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Keshavarz S, Alavi CE, Aghayan H, Jafari-Shakib R, Vojoudi E. Advancements in Degenerative Disc Disease Treatment: A Regenerative Medicine Approach. Stem Cell Rev Rep 2025:10.1007/s12015-025-10882-z. [PMID: 40232618 DOI: 10.1007/s12015-025-10882-z] [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: 04/07/2025] [Indexed: 04/16/2025]
Abstract
Regenerative medicine represents a transformative approach to treating nucleus pulposus degeneration and offers hope for patients suffering from chronic low back pain due to disc degeneration. By focusing on restoring the natural structure and function of the nucleus pulposus rather than merely alleviating symptoms, these innovative therapies hold the potential to significantly improve patient outcomes. As research continues to advance in this field, we may soon witness a paradigm shift in how we approach spinal health and degenerative disc disease. The main purpose of this review is to provide an overview of the various regenerative approaches that target the restoration of the nucleus pulposus, a primary site for initiation of intervertebral disc degeneration.
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Affiliation(s)
- Samaneh Keshavarz
- School of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Cyrus Emir Alavi
- Department of Anesthesiology, Neuroscience Research Center, Avicenna University Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | - Hamidreza Aghayan
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular- Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Jafari-Shakib
- Department of Immunology, School of Medicine, Guilan University of Medical Sciences, P.O.Box 41635 - 3363, Rasht, Iran.
| | - Elham Vojoudi
- Regenerative Medicine, Organ Procurement and Transplantation Multidisciplinary Center, School of Medicine, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran.
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Wu R, Zhao XJ, Du Y, Dong Y, Song X, Zhu Y. Lipid metabolic disorders and their impact on cartilage endplate and nucleus pulposus function in intervertebral disk degeneration. Front Nutr 2025; 12:1533264. [PMID: 40129665 PMCID: PMC11931516 DOI: 10.3389/fnut.2025.1533264] [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: 11/23/2024] [Accepted: 02/06/2025] [Indexed: 03/26/2025] Open
Abstract
Lipid metabolism encompasses the processes of digestion, absorption, synthesis, and degradation of fats within biological systems, playing a crucial role in sustaining normal physiological functions. Disorders of lipid metabolism, characterized by abnormal blood lipid levels and dysregulated fatty acid metabolism, have emerged as significant contributors to intervertebral disk degeneration (IDD). The pathogenesis of IDD is multifaceted, encompassing genetic predispositions, nutritional and metabolic factors, mechanical stressors, trauma, and inflammatory responses, which collectively facilitate the progression of IDD. Although the precise mechanisms underlying IDD remain incompletely elucidated, there is substantial consensus regarding the close association between lipid metabolism disorders and its development. Intervertebral disks are essential for maintaining spinal alignment. Their primary functions encompass shock absorption, preservation of physiological curvature, facilitation of movement, and provision of stability. The elasticity and thickness of these disks effectively absorb daily impacts, safeguard the spine, uphold its natural curvature and flexibility, while also creating space for nerve roots to prevent compression and ensure normal transmission of nerve signals. Research indicates that such metabolic disturbances may compromise the functionality of cartilaginous endplates (CEP) and nucleus pulposus (NP), thereby facilitating IDD's onset and progression. The CEP is integral to internal material exchange and shock absorption while mitigating NP herniation under mechanical load conditions. As the central component of intervertebral disks, NP is essential for maintaining disk height and providing shock-absorbing capabilities; thus, damage to these critical structures accelerates IDD progression. Furthermore, lipid metabolism disorders contribute to IDD through mechanisms including activation of endoplasmic reticulum stress pathways, enhancement of oxidative stress levels, induction of cellular pyroptosis alongside inhibition of autophagy processes-coupled with the promotion of inflammation-induced fibrosis and fibroblast proliferation leading to calcification within intervertebral disks. This review delineates the intricate interplay between lipid metabolism disorders and IDD; it is anticipated that advancing our understanding of this pathogenesis will pave the way for more effective preventive measures and therapeutic strategies against IDD in future research.
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Affiliation(s)
- Ruixia Wu
- Inner Mongolia Medical University, Hohhot, China
| | - Xiao Juan Zhao
- The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Yaxin Du
- Inner Mongolia Medical University, Hohhot, China
| | - Yizhi Dong
- Inner Mongolia Medical University, Hohhot, China
| | - Xinyue Song
- Inner Mongolia Medical University, Hohhot, China
| | - Yong Zhu
- Peking University Cancer Hospital Inner Mongolia Hospital, Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, China
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Kamp B, Radke KL, Knet M, Strunk R, Gallinnis PJ, Nagel AM, Filler TJ, Antoch G, Abrar DB, Frenken M, Wittsack H, Müller‐Lutz A. Sodium MRI of the Lumbar Intervertebral Discs of the Human Spine: An Ex Vivo Study. J Magn Reson Imaging 2025; 61:1503-1512. [PMID: 38963154 PMCID: PMC11803688 DOI: 10.1002/jmri.29521] [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] [Revised: 06/18/2024] [Accepted: 06/18/2024] [Indexed: 07/05/2024] Open
Abstract
BACKGROUND Lower back pain affects 75%-85% of people at some point in their lives. The detection of biochemical changes with sodium (23Na) MRI has potential to enable an earlier and more accurate diagnosis. PURPOSE To measure 23Na relaxation times and apparent tissue sodium concentration (aTSC) in ex-vivo intervertebral discs (IVDs), and to investigate the relationship between aTSC and histological Thompson grade. STUDY TYPE Ex-vivo. SPECIMEN Thirty IVDs from the lumbar spines of 11 human body donors (4 female, 7 male, mean age 86 ± 8 years). FIELD STRENGTH/SEQUENCE 3 T; density-adapted 3D radial sequence (DA-3D-RAD). ASSESSMENT IVD 23Na longitudinal (T1), short and long transverse (T2s* and T2l*) relaxation times and the proportion of the short transverse relaxation (ps) were calculated for one IVD per spine sample (11 IVDs). Furthermore, aTSCs were calculated for all IVDs. The degradation of the IVDs was assessed via histological Thompson grading. STATISTICAL TESTS A Kendall Tau correlation (τ) test was performed between the aTSCs and the Thompson grades. The significance level was set to P < 0.05. RESULTS Mean 23Na relaxation parameters of a subset of 11 IVDs were T1 = 9.8 ± 1.3 msec, T2s* = 0.7 ± 0.1 msec, T2l* = 7.3 ± 1.1 msec, and ps = 32.7 ± 4.0%. A total of 30 IVDs were examined, of which 3 had Thompson grade 1, 4 had grade 2, 5 had grade 3, 5 had grade 4, and 13 had grade 5. The aTSC decreased with increasing degradation, being 274.6 ± 18.9 mM for Thompson grade 1 and 190.5 ± 29.5 mM for Thompson grade 5. The correlation between whole IVD aTSC and Thompson grade was significant and strongly negative (τ = -0.56). DATA CONCLUSION This study showed a significant correlation between aTSC and degenerative IVD changes. Consequently, aTSC has potential to be useful as an indicator of degenerative spinal changes. EVIDENCE LEVEL 2 TECHNICAL EFFICACY: Stage 1.
