial function and alleviate cell senescence and IDD in vivo and vitro.
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Affiliation(s)
- Peng-Zhi Shi
- Department of Orthopedic, Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Jun-Wu Wang
- Department of Orthopedics, Clinical Medical College of Yangzhou University, Yangzhou 225000, Jiangsu Province, China
| | - Ping-Chuan Wang
- Department of Orthopedics, Clinical Medical College of Yangzhou University, Yangzhou 225000, Jiangsu Province, China
| | - Bo Han
- Department of Orthopedic, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Xu-Hua Lu
- Department of Orthopedics, Changzheng Hospital of The Second Military Medical University, Shanghai 200003, China
| | - Yong-Xin Ren
- Department of Orthopedics, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Xin-Min Feng
- Department of Orthopedics, Clinical Medical College of Yangzhou University, Yangzhou 225000, Jiangsu Province, China
| | - Xiao-Fei Cheng
- Department of Orthopedic Surgery, Shanghai Key Laboratory of Orthopedics Implants, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China
| | - Liang Zhang
- Department of Orthopedics, Clinical Medical College of Yangzhou University, Yangzhou 225000, Jiangsu Province, China
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31
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Williams RJ, Tryfonidou MA, Snuggs JW, Le Maitre CL. Cell sources proposed for nucleus pulposus regeneration. JOR Spine 2021; 4:e1175. [PMID: 35005441 PMCID: PMC8717099 DOI: 10.1002/jsp2.1175] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/01/2021] [Accepted: 10/20/2021] [Indexed: 12/13/2022] Open
Abstract
Lower back pain (LBP) occurs in 80% of adults in their lifetime; resulting in LBP being one of the biggest causes of disability worldwide. Chronic LBP has been linked to the degeneration of the intervertebral disc (IVD). The current treatments for chronic back pain only provide alleviation of symptoms through pain relief, tissue removal, or spinal fusion; none of which target regenerating the degenerate IVD. As nucleus pulposus (NP) degeneration is thought to represent a key initiation site of IVD degeneration, cell therapy that specifically targets the restoration of the NP has been reviewed here. A literature search to quantitatively assess all cell types used in NP regeneration was undertaken. With key cell sources: NP cells; annulus fibrosus cells; notochordal cells; chondrocytes; bone marrow mesenchymal stromal cells; adipose-derived stromal cells; and induced pluripotent stem cells extensively analyzed for their regenerative potential of the NP. This review highlights: accessibility; expansion capability in vitro; cell survival in an IVD environment; regenerative potential; and safety for these key potential cell sources. In conclusion, while several potential cell sources have been proposed, iPSC may provide the most promising regenerative potential.
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Affiliation(s)
- Rebecca J. Williams
- Biomedical Research Centre, BiosciencesSheffield Hallam UniversitySheffieldUK
| | - Marianna A. Tryfonidou
- Department of Clinical Sciences, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
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Singh R, Kumar P, Wadhwani J, Yadav RK, Khanna M, Kaur S. A comparative study to evaluate disc degeneration on magnetic resonance imaging in patients with chronic low back pain and asymptomatic individuals. JOURNAL OF ORTHOPAEDICS, TRAUMA AND REHABILITATION 2021. [DOI: 10.1177/22104917211039522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Objectives The present study aimed to investigate the association of disc degeneration with low back pain and the effect of ageing on disc degeneration in low back pain versus asymptomatic individuals. Methodology A total of 50 patients with chronic low back pain (Group A) were compared to 25 healthy controls (Group B). Both the groups were subjected to magnetic resonance imaging of the lumbar spine and the disc degeneration was measured by the Pfirrmann grading system. The study group (Group A) was further sub-grouped into A1 (lumbar spondylosis, n = 11), A2 (mechanical back pain, n = –13) and A3 (lumbar disc herniation, n = 26). Results There was a statistically significant difference in degeneration at the L4-L5 ( p = 0.001) and L5-S1 disc levels ( p = 0.001) between the two groups and contiguous disc involvement was more in low back pain patients. The subgroups of group A showed no statistically significant difference. Age showed a strong positive correlation ( r > 0.5) at all the lumbar levels (except at the L5-S1, r = 0.487) with Pfirrmann grading in Group A ( p = 0.001). There was a weak positive correlation ( r = 0.414) between age and Pfirrmann grade in the controls ( p = 0.04) at the L4-L5 level only. Conclusions Significantly higher Pfirrmann grading on magnetic resonance imaging was found at the L4-5 and L5-S1 levels in symptomatic patients suggesting higher involvement of these levels. Progressive disc degeneration is seen with ageing but in patients with low back pain, it is significantly accelerated.
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Affiliation(s)
- Roop Singh
- Department of Orthopaedic Surgery, Paraplegia & Rehabilitation, Pt. B.D. Sharma PGIMS, India
| | | | - Jitendra Wadhwani
- Department of Orthopaedic Surgery, Paraplegia & Rehabilitation, Pt. B.D. Sharma PGIMS, India
| | - Rohtas K Yadav
- Department of Radiodiagnosis and Imaging, Pt. B.D. Sharma PGIMS, India
| | - Mohit Khanna
- Department of Orthopaedic Surgery, Paraplegia & Rehabilitation, Pt. B.D. Sharma PGIMS, India
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Ji Y, Zhu P, Zhang L, Yang H. A novel rat tail disc degeneration model induced by static bending and compression. Animal Model Exp Med 2021; 4:261-267. [PMID: 34557652 PMCID: PMC8446698 DOI: 10.1002/ame2.12178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 06/07/2021] [Indexed: 11/21/2022] Open
Abstract
Background A new rat tail intervertebral disc degeneration model was established to observe the morphologic and biologic changes of static bending and compression applied to the discs. Methods In total, 20 Sprague-Dawley rats with similar weight were randomly divided into 4 groups. Group 1 served as a control group for a baseline assessment of normal discs. Group 2 underwent a sham surgery, using an external device to bend the vertebrae of coccygeal 8-10. Groups 3 and 4 were the loaded groups, and external devices were instrumented to bend the spine with a compression level of 1.8 N and 4.5 N, respectively. Magnetic resonance imaging (MRI), histological, and quantitative real-time PCR (qRT-PCR) analysis were performed on all animals on day 14 of the experiment. Results Magnetic resonance imaging and histological results showed that the changes of intervertebral disc degeneration increased with the size of compression load. Some architecture disorganizations in nucleus pulposus and annulus fibrosus were found on both of the convex and concave side in the groups of 1.8 N and 4.5 N. An upregulation of MM-3, MM-13, and collagen 1-α1 mRNA expression and a downregulation of collagen 2-α1 and aggrecan mRNA expression were observed in the sham and loading groups. Significant changes were found between the loading groups, whereas the sham group showed similar results to the control group. Conclusions Static bending and compression could induce progressive disc degeneration, which could be used for biologic study on disc degeneration promoted by static complex loading.