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Affiliation(s)
- Benedikt Kamp
- Department of Diagnostic and Interventional RadiologyMedical Faculty and University Hospital Düsseldorf, Heinrich‐Heine‐University DüsseldorfDüsseldorfGermany
| | - Karl Ludger Radke
- Department of Diagnostic and Interventional RadiologyMedical Faculty and University Hospital Düsseldorf, Heinrich‐Heine‐University DüsseldorfDüsseldorfGermany
| | - Marek Knet
- Department of Diagnostic and Interventional RadiologyMedical Faculty and University Hospital Düsseldorf, Heinrich‐Heine‐University DüsseldorfDüsseldorfGermany
| | - Rosanna Strunk
- Department of Diagnostic and Interventional RadiologyMedical Faculty and University Hospital Düsseldorf, Heinrich‐Heine‐University DüsseldorfDüsseldorfGermany
| | - Patrik J. Gallinnis
- Department of Diagnostic and Interventional RadiologyMedical Faculty and University Hospital Düsseldorf, Heinrich‐Heine‐University DüsseldorfDüsseldorfGermany
| | - Armin M. Nagel
- Institute of Radiology, University Hospital ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenGermany
- Division of Medical Physics in RadiologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Timm J. Filler
- Institute of Anatomy IHeinrich‐Heine‐University DüsseldorfDüsseldorfGermany
| | - Gerald Antoch
- Department of Diagnostic and Interventional RadiologyMedical Faculty and University Hospital Düsseldorf, Heinrich‐Heine‐University DüsseldorfDüsseldorfGermany
| | - Daniel B. Abrar
- Department of Diagnostic and Interventional RadiologyMedical Faculty and University Hospital Düsseldorf, Heinrich‐Heine‐University DüsseldorfDüsseldorfGermany
| | - Miriam Frenken
- Department of Diagnostic and Interventional RadiologyMedical Faculty and University Hospital Düsseldorf, Heinrich‐Heine‐University DüsseldorfDüsseldorfGermany
| | - Hans‐Jörg Wittsack
- Department of Diagnostic and Interventional RadiologyMedical Faculty and University Hospital Düsseldorf, Heinrich‐Heine‐University DüsseldorfDüsseldorfGermany
| | - Anja Müller‐Lutz
- Department of Diagnostic and Interventional RadiologyMedical Faculty and University Hospital Düsseldorf, Heinrich‐Heine‐University DüsseldorfDüsseldorfGermany
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Liu Y, Chen X, Chen J, Song C, Wei Z, Liu Z, Liu F. The Significance of MAPK Signaling Pathway in the Diagnosis and Subtype Classification of Intervertebral Disc Degeneration. JOR Spine 2025; 8:e70060. [PMID: 40134951 PMCID: PMC11932887 DOI: 10.1002/jsp2.70060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 12/24/2024] [Accepted: 12/27/2024] [Indexed: 03/27/2025] Open
Abstract
Background Intervertebral disc degeneration (IDD) is a human aging disease related mainly to inflammation, cellular senescence, RNA/DNA methylation, and ECM. The mitogen-activated protein kinase (MAPK) signaling pathway is engaged in multiple biological functions by phosphorylating specific serine and threonine residues on target proteins through phosphorylation cascade effects, but the role and specific mechanisms of the MAPK signaling pathway in IDD are still unclear. Methods We identified 20 MAPK-related differential genes by differential analysis of the GSE124272 and GSE150408 datasets from the GEO database. To explore the biological functions of these differential genes in humans, we performed GO and KEGG analyses. Additionally, we applied PPI networks, LASSO analysis, the RF algorithm, and the SVM-RFE algorithm to identify core MAPK-related genes. Finally, we conducted further validation using clinical samples. Results We ultimately identified and validated four pivotal MAPK-related genes, namely, KRAS, JUN, RAP1B, and TNF, using clinical samples, and constructed the ROC curves to evaluate the predictive accuracy of the hub genes. A nomogram model was subsequently developed based on these four hub MAPK genes to predict the prevalence of IDD. Based on these four hub genes, we classified IDD patients into two MAP clusters by applying the consensus clustering method and identified 1916 DEGs by analyzing the differences between the two clusters. Further analysis using the same approach allowed us to identify two gene clusters based on these DEGs. We used a PCA algorithm to determine the MAPK score for each sample and discovered that MAPK cluster A and gene cluster A had higher scores, suggesting greater sensitivity to MAPK signaling pathway-associated agents in the subtype. We displayed the differing expression levels of four hub MAPK-related genes across the two clusters and their relationship with immune cell infiltration to highlight the distinctions between clusters A and B. Conclusion In summary, four hub MAPK signaling pathway-related genes, KRAS, JUN, RAP1B, and TNF, could be applied to the diagnosis and subtype classification of IDD and benefit the prevention and treatment of IDD.
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Affiliation(s)
- Yong Liu
- Department of Orthopedics, The Affiliated Hospital of Traditional Chinese MedicineSouthwest Medical UniversityLuzhouChina
| | - Xueyan Chen
- Department of Anesthesiology, The Affiliated Traditional Chinese Medicine HospitalSouthwest Medical UniversityLuzhouChina
| | - Jingwen Chen
- Department of Orthopedics, The Affiliated Hospital of Traditional Chinese MedicineSouthwest Medical UniversityLuzhouChina
| | - Chao Song
- Department of Orthopedics, The Affiliated Hospital of Traditional Chinese MedicineSouthwest Medical UniversityLuzhouChina
| | - Zhangchao Wei
- Department of Orthopedics, The Affiliated Hospital of Traditional Chinese MedicineSouthwest Medical UniversityLuzhouChina
| | - Zongchao Liu
- Department of Orthopedics, The Affiliated Hospital of Traditional Chinese MedicineSouthwest Medical UniversityLuzhouChina
- Department of OrthopedicsLuzhou Longmatan District People's HospitalLuzhouChina
| | - Fei Liu
- Department of Orthopedics, The Affiliated Hospital of Traditional Chinese MedicineSouthwest Medical UniversityLuzhouChina
- Department of OrthopedicsRuiKang Hospital Affiliated to Guangxi University of Chinese MedicineNanningChina
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Zàaba NF, Ogaili RH, Ahmad F, Mohd Isa IL. Neuroinflammation and nociception in intervertebral disc degeneration: a review of precision medicine perspective. Spine J 2025:S1529-9430(25)00008-7. [PMID: 39814205 DOI: 10.1016/j.spinee.2024.12.033] [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: 07/29/2024] [Revised: 11/20/2024] [Accepted: 12/30/2024] [Indexed: 01/18/2025]
Abstract
Intervertebral disc (IVD) degeneration is a major cause of low back pain (LBP), which results in disability worldwide. However, the pathogenesis of IVD degeneration mediating LBP remains unclear. Current conservative treatments and surgical interventions are both to relieve the symptoms and minimise pain; nevertheless, they are unable to reverse the degeneration. Previous studies have shown that inflammation and nociception markers are important indicators of pain mechanisms in IVD degeneration underlying LBP. As such, multiomics profiling allows the discovery of these target markers to understand the key pathological mechanisms mediating IVD degeneration underpinnings of LBP. This article provides insights into a precision medicine approach for identifying and understanding the pathophysiology of IVD degeneration associated with LPB based on the severity of the disease from early and mild to severe degenerative stages. Molecular profiling of key markers in degenerative IVDs based on patient stratification at early, mild, and severe stages will contribute to the identification of target markers associated with signalling pathways in mediating neuroinflammation, innervation, and nociception underlying painful IVD degeneration. This approach will offer an understanding of establishing personalised clinical strategies tailored to the severity of IVD degeneration for the treatment of LBP.
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Affiliation(s)
- Nurul Fariha Zàaba
- Department of Anatomy, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Cheras 56000, Kuala Lumpur, Malaysia; CÚRAM Research Ireland Centre for Medical Devices, School of Medicine, University of Galway, Galway H91 W2TY, Ireland
| | - Raed H Ogaili
- Department of Anatomy, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Cheras 56000, Kuala Lumpur, Malaysia
| | - Fairus Ahmad
- Department of Anatomy, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Cheras 56000, Kuala Lumpur, Malaysia
| | - Isma Liza Mohd Isa
- Department of Anatomy, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Cheras 56000, Kuala Lumpur, Malaysia; CÚRAM Research Ireland Centre for Medical Devices, School of Medicine, University of Galway, Galway H91 W2TY, Ireland.
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Farag M, Rezk R, Hutchinson H, Zankevich A, Lucke‐Wold B. Intervertebral disc degeneration and regenerative medicine. CLINICAL AND TRANSLATIONAL DISCOVERY 2024; 4. [DOI: 10.1002/ctd2.289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 03/15/2024] [Indexed: 01/08/2025]
Abstract
AbstractIntervertebral disc (IVD) degeneration is a common phenomenon that affects patients with increasing prevalence with increasing age. Both conservative treatments, such as the use of pain medication or physical therapy, and surgical treatments, such as fusion or disc replacement therapies, are offered to patients. Both non‐invasive and invasive treatments have been shown to improve pain and quality of life for patients. This review explores the role of regenerative medicine techniques as a promising therapeutic intervention that can be used before or in combination with conservative therapy and surgery to enhance the treatment process in patients with IVD degeneration or disc pathology. Currently, there are four major modules of regenerative medicine: genetic therapy, platelet‐rich plasma therapy, stem cell transplantation and tissue engineering. Several research studies have shown promising outcomes of stem cell transplantation and tissue engineering when combined with either surgical or conservative treatment, resulting in improved pain outcomes. The additional benefit of regenerative medicine techniques, specifically stem cell transplantation, is the potential for treating the root pathology of degeneration. Regenerative medicine techniques also have the potential to either halt or reverse degeneration as opposed to current standards of care for managing symptoms. There is a plethora of current research highlighting the benefits of regenerative medicine techniques; however, there remains clinical concerns and ethical concerns regarding the use of regenerative therapy techniques such as stem cell transplantation in the context of IVD degeneration.
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Affiliation(s)
| | - Rogina Rezk
- University of Florida Gainesville Florida USA
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Aikawa T, Miyazaki Y, Kihara S, Muyama H, Nishimura M. Cervical intervertebral disc disease in 307 small-breed dogs (2000-2021): Breed-characteristic features and disc-associated vertebral instability. Aust Vet J 2024; 102:274-281. [PMID: 38342967 DOI: 10.1111/avj.13320] [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: 06/11/2023] [Revised: 11/21/2023] [Accepted: 01/21/2024] [Indexed: 02/13/2024]
Abstract
OBJECTIVE To evaluate the breed-characteristic features of cervical intervertebral disc disease (C-IVDD) and associated vertebral instability in small-breed dogs and to present the concept of intervertebral disc degeneration and associated instability stage, method of diagnosis, treatment and outcomes. ANIMALS In total, 307 client-owned dogs with C-IVDD treated with spinal cord decompression with or without vertebral stabilization (2000-2021). METHODS Information on age, sex, affected sites, stabilized sites, diagnostic methods for vertebral instability and outcomes were retrieved. The patient's age, affected sites (cranial vs caudal discs), and frequency of vertebral stabilization were compared in six CD and five NCD breed. Multivariable analyses of the chondrodystrophic (CD) vs non-CD (NCD) groups, and vertebral stabilization (dogs stabilized vs dogs not stabilized) were performed. RESULTS In total, 222 (72.3%) and 77 (25.1%) were CD and NCD breeds, respectively. Vertebral instabilities were diagnosed based on the survey radiographs with computed tomography/magnetic resonance imaging (n = 2), dynamic myelography (n = 29), intraoperative spinal manipulation (n = 11) or second surgery in dogs with persistent postoperative paraspinal pain (n = 3). Of these dogs, 295 (96.1%) recovered (median follow-up: 8.5 [range, 1-119] months). Significant differences in age, affected sites and frequency of stabilization were noted among the breeds. Older age and frequent vertebral stabilization were the associated factors for the NCD breed dogs. Male dogs, caudal discs affected (C5-T1) and the NCD breed dogs were risk factors for the dogs with vertebral stabilization. CONCLUSION Vertebral stabilization is indicated for small-breed dogs with cervical disc-associated vertebral instability.
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Affiliation(s)
- T Aikawa
- Department of Surgery, Aikawa Veterinary Medical Center, Tokyo, Japan
| | - Y Miyazaki
- Department of Surgery, Aikawa Veterinary Medical Center, Tokyo, Japan
| | - S Kihara
- Department of Surgery, Aikawa Veterinary Medical Center, Tokyo, Japan
| | - H Muyama
- Department of Surgery, Aikawa Veterinary Medical Center, Tokyo, Japan
| | - M Nishimura
- Department of Surgery, Aikawa Veterinary Medical Center, Tokyo, Japan
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Gu J, Zhou X, Xie L. Significance of Oxidative Stress in the Diagnosis and Subtype Classification of Intervertebral Disc Degeneration. Biochem Genet 2024; 62:193-207. [PMID: 37314550 DOI: 10.1007/s10528-023-10412-x] [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: 03/31/2023] [Accepted: 05/30/2023] [Indexed: 06/15/2023]
Abstract
Intervertebral disc degeneration (IVDD) is a common illness of aging, and its pathophysiological process is mainly manifested by cell aging and apoptosis, an imbalance in the production and catabolism of extracellular matrix, and an inflammatory response. Oxidative stress (OS) is an imbalance that decreases the body's intrinsic antioxidant defense system and/or raises the formation of reactive oxygen species and performs multiple biological functions in the body. However, our current knowledge of the effect of OS on the progression and treatment of IVDD is still extremely limited. In this study, we obtained 35 DEGs by differential expression analysis of 437 OS-related genes (OSRGs) between IVDD patients and healthy individuals from GSE124272 and GSE150408. Then, we identified six hub OSRGs (ATP7A, MELK, NCF1, NOX1, RHOB, and SP1) from 35 DEGs, and the high accuracy of these hub genes was confirmed by constructing ROC curves. In addition, to forecast the risk of IVDD patients, we developed a nomogram. We obtained two OSRG clusters (clusters A and B) by consensus clustering based on the six hub genes. Then, 3147 DEGs were obtained by differential expression analysis in the two clusters, and all samples were further divided into two gene clusters (A and B). We investigated differences in immune cell infiltration levels between different clusters and found that most immune cells had higher infiltration levels in OSRG cluster B or gene cluster B. In conclusion, OS is important in the formation and progression of IVDD, and we believe that our work will help guide future research on OS in IVDD.
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Affiliation(s)
- Jun Gu
- Department of Spine Surgery, Third Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China
- Department of Spine Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine for Nanjing University of Chinese Medicine, Nanjing, 210028, China
| | - Xiaoyang Zhou
- Department of Spine Surgery, Third Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China
- Department of Spine Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine for Nanjing University of Chinese Medicine, Nanjing, 210028, China
| | - Lin Xie
- Department of Spine Surgery, Third Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China.
- Department of Spine Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine for Nanjing University of Chinese Medicine, Nanjing, 210028, China.
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Lai A, Iliff D, Zaheer K, Gansau J, Laudier DM, Zachariou V, Iatridis JC. Annulus Fibrosus Injury Induces Acute Neuroinflammation and Chronic Glial Response in Dorsal Root Ganglion and Spinal Cord-An In Vivo Rat Discogenic Pain Model. Int J Mol Sci 2024; 25:1762. [PMID: 38339040 PMCID: PMC10855200 DOI: 10.3390/ijms25031762] [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: 11/27/2023] [Revised: 01/18/2024] [Accepted: 01/25/2024] [Indexed: 02/12/2024] Open
Abstract
Chronic painful intervertebral disc (IVD) degeneration (i.e., discogenic pain) is a major source of global disability needing improved knowledge on multiple-tissue interactions and how they progress in order improve treatment strategies. This study used an in vivo rat annulus fibrosus (AF) injury-driven discogenic pain model to investigate the acute and chronic changes in IVD degeneration and spinal inflammation, as well as sensitization, inflammation, and remodeling in dorsal root ganglion (DRG) and spinal cord (SC) dorsal horn. AF injury induced moderate IVD degeneration with acute and broad spinal inflammation that progressed to DRG to SC changes within days and weeks, respectively. Specifically, AF injury elevated macrophages in the spine (CD68) and DRGs (Iba1) that peaked at 3 days post-injury, and increased microglia (Iba1) in SC that peaked at 2 weeks post-injury. AF injury also triggered glial responses with elevated GFAP in DRGs and SC at least 8 weeks post-injury. Spinal CD68 and SC neuropeptide Substance P both remained elevated at 8 weeks, suggesting that slow and incomplete IVD healing provides a chronic source of inflammation with continued SC sensitization. We conclude that AF injury-driven IVD degeneration induces acute spinal, DRG, and SC inflammatory crosstalk with sustained glial responses in both DRGs and SC, leading to chronic SC sensitization and neural plasticity. The known association of these markers with neuropathic pain suggests that therapeutic strategies for discogenic pain need to target both spinal and nervous systems, with early strategies managing acute inflammatory processes, and late strategies targeting chronic IVD inflammation, SC sensitization, and remodeling.