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Affiliation(s)
- Yichao Ji
- Department of Orthopaedic SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouP.R. China
| | - Pengfei Zhu
- Department of Orthopaedic SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouP.R. China
| | - Linlin Zhang
- Department of Orthopaedic SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouP.R. China
| | - Huilin Yang
- Department of Orthopaedic SurgeryThe First Affiliated Hospital of Soochow UniversitySuzhouP.R. China
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Kague E, Turci F, Newman E, Yang Y, Brown KR, Aglan MS, Otaify GA, Temtamy SA, Ruiz-Perez VL, Cross S, Royall CP, Witten PE, Hammond CL. 3D assessment of intervertebral disc degeneration in zebrafish identifies changes in bone density that prime disc disease. Bone Res 2021; 9:39. [PMID: 34465741 PMCID: PMC8408153 DOI: 10.1038/s41413-021-00156-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 03/22/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023] Open
Abstract
Back pain is a common condition with a high social impact and represents a global health burden. Intervertebral disc disease (IVDD) is one of the major causes of back pain; no therapeutics are currently available to reverse this disease. The impact of bone mineral density (BMD) on IVDD has been controversial, with some studies suggesting osteoporosis as causative for IVDD and others suggesting it as protective for IVDD. Functional studies to evaluate the influence of genetic components of BMD in IVDD could highlight opportunities for drug development and repurposing. By taking a holistic 3D approach, we established an aging zebrafish model for spontaneous IVDD. Increased BMD in aging, detected by automated computational analysis, is caused by bone deformities at the endplates. However, aged zebrafish spines showed changes in bone morphology, microstructure, mineral heterogeneity, and increased fragility that resembled osteoporosis. Elements of the discs recapitulated IVDD symptoms found in humans: the intervertebral ligament (equivalent to the annulus fibrosus) showed disorganized collagen fibers and herniation, while the disc center (nucleus pulposus equivalent) showed dehydration and cellular abnormalities. We manipulated BMD in young zebrafish by mutating sp7 and cathepsin K, leading to low and high BMD, respectively. Remarkably, we detected IVDD in both groups, demonstrating that low BMD does not protect against IVDD, and we found a strong correlation between high BMD and IVDD. Deep learning was applied to high-resolution synchrotron µCT image data to analyze osteocyte 3D lacunar distribution and morphology, revealing a role of sp7 in controlling the osteocyte lacunar 3D profile. Our findings suggest potential avenues through which bone quality can be targeted to identify beneficial therapeutics for IVDD.
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Affiliation(s)
- Erika Kague
- grid.5337.20000 0004 1936 7603School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, Bristol, UK
| | - Francesco Turci
- grid.5337.20000 0004 1936 7603School of Physics, HH Wills Physics Laboratory, University of Bristol, Bristol, UK
| | - Elis Newman
- grid.5337.20000 0004 1936 7603School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, Bristol, UK
| | - Yushi Yang
- grid.5337.20000 0004 1936 7603School of Physics, HH Wills Physics Laboratory, University of Bristol, Bristol, UK ,grid.5337.20000 0004 1936 7603Centre for Nanoscience and Quantum Information, University of Bristol, Bristol, UK ,grid.5337.20000 0004 1936 7603Bristol Centre for Functional Nanomaterials, University of Bristol, Bristol, UK
| | - Kate Robson Brown
- grid.5337.20000 0004 1936 7603Department of Anthropology and Archaeology, University of Bristol, Bristol, UK ,grid.5337.20000 0004 1936 7603Department of Mechanical Engineering, University of Bristol, Bristol, UK
| | - Mona S. Aglan
- grid.419725.c0000 0001 2151 8157Clinical Genetics Department, Human Genetics and Genome Research Division, Center of Excellence for Human Genetics, National Research Centre, Cairo, Egypt
| | - Ghada A. Otaify
- grid.419725.c0000 0001 2151 8157Clinical Genetics Department, Human Genetics and Genome Research Division, Center of Excellence for Human Genetics, National Research Centre, Cairo, Egypt
| | - Samia A. Temtamy
- grid.419725.c0000 0001 2151 8157Clinical Genetics Department, Human Genetics and Genome Research Division, Center of Excellence for Human Genetics, National Research Centre, Cairo, Egypt
| | - Victor L. Ruiz-Perez
- grid.413448.e0000 0000 9314 1427Instituto de Investigaciones, Biomedicas de Madrid, and Ciber de Enfermedades Raras (CIBERER), Madrid, Spain
| | - Stephen Cross
- grid.5337.20000 0004 1936 7603Wolfson Bioimaging Facility, Biomedical Sciences, University of Bristol, Bristol, UK
| | - C. Patrick Royall
- grid.5337.20000 0004 1936 7603School of Physics, HH Wills Physics Laboratory, University of Bristol, Bristol, UK ,grid.5337.20000 0004 1936 7603School of Chemistry, University of Bristol, Bristol, UK
| | - P. Eckhard Witten
- grid.5342.00000 0001 2069 7798Evolutionary Developmental Biology, Department of Biology, Ghent University, Ghent, Belgium
| | - Chrissy L. Hammond
- grid.5337.20000 0004 1936 7603School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, Bristol, UK
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The Role of Polymorphisms in Collagen-Encoding Genes in Intervertebral Disc Degeneration. Biomolecules 2021; 11:biom11091279. [PMID: 34572492 PMCID: PMC8465916 DOI: 10.3390/biom11091279] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/12/2021] [Accepted: 08/23/2021] [Indexed: 12/31/2022] Open
Abstract
(1) Background: The purpose of this review is to analyze domestic and foreign studies on the role of collagen-encoding genes polymorphism in the development of intervertebral discs (IVDs) degeneration in humans. (2) Methods: We have carried out a search for full-text articles published in e-Library, PubMed, Oxford Press, Clinical Case, Springer, Elsevier and Google Scholar databases. The search was carried out using keywords and their combinations. The search depth was 5 years (2016–2021). In addition, this review includes articles of historical interest. Despite an extensive search, it is possible that we might have missed some studies published in recent years. (3) Results: According to the data of genome-wide and associative genetic studies, the following candidate genes that play a role in the biology of IVDs and the genetic basis of the processes of collagen degeneration of the annulus fibrosus and nucleus pulposus of IVDs in humans are of the greatest interest to researchers: COL1A1, COL2A1, COL9A2, COL9A3, COL11A1 and COL11A2. In addition, the role of genes COL1A2, COL9A1 and others is being actively studied. (4) Conclusions: In our review, we summarized and systematized the available information on the role of genetic factors in IVD collagen fibers turnover and also focused on the functions of different types of collagen present in the IVD. Understanding the etiology of impaired collagen formation can allow doctors to prescribe pathogenetically-based treatment, achieving the most effective results.