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Affiliation(s)
- Alon Lai
- Leni and Peter W. May Department of Orthopedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Denise Iliff
- Leni and Peter W. May Department of Orthopedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Kashaf Zaheer
- Leni and Peter W. May Department of Orthopedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Jennifer Gansau
- Leni and Peter W. May Department of Orthopedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Damien M Laudier
- Leni and Peter W. May Department of Orthopedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Venetia Zachariou
- Department of Pharmacology, Physiology and Biophysics, Chobanian and Avedisian School of Medicine at Boston University, Boston, MA 02118, USA
| | - James C Iatridis
- Leni and Peter W. May Department of Orthopedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Desai SU, Srinivasan SS, Kumbar SG, Moss IL. Hydrogel-Based Strategies for Intervertebral Disc Regeneration: Advances, Challenges and Clinical Prospects. Gels 2024; 10:62. [PMID: 38247785 PMCID: PMC10815657 DOI: 10.3390/gels10010062] [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: 11/30/2023] [Revised: 01/08/2024] [Accepted: 01/10/2024] [Indexed: 01/23/2024] Open
Abstract
Millions of people worldwide suffer from low back pain and disability associated with intervertebral disc (IVD) degeneration. IVD degeneration is highly correlated with aging, as the nucleus pulposus (NP) dehydrates and the annulus fibrosus (AF) fissures form, which often results in intervertebral disc herniation or disc space collapse and related clinical symptoms. Currently available options for treating intervertebral disc degeneration are symptoms control with therapy modalities, and/or medication, and/or surgical resection of the IVD with or without spinal fusion. As such, there is an urgent clinical demand for more effective disease-modifying treatments for this ubiquitous disorder, rather than the current paradigms focused only on symptom control. Hydrogels are unique biomaterials that have a variety of distinctive qualities, including (but not limited to) biocompatibility, highly adjustable mechanical characteristics, and most importantly, the capacity to absorb and retain water in a manner like that of native human nucleus pulposus tissue. In recent years, various hydrogels have been investigated in vitro and in vivo for the repair of intervertebral discs, some of which are ready for clinical testing. In this review, we summarize the latest findings and developments in the application of hydrogel technology for the repair and regeneration of intervertebral discs.
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Affiliation(s)
- Shivam U. Desai
- Department of Orthopedic Surgery, Central Michigan University, College of Medicine, Saginaw, MI 48602, USA
| | | | | | - Isaac L. Moss
- Department of Orthopedic Surgery, University of Connecticut, Storrs, CT 06269, USA
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Nakielski P, Rybak D, Jezierska-Woźniak K, Rinoldi C, Sinderewicz E, Staszkiewicz-Chodor J, Haghighat Bayan MA, Czelejewska W, Urbanek O, Kosik-Kozioł A, Barczewska M, Skomorowski M, Holak P, Lipiński S, Maksymowicz W, Pierini F. Minimally Invasive Intradiscal Delivery of BM-MSCs via Fibrous Microscaffold Carriers. ACS APPLIED MATERIALS & INTERFACES 2023; 15:58103-58118. [PMID: 38019273 DOI: 10.1021/acsami.3c11710] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2023]
Abstract
Current treatments of degenerated intervertebral discs often provide only temporary relief or address specific causes, necessitating the exploration of alternative therapies. Cell-based regenerative approaches showed promise in many clinical trials, but limitations such as cell death during injection and a harsh disk environment hinder their effectiveness. Injectable microscaffolds offer a solution by providing a supportive microenvironment for cell delivery and enhancing bioactivity. This study evaluated the safety and feasibility of electrospun nanofibrous microscaffolds modified with chitosan (CH) and chondroitin sulfate (CS) for treating degenerated NP tissue in a large animal model. The microscaffolds facilitated cell attachment and acted as an effective delivery system, preventing cell leakage under a high disc pressure. Combining microscaffolds with bone marrow-derived mesenchymal stromal cells demonstrated no cytotoxic effects and proliferation over the entire microscaffolds. The administration of cells attached to microscaffolds into the NP positively influenced the regeneration process of the intervertebral disc. Injectable poly(l-lactide-co-glycolide) and poly(l-lactide) microscaffolds enriched with CH or CS, having a fibrous structure, showed the potential to promote intervertebral disc regeneration. These features collectively address critical challenges in the fields of tissue engineering and regenerative medicine, particularly in the context of intervertebral disc degeneration.
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Affiliation(s)
- Paweł Nakielski
- Department of Biosystems and Soft Matter, Institute of Fundamental Technological Research, Polish Academy of Sciences, Pawińskiego 5B, Warsaw 02-106, Poland
| | - Daniel Rybak
- Department of Biosystems and Soft Matter, Institute of Fundamental Technological Research, Polish Academy of Sciences, Pawińskiego 5B, Warsaw 02-106, Poland
| | - Katarzyna Jezierska-Woźniak
- Laboratory for Regenerative Medicine, Department of Neurosurgery, School of Medicine, University of Warmia and Mazury, Warszawska 30, Olsztyn 10-082, Poland
| | - Chiara Rinoldi
- Department of Biosystems and Soft Matter, Institute of Fundamental Technological Research, Polish Academy of Sciences, Pawińskiego 5B, Warsaw 02-106, Poland
| | - Emilia Sinderewicz
- Laboratory for Regenerative Medicine, Department of Neurosurgery, School of Medicine, University of Warmia and Mazury, Warszawska 30, Olsztyn 10-082, Poland
| | - Joanna Staszkiewicz-Chodor
- Laboratory for Regenerative Medicine, Department of Neurosurgery, School of Medicine, University of Warmia and Mazury, Warszawska 30, Olsztyn 10-082, Poland
| | - Mohammad Ali Haghighat Bayan
- Department of Biosystems and Soft Matter, Institute of Fundamental Technological Research, Polish Academy of Sciences, Pawińskiego 5B, Warsaw 02-106, Poland
| | - Wioleta Czelejewska
- Laboratory for Regenerative Medicine, Department of Neurosurgery, School of Medicine, University of Warmia and Mazury, Warszawska 30, Olsztyn 10-082, Poland
| | - Olga Urbanek
- Laboratory of Polymers and Biomaterials, Institute of Fundamental Technological Research, Polish Academy of Sciences, Pawińskiego 5B, Warsaw 02-106, Poland
| | - Alicja Kosik-Kozioł
- Department of Biosystems and Soft Matter, Institute of Fundamental Technological Research, Polish Academy of Sciences, Pawińskiego 5B, Warsaw 02-106, Poland
| | - Monika Barczewska
- Laboratory for Regenerative Medicine, Department of Neurosurgery, School of Medicine, University of Warmia and Mazury, Warszawska 30, Olsztyn 10-082, Poland
| | - Mateusz Skomorowski
- Neurosurgery Clinic, University Clinical Hospital in Olsztyn, Warszawska 30, Olsztyn 10-082, Poland
| | - Piotr Holak
- Laboratory for Regenerative Medicine, Department of Neurosurgery, School of Medicine, University of Warmia and Mazury, Warszawska 30, Olsztyn 10-082, Poland
| | - Seweryn Lipiński
- Department of Electrical Engineering, Power Engineering, Electronics and Automation, Faculty of Technical Sciences, University of Warmia and Mazury, Oczapowskiego 11, Olsztyn 10-082, Poland
| | - Wojciech Maksymowicz
- Laboratory for Regenerative Medicine, Department of Neurosurgery, School of Medicine, University of Warmia and Mazury, Warszawska 30, Olsztyn 10-082, Poland
| | - Filippo Pierini
- Department of Biosystems and Soft Matter, Institute of Fundamental Technological Research, Polish Academy of Sciences, Pawińskiego 5B, Warsaw 02-106, Poland
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12
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Toczylowska B, Woznica M, Zieminska E, Krolicki L. Metabolic Biomarkers Differentiate a Surgical Intervertebral Disc from a Nonsurgical Intervertebral Disc. Int J Mol Sci 2023; 24:10572. [PMID: 37445750 DOI: 10.3390/ijms241310572] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/19/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
BACKGROUND Degeneration of the intervertebral disc (IVD) is caused by disturbances in metabolic processes, which lead to structural disorders. The aim of this report is to analyze metabolic disorders in the degeneration process by comparing control discs with degenerated discs. In our research on the nucleus pulposus (NP), we used NMR spectroscopy of extracts of hydrophilic and hydrophobic compounds of the tissue. METHODS Nuclear magnetic resonance (NMR) spectroscopy allows the study of biochemistry and cellular metabolism in vitro. Hydrophilic and hydrophobic compounds were extracted from the NP of the intervertebral disc. In the NMR spectra, metabolites were identified and quantitatively analyzed. The results of our research indicate disturbances in the biosynthesis and metabolism of cholesterol, the biosynthesis and degradation of various fatty acid groups, ketone bodies, or lysine, and the metabolism of glycerophospholipids, purines, glycine, inositol, galactose, alanine, glutamate, and pyruvate in the biosynthesis of valine and isoleucine, leucine. All these disorders indicate pathomechanisms related to oxidative stress, energy, neurotransmission disturbances, and disturbances in the structure and functioning of cell membranes, inflammation, or chronic pain generators. CONCLUSIONS NMR spectroscopy allows the identification of metabolites differentiating surgical from nonsurgical discs. These data may provide guidance in in vivo MRS studies in assessing the severity of lesions of the disc.
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Affiliation(s)
- Beata Toczylowska
- Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, 02-109 Warsaw, Poland
| | | | - Elzbieta Zieminska
- Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland
| | - Leszek Krolicki
- Department of Nuclear Medicine, Warsaw Medical University, 02-091 Warsaw, Poland
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13
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Fine N, Lively S, Séguin CA, Perruccio AV, Kapoor M, Rampersaud R. Intervertebral disc degeneration and osteoarthritis: a common molecular disease spectrum. Nat Rev Rheumatol 2023; 19:136-152. [PMID: 36702892 DOI: 10.1038/s41584-022-00888-z] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/05/2022] [Indexed: 01/27/2023]
Abstract
Intervertebral disc degeneration (IDD) and osteoarthritis (OA) affecting the facet joint of the spine are biomechanically interdependent, typically occur in tandem, and have considerable epidemiological and pathophysiological overlap. Historically, the distinctions between these degenerative diseases have been emphasized. Therefore, research in the two fields often occurs independently without adequate consideration of the co-dependence of the two sites, which reside within the same functional spinal unit. Emerging evidence from animal models of spine degeneration highlight the interdependence of IDD and facet joint OA, warranting a review of the parallels between these two degenerative phenomena for the benefit of both clinicians and research scientists. This Review discusses the pathophysiological aspects of IDD and OA, with an emphasis on tissue, cellular and molecular pathways of degeneration. Although the intervertebral disc and synovial facet joint are biologically distinct structures that are amenable to reductive scientific consideration, substantial overlap exists between the molecular pathways and processes of degeneration (including cartilage destruction, extracellular matrix degeneration and osteophyte formation) that occur at these sites. Thus, researchers, clinicians, advocates and policy-makers should consider viewing the burden and management of spinal degeneration holistically as part of the OA disease continuum.
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Affiliation(s)
- Noah Fine
- Osteoarthritis Research Program, Division of Orthopaedics, Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada.,Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Starlee Lively
- Osteoarthritis Research Program, Division of Orthopaedics, Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada.,Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Cheryle Ann Séguin
- Department of Physiology & Pharmacology, Schulich School of Medicine & Dentistry, Bone and Joint Institute, University of Western Ontario London, London, Ontario, Canada
| | - Anthony V Perruccio
- Osteoarthritis Research Program, Division of Orthopaedics, Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada.,Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.,Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.,Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Mohit Kapoor
- Osteoarthritis Research Program, Division of Orthopaedics, Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada.,Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.,Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Raja Rampersaud
- Osteoarthritis Research Program, Division of Orthopaedics, Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada. .,Krembil Research Institute, University Health Network, Toronto, Ontario, Canada. .,Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
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14
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Zhou Z, Suo Y, Bai J, Lin F, Gao X, Shan H, Ni Y, Zhou X, Sheng L, Dai J. Matrix Stiffness Activating YAP/TEAD1-Cyclin B1 in Nucleus Pulposus Cells Promotes Intervertebral Disc Degeneration. Aging Dis 2023:AD.2023.00205. [PMID: 37196128 DOI: 10.14336/ad.2023.00205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 02/05/2023] [Indexed: 05/19/2023] Open
Abstract
Intervertebral disc degeneration is a leading cause of disability in the elderly population. Rigid extracellular matrix is a critical pathological feature of disc degeneration, leading to aberrant nucleus pulposus cells (NPCs) proliferation. However, the underlying mechanism is unclear. Here, we hypothesize that increased matrix stiffness induces proliferation and thus degenerative phenotypes of NPCs through YAP/TEAD1 signaling pathway. We established hydrogel substrates to mimic stiffness of degenerated human nucleus pulposus tissues. RNA-sequencing identified differentially expressed genes between primary rat NPCs cultured on rigid and soft hydrogels. Dual luciferase assay and gain- and loss-function experiments evaluated the correlation between YAP/TEAD1 and Cyclin B1. Furthermore, single-cell RNA-sequencing of human NPCs was performed to identify specific cell clusters with high YAP expression. Matrix stiffness increased in severely degenerated human nucleus pulposus tissues (p < 0.05). Rigid substrate enhanced rat NPCs proliferation mainly through Cyclin B1, which was directly targeted and positively regulated by YAP/TEAD1. Depletion of YAP or Cyclin B1 arrested G2/M phase progression of rat NPCs and reduced fibrotic phenotypes including MMP13 and CTGF (p < 0.05). Fibro NPCs with high YAP expression were identified in human tissues and responsible for fibrogenesis during degeneration. Furthermore, inhibition of YAP/TEAD interaction by verteporfin suppressed cell proliferation and alleviated degeneration in the disc needle puncture model (p < 0.05). Our results demonstrate that elevated matrix stiffness stimulates fibro NPCs proliferation through YAP/TEAD1-Cyclin B1 axis, indicating a therapeutic target for disc degeneration.
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Affiliation(s)
- Zijie Zhou
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yinxuan Suo
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Jinyu Bai
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Fanguo Lin
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Xiang Gao
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Huajian Shan
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yichao Ni
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Xiaozhong Zhou
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Lei Sheng
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Jun Dai
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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15
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Yahia S, Khalil IA, El-Sherbiny IM. Fortified gelatin-based hydrogel scaffold with simvastatin-mixed nanomicelles and platelet rich plasma as a promising bioimplant for tissue regeneration. Int J Biol Macromol 2023; 225:730-744. [PMID: 36400213 DOI: 10.1016/j.ijbiomac.2022.11.136] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/13/2022] [Accepted: 11/14/2022] [Indexed: 11/17/2022]
Abstract
Treatment of intervertebral disc (IVD) degeneration includes conservative and surgical strategies that have a high risk of recurrence. Consequently, tissue engineering represents a promising alternative treatment. This study aimed at healing damaged IVD with a bioimplant that can maintain the function of defected IVD. The developed IVD scaffold is composed of a fortified biocompatible gelatin-based hydrogel to mimic the ECM mechanical properties of IVD and to allow a sustained release of loaded bioactive agents. The hydrogel is laden with platelet-rich plasma (PRP) and simvastatin (SIM)-loaded mixed pluronics nanomicelles because of their regenerative ability and anti-inflammatory effect, respectively. The gelatin-based hydrogel attained swelling of 508.9 ± 7.9 % to 543.1 ± 5.9 % after 24 h. Increasing crosslinking degree of the hydrogel improved its mechanical elasticity up to 0.3 ± 0.1 N/mm2, and retarded its degradation. The optimum mixed nanomicelles had particle size of 84 ± 0.5 nm, a surface charge of -10 ± 7.1 mv, EE% of 84.9 %, and released 88.4 % of SIM after 21 days. Cytotoxicity of IVD components was evaluated using human skin fibroblast for 3 days. WST-test results proved biocompatibility of IVD scaffold. Subcutaneous implantation of the IVD scaffold was performed for 28 days to test in-vivo biocompatibility. Histological and histochemical micrographs depicted normal healing signs such as macrophages, T-cells, angiogenesis and granulation reactions. Introducing PRP in IVD improved healing process and decreased inflammation reactions. The developed multicomponent implant could be used as potential IVD scaffold with desirable mechanical properties, biocompatibility and healing process.
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Affiliation(s)
- Sarah Yahia
- Nanomedicine Research Labs, Center for Materials Sciences, Zewail City of Science and Technology, 6th of October City, 12578, Giza, Egypt
| | - Islam A Khalil
- Department of Pharmaceutics, College of Pharmacy and Drug Manufacturing, Misr University of Science and Technology (MUST), 6th of October, Giza 12582, Egypt
| | - Ibrahim M El-Sherbiny
- Nanomedicine Research Labs, Center for Materials Sciences, Zewail City of Science and Technology, 6th of October City, 12578, Giza, Egypt.