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Bonnaire FC, Danalache M, Sigwart VA, Breuer W, Rolauffs B, Hofmann UK. The intervertebral disc from embryonic development to disc degeneration: insights into spatial cellular organization. Spine J 2021; 21:1387-1398. [PMID: 33872805 DOI: 10.1016/j.spinee.2021.04.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 04/10/2021] [Accepted: 04/13/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Low back pain is commonly attributed to intervertebral disc (IVD) degeneration. IVD resembles articular cartilage in its biochemical and cellular composition in many ways. For articular cartilage, degeneration stage-specific characteristic spatial chondrocyte patterns have recently been described. PURPOSE This study addresses how spatial chondrocyte organization in the IVD changes from early embryonic development to end stage degeneration. STUDY DESIGN Ex vivo immunohistochemical analysis. METHODS We immunohistochemically investigated bovine IVD-tissue (n=72) from early embryonic development to early disc degeneration and human adult IVD-tissue (n=25) operated for trauma or degeneration for cellular density and chondrocyte spatial organization. IVD samples were sectioned along the main collagen fiber orientation. Nuclei were stained with DAPI and their number and spatial patterns were analyzed in an area of 250,000 µm² for each tissue category. RESULTS The initially very high cellular density in the early embryonic bovine disc (11,431 cells/mm²) steadily decreases during gestation, growth and maturation to about 71 cell/mm² in the fully grown cattle. Interestingly, in human degenerative discs, a new increase in this figure could be noted (184 cells/mm). The IVD chondrocytes appear to be predominantly present as single cells. Especially in the time after birth, string-formations represent up to 32% of all cells in the anulus fibrosus, although single cells are the predominant spatial pattern (>50%) over the entire time. With increasing degeneration, the relative proportion of single cells in human IVDs continuously decreases (12%). At the same time, the share of cells organized in clusters increases (70%). CONCLUSION Similar to articular cartilage, spatial chondrocyte organization appears to be a strong indicator for local tissue degeneration in the IVD. CLINICAL SIGNIFICANCE In the future these findings may be important for the detection and therapy of IVD degeneration in early stages.
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Affiliation(s)
- Florian Christof Bonnaire
- Laboratory of Cell Biology, Department of Orthopedic Surgery University Hospital of Tübingen, Waldhörnlestraße 22, 72072 Tübingen, Germany; Department of Orthopedic Surgery University Hospital of Tübingen, Hoppe-Seyler-Straße 3, 72076 Tübingen, Germany.
| | - Marina Danalache
- Laboratory of Cell Biology, Department of Orthopedic Surgery University Hospital of Tübingen, Waldhörnlestraße 22, 72072 Tübingen, Germany
| | - Viktor Amadeus Sigwart
- Laboratory of Cell Biology, Department of Orthopedic Surgery University Hospital of Tübingen, Waldhörnlestraße 22, 72072 Tübingen, Germany; Medical Faculty of the University of Tübingen, Geissweg 5/1, 72076 Tübingen, Germany
| | - Wolfram Breuer
- Bavarian Health and Food Authority, Veterinärstraße 2, 85764 Oberschleißheim, Germany
| | - Bernd Rolauffs
- Research Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center - Albert-Ludwigs-University of Freiburg, Hugstetter Straße 55, 79106 Freiburg im Breisgau, Germany
| | - Ulf Krister Hofmann
- Laboratory of Cell Biology, Department of Orthopedic Surgery University Hospital of Tübingen, Waldhörnlestraße 22, 72072 Tübingen, Germany; Department of Orthopedic Surgery University Hospital of Tübingen, Hoppe-Seyler-Straße 3, 72076 Tübingen, Germany
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Yokozeki Y, Kawakubo A, Miyagi M, Kuroda A, Sekiguchi H, Inoue G, Takaso M, Uchida K. Reduced TGF- β Expression and CD206-Positive Resident Macrophages in the Intervertebral Discs of Aged Mice. BIOMED RESEARCH INTERNATIONAL 2021; 2021:7988320. [PMID: 34337052 PMCID: PMC8289593 DOI: 10.1155/2021/7988320] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 07/03/2021] [Indexed: 11/18/2022]
Abstract
Age is a key factor in intervertebral disc (IVD) degeneration; however, the changes that occur in IVDs with age are not fully understood. Tissue-resident macrophages are critical for tissue homeostasis and are regulated by transforming growth factor- (TGF-) β. We examined changes in the proportion of resident macrophages in young versus aged mice and the role of TGF-β in regulating resident macrophages in IVDs. IVDs were harvested from 4-month (young) and 18-month-old (aged) C57BL/6J mice. The proportion of macrophages in IVDs was determined using flow cytometry (n = 5 for each time point) and the expression of Cd11b, Cd206, and Tgfb genes, which encode CD11b, CD206, and TGF-β protein, respectively, using real-time PCR. To study the role of TGF-β in the polarization of resident macrophages, resident macrophages isolated from IVDs from young and aged mice were treated with recombinant TGF-β with and without a TGF-β inhibitor (SB431542). Additionally, SB431542 was intraperitoneally injected into young and aged mice, and Cd206 expression was examined using real-time PCR (n = 10 for each time point). The proportion of CD11b+ and CD11b+ CD206+ cells was significantly reduced in aged versus young mice, as was Cd11b, Cd206, and Tgfb expression. TGF-β/IL10 stimulation significantly increased the expression of Cd206, an M2 macrophage marker, in disc macrophages from both young and aged mice. Meanwhile, administration of a TGF-β inhibitor significantly reduced Cd206 expression compared to vehicle control in both groups. Conclusion. Resident macrophages decrease with age in IVDs, which may be associated with the concomitant decrease in TGF-β. Our findings provide new insight into the mechanisms of age-related IVD pathology.
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Affiliation(s)
- Yuji Yokozeki
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa 252-0374, Japan
| | - Ayumu Kawakubo
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa 252-0374, Japan
| | - Masayuki Miyagi
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa 252-0374, Japan
| | - Akiyoshi Kuroda
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa 252-0374, Japan
| | - Hiroyuki Sekiguchi
- Shonan University of Medical Sciences Research Institute, Nishikubo 500, Chigasaki City, Kanagawa 253-0083, Japan
| | - Gen Inoue
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa 252-0374, Japan
| | - Masashi Takaso
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa 252-0374, Japan
| | - Kentaro Uchida
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa 252-0374, Japan
- Shonan University of Medical Sciences Research Institute, Nishikubo 500, Chigasaki City, Kanagawa 253-0083, Japan
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Zhang Y, Grant RA, Shivakumar MK, Zaleski M, Sofoluke N, Slotkin JR, Williams MS, Lee MTM. Genome-wide Association Analysis Across 16,956 Patients Identifies a Novel Genetic Association Between BMP6, NIPAL1, CNGA1 and Spondylosis. Spine (Phila Pa 1976) 2021; 46:E625-E631. [PMID: 33332786 DOI: 10.1097/brs.0000000000003880] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN A case-control genome-wide association study (GWAS) on spondylosis. OBJECTIVE Leveraging Geisinger's MyCode initiative's multimodal dataset, we aimed to identify genetic associations with degenerative spine disease. SUMMARY OF BACKGROUND DATA Degenerative spine conditions are a leading cause of global disability; however, the genetic underpinnings of these conditions remain under-investigated. Previous studies using candidate-gene approach suggest a genetic risk for degenerative spine conditions, but large-scale GWASs are lacking. METHODS We identified 4434 patients with a diagnosis of spondylosis using ICD diagnosis codes with genotype data available. We identified a population-based control of 12,522 patients who did not have any diagnosis for osteoarthritis. A linear-mix, additive genetic model was employed to perform the genetic association tests adjusting for age, sex, and genetic principal components to account for the population structure and relatedness. Gene-based association tests were performed and heritability and genetic correlations with other traits were investigated. RESULTS We identified a genome-wide significant locus at rs12190551 (odds ratio = 1.034, 95% confidence interval 1.022-1.046, P = 8.5 × 10-9, minor allele frequency = 36.9%) located in the intron of BMP6. Additionally, NIPAL1 and CNGA1 achieved Bonferroni significance in the gene-based association tests. The estimated heritability was 7.19%. Furthermore, significant genetic correlations with pain, depression, lumbar spine bone mineral density, and osteoarthritis were identified. CONCLUSION We demonstrated the use of a massive database of genotypes combined with electronic health record data to identify a novel and significant association spondylosis. We also identified significant genetic correlations with pain, depression, bone mineral density, and osteoarthritis, suggesting shared genetic etiology and molecular pathways with these phenotypes.Level of Evidence: N/A.