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Velnar T, Gradisnik L. Endplate role in the degenerative disc disease: A brief review. World J Clin Cases 2023; 11:17-29. [PMID: 36687189 PMCID: PMC9846967 DOI: 10.12998/wjcc.v11.i1.17] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 10/19/2022] [Accepted: 12/16/2022] [Indexed: 01/04/2023] Open
Abstract
The degenerative disease of the intervertebral disc is nowadays an important health problem, which has still not been understood and solved adequately. The vertebral endplate is regarded as one of the vital elements in the structure of the intervertebral disc. Its constituent cells, the chondrocytes in the endplate, may also be involved in the process of the intervertebral disc degeneration and their role is central both under physiological and pathological conditions. They main functions include a role in homeostasis of the extracellular environment of the intervertebral disc, metabolic support and nutrition of the discal nucleus and annulus beneath and the preservation of the extracellular matrix. Therefore, it is understandable that the cells in the endplate have been in the centre of research from several viewpoints, such as development, degeneration and growth, reparation and remodelling, as well as treatment strategies. In this article, we briefly review the importance of vertebral endplate, which are often overlooked, in the intervertebral disc degeneration.
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Affiliation(s)
- Tomaz Velnar
- Department of Neurosurgery, University Medical Centre Ljubljana, Ljubljana 1000, Slovenia
- Alma Mater Europaea Maribor, Maribor 2000, Slovenia
| | - Lidija Gradisnik
- Alma Mater Europaea Maribor, Maribor 2000, Slovenia
- Institute of Biomedical Sciences, University of Maribor, University of Maribor, Maribor 2000, Slovenia
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17
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Fiordalisi MF, Ferreira JR, Pinto ML, Ribeiro-Machado C, Teixeira Pinto M, Oliveira MJ, Barbosa MA, Madeira Gonçalves R, Caldeira J. The impact of matrix age on intervertebral disc regeneration. BIOMATERIALS ADVANCES 2022; 143:213192. [PMID: 36403438 DOI: 10.1016/j.bioadv.2022.213192] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 09/26/2022] [Accepted: 11/03/2022] [Indexed: 06/16/2023]
Abstract
With the lack of effective treatments for low back pain, the use of extracellular matrix (ECM)-based biomaterials have emerged with undeniable promise for IVD regeneration. Decellularized scaffolds can recreate an ideal microenvironment inducing tissue remodeling and repair. In particular, fetal tissues have a superior regenerative capacity given their ECM composition. In line with this, we unraveled age-associated alterations of the nucleus pulposus (NP) matrisome. Thus, the aim of the present work was to evaluate the impact of ECM donor age on IVD de/regeneration. Accordingly, we optimized an SDS (0.1 %, 1 h)-based decellularization protocol that preserves ECM cues in bovine NPs from different ages. After repopulation with adult NP cells, younger matrices showed the highest repopulation efficiency. Most importantly, cells seeded on younger scaffolds produced healthy ECM proteins suggesting an increased capacity to restore a functional IVD microenvironment. In vivo, only fetal matrices decreased neovessel formation, showing an anti-angiogenic potential. Our findings demonstrate that ECM donor age has a strong influence on angiogenesis and ECM de novo synthesis, opening new avenues for novel therapeutic strategies for the IVD. Additionally, more appropriate 3D models to study age-associated IVD pathology were unveiled.
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Affiliation(s)
- Morena Francesca Fiordalisi
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; INEB - Instituto de Engenharia Biomédica, Porto 4200-135, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto 4050-313, Portugal
| | - Joana Rita Ferreira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; INEB - Instituto de Engenharia Biomédica, Porto 4200-135, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto 4050-313, Portugal
| | - Marta Laranjeiro Pinto
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal
| | - Cláudia Ribeiro-Machado
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; INEB - Instituto de Engenharia Biomédica, Porto 4200-135, Portugal
| | - Marta Teixeira Pinto
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto 4200-135, Portugal
| | - Maria José Oliveira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; INEB - Instituto de Engenharia Biomédica, Porto 4200-135, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto 4050-313, Portugal; Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto 4200-319, Portugal
| | - Mário Adolfo Barbosa
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; INEB - Instituto de Engenharia Biomédica, Porto 4200-135, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto 4050-313, Portugal
| | - Raquel Madeira Gonçalves
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; INEB - Instituto de Engenharia Biomédica, Porto 4200-135, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto 4050-313, Portugal
| | - Joana Caldeira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; INEB - Instituto de Engenharia Biomédica, Porto 4200-135, Portugal.
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18
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Shanmuganathan R, Tangavel C, K S SVA, Muthurajan R, Nayagam SM, Matchado MS, Rajendran S, Kanna RM, Shetty AP. Comparative metagenomic analysis of human intervertebral disc nucleus pulposus and cartilaginous end plates. Front Cardiovasc Med 2022; 9:927652. [PMID: 36247458 PMCID: PMC9554234 DOI: 10.3389/fcvm.2022.927652] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 09/01/2022] [Indexed: 11/13/2022] Open
Abstract
Study design The diversity of microflora inhabiting endplate (EP) and nucleus pulposus (NP) tissues of human intervertebral disc (IVD) was profiled through NGS-supported 16S rRNA amplicon sequencing. Sixteen EP and their corresponding NP were excised from the brain-dead voluntary organ donors with no clinical history of low back pain, and 12 herniated and 8 degenerated NP tissues isolated from the patients undergoing spinal surgery were subjected to study the alteration in the microbial diversity. Objective(s) To understand in normal IVD, whether the colonization of bacteria to the NP is through the EP in discs with intact annulus fibrosus. To identify significantly differing microbial population(s) between normal and diseased IVD (NP). Background of the study There is increasing evidence for subclinical infection by fastidious low, growing bacteria to be a cause of disc degeneration. Although the presence of bacteria in NP has been reported well in literature, the source of bacteria is not clearly proved as the disc is avascular in healthy condition. Documentation of similar bacterial populations in the EP and NP may add proof that bacterial inoculation of NP occurs via the EP. Materials and methods Sixteen EP and their corresponding NP excised from brain-dead voluntary organ donors with no history of back pain and 20 diseased discs collected from patients undergoing microdiscectomy/fusion surgery were used for profiling microbiome through 16S rRNA amplicon sequencing using primers specific for V1-V9 hypervariable regions. Changes in bacterial diversity and abundance were analysed to identify the key microbial populations in normal IVD NP and EP tissues and those significantly altered in diseased IVD (NP). Results NP and EP shared a similar spectrum of microbiome but with varying abundance. The five dominant phyla identified were Proteobacteria, Firmicutes, Actinobacteria, OD1, and Bacteroidetes. Proteobacteria was found to be the most abundant phyla in both NP (62%) and EP (53%) of the normal IVD. This was followed by Firmicutes (16%), Actinobacteriota (11%), OD1 (Parcubacteria) (7.6%), and Bacteroidetes (2%) in NP and Firmicutes (23.4%), OD1 (Parcubacteria) (17.6%), Actinobacteriota (2.8%), and Bacteroidetes (2.6%) in EP, respectively. Under diseased conditions, Proteobacteria (68%) was dominant when compared with other phyla. However, there was no significant difference in the abundance of Proteobacteria between the normal and diseased discs. Interestingly, the other dominant phyla such as Firmicutes (Normal-NP: 16.2%; Diseased-NP: 4.02%) and Actinobacteria (Normal-NP: 11%; Diseased-NP: 0.99%) showed a significant reduction in degenerated discs. To understand the key microbial populations that are significantly altered during disease, correlation analysis was performed among the three phyla, which revealed a negative correlation in the ratio of Actinobacteria + Firmicutes vs. Proteobacteria (p = 0.001) in DD. Conclusion Results of our study clearly demonstrated a similar bacterial diversity but with varying abundance between the EP and NP, suggesting the existence of the endplate–nucleus pulposus axis in the normal IVD microbiome. Further, our results have indicated that the changes in the abundance of Actinobacteria + Firmicutes vs. Proteobacteria during DDD need further investigation.
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Affiliation(s)
- Rajasekaran Shanmuganathan
- Department of Spine Surgery, Ganga Hospital, Coimbatore, India
- *Correspondence: Rajasekaran Shanmuganathan
| | - Chitraa Tangavel
- Department of Biotechnology, Ganga Research Centre, Coimbatore, India
| | | | - Raveendran Muthurajan
- Department of Plant Biotechnology, Tamil Nadu Agricultural University, Coimbatore, India
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Chang C, Zhu J, Li H, Yang Q. Enhanced magnetic resonance imaging manifestations of paediatric intervertebral disc calcification combined with ossification of the posterior longitudinal ligament: case report and literature review. BMC Pediatr 2022; 22:400. [PMID: 35804316 PMCID: PMC9264604 DOI: 10.1186/s12887-022-03461-5] [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: 04/16/2022] [Accepted: 06/30/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Since the first description of paediatric intervertebral disc calcification (IDC) by Báron in 1924, only approximately 400 cases have been reported in the literature. Paediatric IDC combined with ossification of the posterior longitudinal ligament (OPLL) is an even rarer condition, with only 8 cases described in detail to date. In this paper, we present a review of the disease characteristics described in the relevant English language literature and discuss the possible mechanisms of lesion enhancement in contrast-enhanced magnetic resonance imaging (MRI). CASE PRESENTATION In May 2020, a 6-year-old Han nationality girl presented with the chief complaint of neck pain that had lasted for a week. She did not report a history of trauma or a past illness. On admission, there was no personal and family history, congenital diseases, or non-specific infections such as tuberculosis, among others. Further physical examination revealed that the movement of her cervical spine was limited. Computed tomography (CT) and MRI revealed ossification of the intervertebral discs and posterior longitudinal ligament (PLL) at the C4/5 levels and an absence of obvious spinal cord compression. When contrast-enhanced MRI was performed, significant enhancement was observed in the intervertebral discs and PLL at the C4/5 level. We adopted a non-interventional approach and performed an imaging re-examination 8 months later. Both the plain and contrast-enhanced MRI scans indicated swelling in the C4/5 intervertebral discs and disappearance of the previously observed enhancement in the nucleus pulposus (NP) and PLL at the corresponding levels; CT examination revealed that the ossified lesions had been completely resorbed. CONCLUSION Obvious lesion enhancement in contrast-enhanced MRI is an extremely rare manifestation of paediatric IDC combined with OPLL. However, the exact mechanisms of this phenomenon remain unclear. We surmise that it may be caused by a series of biophysical changes related to vertebral endplate injury and repair, but further research will be required for in-depth investigation.
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Affiliation(s)
- Cancan Chang
- Department of Medical Imaging, Bozhou Hospital of Traditional Chinese Medicine, Bozhou, 236800, Anhui, China.,Clinical Medicine Standardisation Training Trainees, Department of Medical Imaging, Anqing Hospital Affiliated to Anhui Medical University, Anqing, 246000, Anhui, China
| | - Juan Zhu
- Department of Medical Imaging, Anqing Hospital Affiliated to Anhui Medical University, Anqing, 246000, Anhui, China
| | - Hongyi Li
- Department of Radiology, The People's Hospital of Liaoning Province, Shenyang, 110016, China
| | - Qing Yang
- Department of Medical Imaging, Anqing Hospital Affiliated to Anhui Medical University, Renmin road, Anqing, 246000, Anhui, China.
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20
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Azzouzi H, Ichchou L. Schmorl's nodes: demystification road of endplate defects-a critical review. Spine Deform 2022; 10:489-499. [PMID: 34825353 DOI: 10.1007/s43390-021-00445-w] [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: 09/13/2021] [Accepted: 11/11/2021] [Indexed: 11/24/2022]
Abstract
BACKGROUND Schmorl's nodes (SN) were the first vertebral endplate defects described. Debate continues about their epidemiology, physiopathology, and clinical significance. The purpose of this work was to summarize and discuss available literature about SN. METHODS We have searched for relevant papers about SN until April 2020, with 104 articles have been reviewed. RESULTS More than half of the available literature described the epidemiological aspects of SN or reported rare clinical presentations and treatment options. The lack of a consensual definition of SN, among other endplate defects, contributed to difficulties in literature results' interpretation. Summing up, SN is a frequent vertebral defect at the thoracolumbar juncture, with ethnic and gender influence. Lumbar Schmorl's nodes were frequently associated with disc degenerative disease and back pain. Their physiopathology remains unknown. However, strain energy changes in the spine along with morphological aspects of the vertebra, the genetic background, and the osteoimmunology may constitute possible clues. New SN could be confused in malignancy context with bone metastasis. The literature describes some imaging techniques to differentiate them, avoiding invasive approaches. Treatment options for rare painful presentations remain few with low evidence. Further studies are needed to establish a consensual definition for SN, understand clinical aspects, and provide adequate therapeutic strategies.
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Affiliation(s)
- Hamida Azzouzi
- Department of Rheumatology, Faculty of Medicine, Mohammed VI University Hospital of Oujda, Université Mohammed Premier, Oujda, Morocco.
| | - Linda Ichchou
- Department of Rheumatology, Faculty of Medicine, Mohammed VI University Hospital of Oujda, Université Mohammed Premier, Oujda, Morocco
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21
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Gradišnik L, Maver U, Gole B, Bunc G, Voršič M, Ravnik J, Šmigoc T, Bošnjak R, Velnar T. The Endplate Role in Degenerative Disc Disease Research: The Isolation of Human Chondrocytes from Vertebral Endplate-An Optimised Protocol. Bioengineering (Basel) 2022; 9:137. [PMID: 35447697 PMCID: PMC9029037 DOI: 10.3390/bioengineering9040137] [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: 01/24/2022] [Revised: 03/12/2022] [Accepted: 03/23/2022] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Degenerative disc disease is a progressive and chronic disorder with many open questions regarding its pathomorphological mechanisms. In related studies, in vitro organ culture systems are becoming increasingly essential as a replacement option for laboratory animals. Live disc cells are highly appealing to study the possible mechanisms of intervertebral disc (IVD) degeneration. To study the degenerative processes of the endplate chondrocytes in vitro, we established a relatively quick and easy protocol for isolating human chondrocytes from the vertebral endplates. METHODS The fragments of human lumbar endplates following lumbar fusion were collected, cut, ground and partially digested with collagenase I in Advanced DMEM/F12 with 5% foetal bovine serum. The sediment was harvested, and cells were seeded in suspension, supplemented with special media containing high nutrient levels. Morphology was determined with phalloidin staining and the characterisation for collagen I, collagen II and aggrecan with immunostaining. RESULTS The isolated cells retained viability in appropriate laboratory conditions and proliferated quickly. The confluent culture was obtained after 14 days. Six to 8 h after seeding, attachments were observed, and proliferation of the isolated cells followed after 12 h. The cartilaginous endplate chondrocytes were stable with a viability of up to 95%. Pheno- and geno-typic analysis showed chondrocyte-specific expression, which decreased with passages. CONCLUSIONS The reported cell isolation process is simple, economical and quick, allowing establishment of a viable long-term cell culture. The availability of a vertebral endplate cell model will permit the study of cell properties, biochemical aspects, the potential of therapeutic candidates for the treatment of disc degeneration, and toxicology studies in a well-controlled environment.
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Affiliation(s)
- Lidija Gradišnik
- Institute of Biomedical Sciences, Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia; (L.G.); (U.M.)
| | - Uroš Maver
- Institute of Biomedical Sciences, Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia; (L.G.); (U.M.)
| | - Boris Gole
- Centre for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia;
| | - Gorazd Bunc
- Department of Neurosurgery, University Medical Centre Maribor, 2000 Maribor, Slovenia; (G.B.); (M.V.); (J.R.); (T.Š.)
| | - Matjaž Voršič
- Department of Neurosurgery, University Medical Centre Maribor, 2000 Maribor, Slovenia; (G.B.); (M.V.); (J.R.); (T.Š.)
| | - Janez Ravnik
- Department of Neurosurgery, University Medical Centre Maribor, 2000 Maribor, Slovenia; (G.B.); (M.V.); (J.R.); (T.Š.)
| | - Tomaž Šmigoc
- Department of Neurosurgery, University Medical Centre Maribor, 2000 Maribor, Slovenia; (G.B.); (M.V.); (J.R.); (T.Š.)
| | - Roman Bošnjak
- Department of Neurosurgery, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia;
| | - Tomaž Velnar
- Department of Neurosurgery, University Medical Centre Maribor, 2000 Maribor, Slovenia; (G.B.); (M.V.); (J.R.); (T.Š.)