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Affiliation(s)
- Yanfei Zhang
- Genomic Medicine Institute, Geisinger, Danville, PA
- Genomic Research, Musculoskeletal Institute, Geisinger, Danville, PA
| | - Ryan A Grant
- Department of Neurosurgery, Geisinger, Danville, PA
| | - Manu K Shivakumar
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, PA
| | | | | | | | | | - Ming Ta Michael Lee
- Genomic Medicine Institute, Geisinger, Danville, PA
- Genomic Research, Musculoskeletal Institute, Geisinger, Danville, PA
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Roberts S, Gardner C, Jiang Z, Abedi A, Buser Z, Wang JC. Analysis of trends in lumbar disc degeneration using kinematic MRI. Clin Imaging 2021; 79:136-141. [PMID: 33940491 DOI: 10.1016/j.clinimag.2021.04.028] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 03/16/2021] [Accepted: 04/12/2021] [Indexed: 01/08/2023]
Abstract
OBJECTIVE The aim of the current study was to classify and analyze trends in lumbar disc degeneration across age, sex, and disc level using weightbearing kinematic MRI. MATERIALS AND METHODS Between January 2019 and July 2019, 1198 cases were retrospectively analyzed with kinematic MRI. Patients were divided into 5 groups based on age (20-29, 30-39, 40-49, 50-59, and 60+) and evaluated using the Pfirrmann classification to assess for disc degeneration at 5 vertebral levels: L1/2, L2/3, L3/4, L4/5, and L5/S1. Trends in degeneration were analyzed with regression and time series. RESULTS The L5/S1 vertebral disc had the highest prevalence of severe degeneration across all age groups. The most common multi-level degeneration combinations were L4/5 and L5/S1 for two levels and L3/4, L4/5, and L5/S1 for three levels. All vertebral levels showed significant difference in mean Pfirrmann grade among the age groups (p < 0.001 at all levels). Statistically significant differences in mean Pfirmmann grade among males and females were found only in ages 20-29 and 30-39, in which males showed more degeneration. CONCLUSION Our findings using kinematic MRI demonstrate that degeneration increases with age and is most severe in the L5/S1 disc. In multi-level degeneration the most prevalent combinations are those that are contiguous and include L5/S1. Young males were more likely to have degeneration than young females, but there was no significant difference from the fifth decade of life on.
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Affiliation(s)
- Sidney Roberts
- Department Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Carson Gardner
- Department Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Zhenhuan Jiang
- Department Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Aidin Abedi
- Department Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Zorica Buser
- Department Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
| | - Jeffrey C Wang
- Department Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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Frenken M, Nebelung S, Schleich C, Müller-Lutz A, Radke KL, Kamp B, Boschheidgen M, Wollschläger L, Bittersohl B, Antoch G, Konieczny MR, Abrar DB. Non-Specific Low Back Pain and Lumbar Radiculopathy: Comparison of Morphologic and Compositional MRI as Assessed by gagCEST Imaging at 3T. Diagnostics (Basel) 2021; 11:diagnostics11030402. [PMID: 33652924 PMCID: PMC7996864 DOI: 10.3390/diagnostics11030402] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/16/2021] [Accepted: 02/23/2021] [Indexed: 12/15/2022] Open
Abstract
Using glycosaminoglycan Chemical Exchange Saturation Transfer (gagCEST) magnetic resonance imaging (MRI), this study comparatively evaluated the GAG contents of lumbar intervertebral disks (IVDs) of patients with non-specific low back pain (nsLBP), radiculopathy, and asymptomatic volunteers to elucidate the association of clinical manifestation and compositional correlate. A total of 18 patients (mean age 57.5 ± 22.5 years) with radiculopathy, 16 age-matched patients with chronic nsLBP and 20 age-matched volunteers underwent standard morphologic and compositional gagCEST MRI on a 3T scanner. In all cohorts, GAG contents of lumbar IVDs were determined using gagCEST MRI. An assessment of morphologic IVD degeneration based on the Pfirrmann classification and T2-weighted sequences served as a reference. A linear mixed model adjusted for multiple confounders was used for statistical evaluation. IVDs of patients with nsLBP showed lower gagCEST values than those of volunteers (nsLBP: 1.3% [99% confidence intervals (CI): 1.0; 1.6] vs. volunteers: 1.9% [99% CI: 1.6; 2.2]). Yet, IVDs of patients with radiculopathy (1.8% [99% CI: 1.4; 2.1]) were not different from patients with nsLBP or volunteers. In patients with radiculopathy, IVDs directly adjacent to IVD extrusions demonstrated lower gagCEST values than distant IVDs (adjacent: 0.9% [99% CI: 0.3; 1.5], distant: 2.1% [99% CI: 1.7; 2.5]). Advanced GAG depletion in nsLBP and directly adjacent to IVD extrusions in radiculopathy indicates close interrelatedness of clinical pathology and compositional degeneration.
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Affiliation(s)
- Miriam Frenken
- Department of Diagnostic and Interventional Radiology, Medical Faculty, University Dusseldorf, D-40225 Dusseldorf, Germany; (M.F.); (S.N.); (C.S.); (A.M.-L.); (K.L.R.); (B.K.); (M.B.); (G.A.)
| | - Sven Nebelung
- Department of Diagnostic and Interventional Radiology, Medical Faculty, University Dusseldorf, D-40225 Dusseldorf, Germany; (M.F.); (S.N.); (C.S.); (A.M.-L.); (K.L.R.); (B.K.); (M.B.); (G.A.)
| | - Christoph Schleich
- Department of Diagnostic and Interventional Radiology, Medical Faculty, University Dusseldorf, D-40225 Dusseldorf, Germany; (M.F.); (S.N.); (C.S.); (A.M.-L.); (K.L.R.); (B.K.); (M.B.); (G.A.)
| | - Anja Müller-Lutz
- Department of Diagnostic and Interventional Radiology, Medical Faculty, University Dusseldorf, D-40225 Dusseldorf, Germany; (M.F.); (S.N.); (C.S.); (A.M.-L.); (K.L.R.); (B.K.); (M.B.); (G.A.)
| | - Karl Ludger Radke
- Department of Diagnostic and Interventional Radiology, Medical Faculty, University Dusseldorf, D-40225 Dusseldorf, Germany; (M.F.); (S.N.); (C.S.); (A.M.-L.); (K.L.R.); (B.K.); (M.B.); (G.A.)
| | - Benedikt Kamp
- Department of Diagnostic and Interventional Radiology, Medical Faculty, University Dusseldorf, D-40225 Dusseldorf, Germany; (M.F.); (S.N.); (C.S.); (A.M.-L.); (K.L.R.); (B.K.); (M.B.); (G.A.)
| | - Matthias Boschheidgen
- Department of Diagnostic and Interventional Radiology, Medical Faculty, University Dusseldorf, D-40225 Dusseldorf, Germany; (M.F.); (S.N.); (C.S.); (A.M.-L.); (K.L.R.); (B.K.); (M.B.); (G.A.)
| | - Lena Wollschläger
- Department of Orthopedic and Trauma Surgery, University Hospital of Duesseldorf, D-40225 Duesseldorf, Germany; (L.W.); (B.B.); (M.R.K.)
| | - Bernd Bittersohl
- Department of Orthopedic and Trauma Surgery, University Hospital of Duesseldorf, D-40225 Duesseldorf, Germany; (L.W.); (B.B.); (M.R.K.)
| | - Gerald Antoch
- Department of Diagnostic and Interventional Radiology, Medical Faculty, University Dusseldorf, D-40225 Dusseldorf, Germany; (M.F.); (S.N.); (C.S.); (A.M.-L.); (K.L.R.); (B.K.); (M.B.); (G.A.)
| | - Markus R. Konieczny
- Department of Orthopedic and Trauma Surgery, University Hospital of Duesseldorf, D-40225 Duesseldorf, Germany; (L.W.); (B.B.); (M.R.K.)
| | - Daniel B. Abrar
- Department of Diagnostic and Interventional Radiology, Medical Faculty, University Dusseldorf, D-40225 Dusseldorf, Germany; (M.F.); (S.N.); (C.S.); (A.M.-L.); (K.L.R.); (B.K.); (M.B.); (G.A.)
- Correspondence:
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López-Cuevas P, Deane L, Yang Y, Hammond CL, Kague E. Transformed notochordal cells trigger chronic wounds destabilizing the vertebral column and bone homeostasis. Dis Model Mech 2021; 14:dmm.047001. [PMID: 33579726 PMCID: PMC7988777 DOI: 10.1242/dmm.047001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 02/01/2021] [Indexed: 12/14/2022] Open
Abstract
Notochordal cells play a pivotal role in vertebral column patterning, contributing to the formation of the inner architecture of intervertebral discs (IVDs). Their disappearance during development has been associated with reduced repair capacity and IVD degeneration. Notochord cells can give rise to chordomas, a highly invasive bone cancer associated with late diagnosis. Understanding the impact of neoplastic cells during development and on the surrounding vertebral column could open avenues for earlier intervention and therapeutics. We investigated the impact of transformed notochord cells in the zebrafish skeleton using a line expressing RAS in the notochord under the control of the kita promoter, with the advantage of adulthood endurance. Transformed cells caused damage in the notochord and destabilised the sheath layer, triggering a wound repair mechanism, with enrolment of sheath cells (col9a2+) and expression of wt1b, similar to induced notochord wounds. Moreover, increased recruitment of neutrophils and macrophages, displaying abnormal behaviour in proximity to the notochord sheath and transformed cells, supported parallels between chordomas, wound and inflammation. Cancerous notochordal cells interfere with differentiation of sheath cells to form chordacentra domains, leading to fusions and vertebral clefts during development. Adults displayed IVD irregularities reminiscent of degeneration, including reduced bone mineral density and increased osteoclast activity, along with disorganised osteoblasts and collagen, indicating impaired bone homeostasis. By depleting inflammatory cells, we abrogated chordoma development and rescued the skeletal features of the vertebral column. Therefore, we showed that transformed notochord cells alter the skeleton during life, causing a wound-like phenotype and activating chronic wound response, suggesting parallels between chordoma, wound, IVD degeneration and inflammation, highlighting inflammation as a promising target for future therapeutics. This article has an associated First Person interview with the first author of the paper. Summary: Analyses using a zebrafish line expressing RAS in the notochord, under the control of the kita promoter, revealed that transformed notochord cells alter the skeleton during life, causing a wound-like phenotype and activating chronic wound response.
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Affiliation(s)
- Paco López-Cuevas
- The School of Biochemistry, Biomedical Sciences, University of Bristol, BS8 1TD, UK
| | - Luke Deane
- The School of Biochemistry, Biomedical Sciences, University of Bristol, BS8 1TD, UK
| | - Yushi Yang
- School of Physics, HH Wills Physics Laboratory, University of Bristol, BS8 1TL, UK.,Centre for Nanoscience and Quantum Information, University of Bristol, Bristol, BS8 1FD, UK.,Bristol Centre for Functional Nanomaterials, University of Bristol, Bristol, BS8 1TL, UK
| | - Chrissy L Hammond
- The School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, BS8 1TD, UK
| | - Erika Kague
- The School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, BS8 1TD, UK
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Whittal MC, Molladavoodi S, Zwambag DP, Millecamps M, Stone LS, Gregory DE. Mechanical Consequence of Induced Intervertebral Disc Degeneration in the SPARC-Null Mouse. J Biomech Eng 2021; 143:024501. [PMID: 32734296 DOI: 10.1115/1.4047995] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Indexed: 11/08/2022]
Abstract
Intervertebral disc (IVD) degeneration is associated with low back pain (LBP) and accompanied by mechanical changes to the spine. Secreted protein acidic and rich in cysteine (SPARC) is a protein that contributes to the functioning and maintenance of the extracellular matrix. SPARC-null mice display accelerated IVD degeneration and pain-associated behaviors. This study examined if SPARC-null mice also display altered spine mechanics as compared to wild-type (WT) mice. Lumbar spines from SPARC-null (n = 36) and WT (n = 18) mice aged 14-25 months were subjected to cyclic axial tension and compression to determine neutral zone (NZ) length and stiffness. Three separate mechanical tests were completed for each spine to determine the effect of the number of IVDs tested in series (one versus two versus three IVDs). SPARC-null spine NZs were both stiffer (p < 0.001) and smaller in length (p < 0.001) than WT spines. There was an effect of the number of IVDs tested in series for NZ length but not NZ stiffness when collapsed across condition (SPARC-null and WT). Correlation analysis revealed a weak negative correlation (r = -0.24) between age and NZ length in SPARC-null mice and a weak positive correlation (r = 0.30) between age and NZ stiffness in WT mice. In conclusion, SPARC-null mice had stiffer and smaller NZs than WT mice, regardless of the number of IVDs in series being tested. The increased stiffness of these IVDs likely influences mobility at these spinal joints thereby potentially contributing to low back pain.
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Affiliation(s)
- Mitchel C Whittal
- Department of Kinesiology and Physical Education, Wilfrid Laurier University, 75 University Avenue W, Waterloo, ON N2 L 3C5, Canada
| | - Sara Molladavoodi
- Department of Kinesiology and Physical Education, Wilfrid Laurier University, 75 University Avenue W, Waterloo, ON N2 L 3C5, Canada
| | - Derek P Zwambag
- Department of Kinesiology and Physical Education, Wilfrid Laurier University, 75 University Avenue W, Waterloo, ON N2 L 3C5, Canada
| | - Magali Millecamps
- Faculty of Dentistry, McGill University, 845 Sherbrooke Street West, Montréal, QC H3A 0G4, Canada
| | - Laura S Stone
- Faculty of Dentistry, McGill University, 845 Sherbrooke Street West, Montréal, QC H3A 0G4, Canada
| | - Diane E Gregory
- Department of Kinesiology and Physical Education/Department of Health Sciences, Wilfrid Laurier University, 75 University Avenue W, Waterloo, ON N2 L 3C5, Canada
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Lan T, Shiyu-Hu, Shen Z, Yan B, Chen J. New insights into the interplay between miRNAs and autophagy in the aging of intervertebral discs. Ageing Res Rev 2021; 65:101227. [PMID: 33238206 DOI: 10.1016/j.arr.2020.101227] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 10/27/2020] [Accepted: 11/19/2020] [Indexed: 02/06/2023]
Abstract
Intervertebral disc degeneration (IDD) has been widely known as a main contributor to low back pain which has a negative socioeconomic impact worldwide. However, the underlying mechanism remains unclear. MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate gene expression and serve key roles in the ageing process of intervertebral disc. Autophagy is an evolutionarily conserved process that maintains cellular homeostasis through recycling of nutrients and degradation of damaged or aged cytoplasmic organelles. Autophagy has been proposed as a "double-edged sword" and autophagy dysfunction of IVD cells is considered as a crucial reason of IDD. A rapidly growing number of recent studies demonstrate that both miRNAs and autophagy play important roles in the progression of IDD. Furthermore, accumulated research has indicated that miRNAs target autophagy-related genes and influence the onset and development of IDD. Hence, this review focuses mainly on the current findings regarding the correlations between miRNA, autophagy, and IDD and provides new insights into the role of miRNA-autophagy pathway involved in IDD pathophysiology.
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Yoon SH, Kim DH, Cho S, Kim KJ. Evaluation of Bone Marrow-derived Stem Cells and Adipose-derived Stem Cells Co-cultured on Human Nucleus Pulposus Cells: A Pilot Study. Korean J Neurotrauma 2020; 16:138-146. [PMID: 33163421 PMCID: PMC7607015 DOI: 10.13004/kjnt.2020.16.e36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 09/09/2020] [Accepted: 09/15/2020] [Indexed: 11/15/2022] Open
Abstract
Objective We aimed to determine whether bone marrow-derived mesenchymal stem cells (BDMSCs) effectively attenuate the degeneration of human nucleus pulposus cells (NPCs). Methods Four NPC lines were obtained from 3 subjects who underwent spinal surgery for cervical disc herniation (n=1) or lumbar disc herniation (n=2). For co-culture wells without contact, BDMSCs and adipose-derived mesenchymal stem cells (ADMSCs) were seeded on tissue culture plates and maintained for 3 days. Senescence-associated β-gal (SA-β-gal) staining was represented as a percentage of the total number of stained cells (%). The cells with intracellular lipid droplets (LDs) were represented as the percentage of the number of cells with LDs. Glycosaminoglycan (GAG) secretion was measured at 450 nm, using a commercial kit, to analyze optical density. Results The ratio of cells stained with SA-β-gal to the total number of cells reduced significantly when co-cultured with BDMSCs and ADMSCs (p<0.001 vs. p<0.001). The proportion of NPCs containing LDs was lower when co-cultured with BDMSCs than with ADMSCs (p<0.001). The optical density related to GAG secretion was lower in BDMSCs and ADMSCs co-cultured with NPCs than in the controls (p<0.001 vs. p<0.001). Conclusion SA-β-gal staining showed significant attenuation of degenerative changes in NPCs co-cultured with BDMSCs. Moreover, the unexpected increase in LDs was significantly higher in NPCs co-cultured with ADMSCs than in those co-cultured with BDMSCs. However, GAG secretion was significantly decreased in NPCs co-cultured with MSCs.
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Affiliation(s)
- Sang Hoon Yoon
- Department of Neurosurgery, Armed Forces Capital Hospital, Seongnam, Korea
- Department of Neurosurgery & Spine Care, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Dae Hee Kim
- Department of Neurosurgery, Armed Forces Capital Hospital, Seongnam, Korea
- Department of Neurosurgery & Spine Care, Seoul National University Bundang Hospital, Seongnam, Korea
- Neurosurgical Laboratory, Seoul National University Bundang Hospital, Seongnam, Korea
- Research Institute, Sociotech Co. Ltd., Seongnam, Korea
| | - Sam Cho
- Department of Neurosurgery, Armed Forces Capital Hospital, Seongnam, Korea
- Department of Neurosurgery & Spine Care, Seoul National University Bundang Hospital, Seongnam, Korea
- Research Institute, Sociotech Co. Ltd., Seongnam, Korea
| | - Ki-Jeong Kim
- Department of Neurosurgery & Spine Care, Seoul National University Bundang Hospital, Seongnam, Korea
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Nan LP, Wang F, Ran D, Zhou SF, Liu Y, Zhang Z, Huang ZN, Wang ZY, Wang JC, Feng XM, Zhang L. Naringin alleviates H 2O 2-induced apoptosis via the PI3K/Akt pathway in rat nucleus pulposus-derived mesenchymal stem cells. Connect Tissue Res 2020; 61:554-567. [PMID: 31294637 DOI: 10.1080/03008207.2019.1631299] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Purpose: To investigate the protective effect of naringin (Nar) on H2O2-induced apoptosis of nucleus pulposus-derived mesenchymal stem cells (NPMSC) and the potential mechanism in this process. Methods: Rat NPMSC were cultured in MSC culture medium or culture medium with different concentrations of H2O2. Nar or the combination of Nar and LY294002 was added into the culture medium to investigate the effects of Nar. Cell viability was evaluated by cell counting kit-8 (CCK-8) assay. The apoptosis rate was determined using Annexin V/PI dual staining and terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assays. Additionally, the levels of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were analyzed by flow cytometry. ATP level in NPMSC was analyzed via ATP detection kit. Mitochondrial ultrastructure change was observed through transmission electron microscope (TEM). Levels of apoptosis-associated molecules (cleaved caspase-3, Bax and Bcl-2) were evaluated via RT-PCR and western blot, respectively. Results: The cells isolated from NP met the criteria for MSC. H2O2 significantly promoted NPMSC apoptosis in a dose and time-dependent manner. Nar showed no cytotoxicity effect on NPMSC up to a concentration of 100 μM for 24 h. Nar exhibited protective effects against H2O2-induced NPMSC apoptosis including apoptosis rate, expressions of proapoptosis and antiapoptosis related genes and protein. Nar could also alleviate H2O2-induced mitochondrial dysfunction of increased mitochondrial ROS production, reduced MMP, decreased intracellular ATP and mitochondrial ultrastructure change. However, these protected effects were inhibited after LY294002 treatment. Conclusions: Our results demonstrated that Nar efficiently attenuated H2O2-induced NPMSC apoptosis and mitochondrial dysfunction. The activation of ROS-mediated PI3K/Akt pathway may be the potential mechanism in this process.
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Affiliation(s)
- Li-Ping Nan
- Department of Orthopedics, Dalian Medical University , Dalian, Liaoning, China.,Department of Orthopedics, Clinical Medical College of Yangzhou University , Yangzhou, Jiangsu, China
| | - Feng Wang
- Department of Orthopedics, Dalian Medical University , Dalian, Liaoning, China.,Department of Orthopedics, Clinical Medical College of Yangzhou University , Yangzhou, Jiangsu, China
| | - Di Ran
- College of Veterinary Medicine, Yangzhou University , Yangzhou, China
| | - Shi-Feng Zhou
- Department of Orthopedics, Clinical Medical College of Yangzhou University , Yangzhou, Jiangsu, China
| | - Yang Liu
- Department of Orthopedics, Dalian Medical University , Dalian, Liaoning, China.,Department of Orthopedics, Clinical Medical College of Yangzhou University , Yangzhou, Jiangsu, China
| | - Zhen Zhang
- Department of Orthopedics, Dalian Medical University , Dalian, Liaoning, China.,Department of Orthopedics, Clinical Medical College of Yangzhou University , Yangzhou, Jiangsu, China
| | - Ze-Nan Huang
- Department of Orthopedics, Clinical Medical College of Yangzhou University , Yangzhou, Jiangsu, China
| | - Ze-Yu Wang
- Department of Orthopedics, Clinical Medical College of Yangzhou University , Yangzhou, Jiangsu, China
| | - Jing-Cheng Wang
- Department of Orthopedics, Clinical Medical College of Yangzhou University , Yangzhou, Jiangsu, China
| | - Xin-Min Feng
- Department of Orthopedics, Clinical Medical College of Yangzhou University , Yangzhou, Jiangsu, China
| | - Liang Zhang
- Department of Orthopedics, Clinical Medical College of Yangzhou University , Yangzhou, Jiangsu, China
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Mesregah MK, Lee H, Roberts S, Gardner C, Shah I, Buchanan IA, Li C, Buser Z, Wang JC. Evaluation of facet joints and segmental motion in patients with different grades of L5/S1 intervertebral disc degeneration: a kinematic MRI study. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2020; 29:2609-2618. [PMID: 32504265 DOI: 10.1007/s00586-020-06482-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 05/27/2020] [Indexed: 11/24/2022]
Abstract
PURPOSE This study aimed to evaluate facet joint parameters and osteoarthritis grades, and segmental angular and translational motions among different grades of L5/S1 intervertebral disc (IVD) degeneration. METHODS This retrospective study analysed kinematic magnetic resonance imaging (kMRI) images of the lumbar spine of 214 patients with low back pain. Degenerations of the L5/S1 IVDs and facet joints osteoarthritis were assessed using the Pfirrmann and Pathria grading scales, respectively. Facet joint parameters included facet joint angle and facet joint space width. Angular and translation segmental motions were measured using MRI Analyzer software. RESULTS The mean age of the studied patients was 44.1 ± 13.9 years. Patients with L5/S1 disc degeneration were associated with higher odds of facet joint osteoarthritis (odds ratio = 2.28, 95% confidence interval = 1.23-4.23, P = 0.008). There was a positive correlation between L5/S1 disc degeneration grade and the facet joint grade (r = 0.365, P > 0.001). Grade IV facet joint osteoarthritis did not appear in grades I or II disc degeneration (P > 0.001). The average facet joint width decreased significantly with increasing Pfirrmann grading (P = 0.017). The difference in facet joint angle between groups was not statistically significant (P = 0.532). The differences in the angular and translational motions were not statistically significant (P = 0.530, and 0.510, respectively). CONCLUSION A positive correlation exists between L5/S1 disc degeneration and facet joint osteoarthritis grades. The facet joint space width decreases significantly with increasing grade of disc degeneration.
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Affiliation(s)
- Mohamed Kamal Mesregah
- Department Orthopaedic Surgery, Keck School of Medicine, University of Southern California, 1540 Alcazar Street, CHP 207, Los Angeles, CA, 90033, USA.,Department Orthopaedic Surgery, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | - Haiyin Lee
- Department Orthopaedic Surgery, Keck School of Medicine, University of Southern California, 1540 Alcazar Street, CHP 207, Los Angeles, CA, 90033, USA.,Department of Orthopaedics, Xinqiao Hospital, The Third Military Medical University, Chongqing, China
| | - Sidney Roberts
- Department Orthopaedic Surgery, Keck School of Medicine, University of Southern California, 1540 Alcazar Street, CHP 207, Los Angeles, CA, 90033, USA
| | - Carson Gardner
- Department Orthopaedic Surgery, Keck School of Medicine, University of Southern California, 1540 Alcazar Street, CHP 207, Los Angeles, CA, 90033, USA
| | - Ishan Shah
- Department Orthopaedic Surgery, Keck School of Medicine, University of Southern California, 1540 Alcazar Street, CHP 207, Los Angeles, CA, 90033, USA
| | - Ian A Buchanan
- Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Changqing Li
- Department of Orthopaedics, Xinqiao Hospital, The Third Military Medical University, Chongqing, China
| | - Zorica Buser
- Department Orthopaedic Surgery, Keck School of Medicine, University of Southern California, 1540 Alcazar Street, CHP 207, Los Angeles, CA, 90033, USA.
| | - Jeffrey C Wang
- Department Orthopaedic Surgery, Keck School of Medicine, University of Southern California, 1540 Alcazar Street, CHP 207, Los Angeles, CA, 90033, USA
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Williams FM, Tsepilov YA, Freidin MB, Shashkova TI, Suri P, Aulchenko YS. Sequence variation at 8q24.21 and risk of back pain. F1000Res 2020. [DOI: 10.12688/f1000research.22725.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Back pain (BP) is a common condition of major social importance and poorly understood pathogenesis. Intervertebral lumbar disc degeneration in all its guises is one of the major biological risk factors for BP. Previously, we identified the locus at 8q24.21 associated with chronic BP, which has been found elsewhere associated with sciatica after surgery for lumbar disc herniation. In the current study we used co-localisation methods to identify the gene most likely to harbor the causal variant. We show that the same functional variant at the 8q24.21 locus is responsible for both lumbar disc degeneration and BP, and we also studied the effects of this locus on related phenotypes. Our results link the locus to intervertebral disc and bone mineral density, but not to anthropometric measurements, thus corroborating the epidemiological evidence. Moreover, the same functional variant at the locus is more likely to affect the expression of the nearby FAM49B gene, rather than the GSDMC gene, which was previously proposed as a causative one for BP.
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48
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Insight into the genetic architecture of back pain and its risk factors from a study of 509,000 individuals. Pain 2020; 160:1361-1373. [PMID: 30747904 DOI: 10.1097/j.pain.0000000000001514] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Back pain (BP) is a common condition of major social importance and poorly understood pathogenesis. Combining data from the UK Biobank and CHARGE consortium cohorts allowed us to perform a very large genome-wide association study (total N = 509,070) and examine the genetic correlation and pleiotropy between BP and its clinical and psychosocial risk factors. We identified and replicated 3 BP-associated loci, including one novel region implicating SPOCK2/CHST3 genes. We provide evidence for pleiotropic effects of genetic factors underlying BP, height, and intervertebral disk problems. We also identified independent genetic correlations between BP and depression symptoms, neuroticism, sleep disturbance, overweight, and smoking. A significant enrichment for genes involved in the central nervous system and skeletal tissue development was observed. The study of pleiotropy and genetic correlations, supported by the pathway analysis, suggests at least 2 strong molecular axes of BP genesis, one related to structural/anatomical factors such as intervertebral disk problems and anthropometrics, and another related to the psychological component of pain perception and pain processing. These findings corroborate with the current biopsychosocial model as a paradigm for BP. Overall, the results demonstrate BP to have an extremely complex genetic architecture that overlaps with the genetic predisposition to its biopsychosocial risk factors. The work sheds light on pathways of relevance in the prevention and management of low BP.
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Liu Y, Li Y, Nan LP, Wang F, Zhou SF, Feng XM, Liu H, Zhang L. Insights of stem cell-based endogenous repair of intervertebral disc degeneration. World J Stem Cells 2020; 12:266-276. [PMID: 32399135 PMCID: PMC7202923 DOI: 10.4252/wjsc.v12.i4.266] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 03/26/2020] [Accepted: 04/05/2020] [Indexed: 02/06/2023] Open
Abstract
Low back pain has become more prevalent in recent years, causing enormous economic burden for society and government. Common therapies used in clinics including conservative treatment and surgery can only relieve pain. Subsequent cell-based treatment such as mesenchymal stem cell transplantation poses problems such as short duration of therapeutic effect and tumorigenesis. Recently, the discovery and identification of stem cell niche and stem/progenitor cells in intervertebral disc bring increased attention to endogenous repair strategy. Therefore, we review the studies involving endogenous repair strategy and present the characteristics and current status of this treatment. Meanwhile, we also discuss the strategy and perspective of endogenous repair strategy in future.
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Affiliation(s)
- Yang Liu
- Department of Orthopedics, West China Hospital of Sichuan University, Chengdu 610000, Sichuan Province, China
- Department of Orthopedics, Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Yan Li
- Department of Oncology, The Affiliated Cancer Hospital, School of Medicine, UESTC, Chengdu 610000, Sichuan Province, China
| | - Li-Ping Nan
- Department of Orthopedics, Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Feng Wang
- Department of Orthopedics, Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Shi-Feng Zhou
- Department of Orthopedics, Clinical Medical College of Yangzhou University, Yangzhou 225000, Jiangsu Province, China
| | - Xin-Min Feng
- Department of Orthopedics, Clinical Medical College of Yangzhou University, Yangzhou 225000, Jiangsu Province, China
| | - Hao Liu
- Department of Orthopedics, West China Hospital of Sichuan University, Chengdu 610000, Sichuan Province, China
| | - Liang Zhang
- Department of Orthopedics, Clinical Medical College of Yangzhou University, Yangzhou 225000, Jiangsu Province, China
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50
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Guan Y, Wang S, Wang J, Meng D, Wu H, Wei Q, Jiang H. Gene polymorphisms and expression levels of interleukin-6 and interleukin-10 in lumbar disc disease: a meta-analysis and immunohistochemical study. J Orthop Surg Res 2020; 15:54. [PMID: 32070384 PMCID: PMC7027108 DOI: 10.1186/s13018-020-01588-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Accepted: 02/11/2020] [Indexed: 12/15/2022] Open
Abstract
Background To investigate the association between interleukin-6 (IL-6) (rs1800795, rs1800796, rs1800797, rs13306435, rs2069849) and interleukin-10 (IL-10) (rs1800871, rs1800896) gene polymorphisms, expression levels, and lumbar disc disease (LDD). Methods We conducted a literature research on PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure (CNKI) until February 28, 2019. We included all case-control studies about the association between IL-6 and IL-10 gene polymorphisms and LDD. The odds ratio (OR) and 95% confidence interval (CI) were calculated to estimate the strength of association. Statistical analysis was conducted by Review Manager (RevMan) 5.3 software. Furthermore, immunohistochemistry (IHC) and RT-PCR were performed to evaluate IL-6 and IL-10 expressions in the normal and degenerated disc. Results A total of 6 studies, involving 1456 cases and 1611 controls, were included in this meta-analysis. G alleles of rs1800795 and rs1800797 in the IL-6 gene were significantly associated with LDD (rs1800795: G vs. C, OR = 1.38, 95% CI = 1.16–1.64, P = 0.0002; rs1800797: G vs. A, OR = 1.35, 95% CI = 1.14–1.61, P = 0.0006). Begg’s funnel plot and Egger’s tests did not show any evidence of publication bias. IL-6 expression and IL-6 mRNA levels were significantly increased in the degenerated disc compared with those in the normal disc (IL-6 immunopositive cells, 73.68 ± 10.99% vs. 37.23 ± 6.42%, P < 0.001). Conclusions IL-6 gene polymorphisms (rs1800795 and rs1800797) were significantly associated with susceptibility to LDD. A high expression level of IL-6 may be an important risk factor for LDD.
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Affiliation(s)
- Yewen Guan
- Division of Spine Surgery, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, 530021, China
| | - Siting Wang
- Division of Spine Surgery, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, 530021, China
| | - Jiaqi Wang
- Division of Spine Surgery, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, 530021, China
| | - Dihua Meng
- Division of Spine Surgery, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, 530021, China
| | - Huihong Wu
- Division of Spine Surgery, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, 530021, China
| | - Qingjun Wei
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, 530021, China.
| | - Hua Jiang
- Division of Spine Surgery, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, 530021, China. .,Department of Orthopaedic Surgery, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, 530021, China.
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