- Department of Neurosurgery, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia;
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22
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Hickman TT, Rathan-Kumar S, Peck SH. Development, Pathogenesis, and Regeneration of the Intervertebral Disc: Current and Future Insights Spanning Traditional to Omics Methods. Front Cell Dev Biol 2022; 10:841831. [PMID: 35359439 PMCID: PMC8963184 DOI: 10.3389/fcell.2022.841831] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 02/09/2022] [Indexed: 02/06/2023] Open
Abstract
The intervertebral disc (IVD) is the fibrocartilaginous joint located between each vertebral body that confers flexibility and weight bearing capabilities to the spine. The IVD plays an important role in absorbing shock and stress applied to the spine, which helps to protect not only the vertebral bones, but also the brain and the rest of the central nervous system. Degeneration of the IVD is correlated with back pain, which can be debilitating and severely affects quality of life. Indeed, back pain results in substantial socioeconomic losses and healthcare costs globally each year, with about 85% of the world population experiencing back pain at some point in their lifetimes. Currently, therapeutic strategies for treating IVD degeneration are limited, and as such, there is great interest in advancing treatments for back pain. Ideally, treatments for back pain would restore native structure and thereby function to the degenerated IVD. However, the complex developmental origin and tissue composition of the IVD along with the avascular nature of the mature disc makes regeneration of the IVD a uniquely challenging task. Investigators across the field of IVD research have been working to elucidate the mechanisms behind the formation of this multifaceted structure, which may identify new therapeutic targets and inform development of novel regenerative strategies. This review summarizes current knowledge base on IVD development, degeneration, and regenerative strategies taken from traditional genetic approaches and omics studies and discusses the future landscape of investigations in IVD research and advancement of clinical therapies.
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Affiliation(s)
- Tara T. Hickman
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
- Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, United States
- Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Sudiksha Rathan-Kumar
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
- Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, United States
- Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Sun H. Peck
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
- Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, United States
- Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, United States
- *Correspondence: Sun H. Peck,
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23
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Molladavoodi S, DeWitte‐Orr SJ, Gregory DE. An in vitro 3D annulus fibrosus cell culture model with type I collagen: An examination of cell-matrix interactions. JOR Spine 2022; 5:e1193. [PMID: 35386752 PMCID: PMC8966884 DOI: 10.1002/jsp2.1193] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 01/11/2022] [Accepted: 01/13/2022] [Indexed: 11/07/2022] Open
Abstract
Background Disorders of the intervertebral disc (IVD) are widely known to result in low back pain; one of the most common debilitating conditions worldwide. As a multifaceted condition, both inflammatory environment and mechanical factors can play a crucial role in IVD damage, and in particular, in the annulus fibrosus (AF), the highly collagenous outer ring of the IVD. As a result, a better understanding of how cells from the IVD, and specifically the AF, interact and respond to their environment is imperative. Goal The goal of this study is to use collagen type I as an in vitro three-dimensional extracellular matrix for AF cells of IVD and briefly examine both the cellular and mechanical effect of exposure to an inflammatory stimulant. Methods We utilized type I collagen as a 3D in vitro model material for culturing AF cells of Sprague Dawley rat tail IVDs. Results We showed that the cultured cells are viable and metabolically active; these cells also induced a distinct and significant contraction on their collagen matrix. Furthermore, to demonstrate potential versatility of our model our model and its versatility, we used lipopolysaccharide (LPS), as a known inflammatory stimulant in IVDs, to manipulate the cells and their interaction. LPS treatment resulted in detectable changes to the contraction cells induced on the collagen matrix and affected the mechanical properties of these constructs.
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Affiliation(s)
- Sara Molladavoodi
- Department of Kinesiology and Physical EducationWilfrid Laurier UniversityWaterlooOntarioCanada
| | - Stephanie J. DeWitte‐Orr
- Department of Health SciencesWilfrid Laurier UniversityWaterlooOntarioCanada
- Department of BiologyWilfrid Laurier UniversityWaterlooOntarioCanada
| | - Diane E. Gregory
- Department of Kinesiology and Physical EducationWilfrid Laurier UniversityWaterlooOntarioCanada
- Department of Health SciencesWilfrid Laurier UniversityWaterlooOntarioCanada
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24
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CGRP Regulates Nucleus Pulposus Cell Apoptosis and Inflammation via the MAPK/NF- κB Signaling Pathways during Intervertebral Disc Degeneration. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2021:2958584. [PMID: 34987701 PMCID: PMC8720589 DOI: 10.1155/2021/2958584] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 12/03/2021] [Indexed: 12/22/2022]
Abstract
Chronic low back pain (CLBP) has been proved to be the dominating cause of disability in patients with lumbar degenerative diseases. Of the various etiological factors, intervertebral disc degeneration (IVDD) has been the dominating cause. In the past few decades, the role and changes of nerve systems, especially the peripheral sensory fibers and their neurotransmitters, in the induction and progression of IVDD have attracted growing concerns. The expression of many neuropeptides, such as SP, NPY, and CGRP, in the nociceptive pathways is increased during the progression of IVDD and responsible for the discogenic pain. Here, the role of CGRP in the progression of IVDD was firstly investigated both in vitro and in vivo. Firstly, we confirmed that human degenerated intervertebral disc tissue exhibited elevated expression of CGRP and its receptor. Secondly, in vitro experiments suggested that CGRP could inhibit the proliferation and induce apoptosis in human nucleus pulposus (NP) cells, as well as promote inflammation and degenerated phenotypes through activating NF-κB and MAPK signaling pathways. Thirdly, CGRP receptor antagonist, Rimegepant, can ameliorate the adverse effects of CGRP imposed on NP cells, which were confirmed in vitro and in vivo. Our results will bring about a brand-new insight into the roles of neuromodulation in IVDD and related therapeutic attempts.
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25
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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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26
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Gkantsinikoudis N, Kapetanakis S, Magras I, Tsiridis E, Kritis A. Tissue-Engineering of Human Intervertebral Disc: A Concise Review. TISSUE ENGINEERING PART B-REVIEWS 2021; 28:848-860. [PMID: 34409867 DOI: 10.1089/ten.teb.2021.0090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Intervertebral disc (IVD) represents a structure of crucial structural and functional importance for human spine. Pathology of IVD institutes a frequently encountered condition in current clinical practice. Degenerative Disc Disease (DDD), the principal clinical representative of IVD pathology, constitutes an increasingly diagnosed spinal disorder associated with substantial morbidity and mortality in recent years. Despite the considerable incidence and socioeconomic burden of DDD, existing treatment modalities including conservative and surgical methods have been demonstrated to provide a limited therapeutic effect, being not capable of interrupting or reversing natural progress of underlying disease. These limitations underline the requirement for development of novel, innovative and more effective therapeutic strategies for DDD management. Within this literature framework, compromised IVD replacement with a viable IVD construct manufactured with Tissue-Engineering (TE) methods has been recommended as a promising therapeutic strategy for DDD. Existing preliminary preclinical data demonstrate that proper combination of cells from various sources, different scaffold materials and appropriate signaling molecules renders manufacturing of whole-IVD tissue-engineered constructs a technically feasible process. Aim of this narrative review is to critically summarize current published evidence regarding particular aspects of IVD-TE, primarily emphasizing in providing researchers in this field with practicable knowledge in order to enhance clinical translatability of their research and informing clinical practitioners about the features and capabilities of innovative TE science in the field of IVD-TE.
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Affiliation(s)
- Nikolaos Gkantsinikoudis
- School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki (A.U.Th.), Department of Physiology and Pharmacology , Thessaloniki, Greece.,School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki (A.U.Th), cGMP Regenerative Medicine Facility, Department of Physiology and Pharmacology, Thessaloniki, Greece;
| | - Stylianos Kapetanakis
- Interbalkan European Medical Center, Spine Department and Deformities, Thessaloniki, Greece;
| | - Ioannis Magras
- AHEPA University General Hospital, Aristotle University of Thessaloniki, Department of Neurosurgery, Thessaloniki, Greece;
| | - Eleftherios Tsiridis
- Papageorgiou General Hospital, Aristotle University Medical School, Academic Orthopaedic Department, Thessaloniki Ring Road, Nea Efkarpia, Greece.,Aristotle University Thessaloniki, Balkan Center, Buildings A & B, Center of Orthopaedics and Regenerative Medicine (C.O.RE.), Center of Interdisciplinary Research and Innovation (C.I.R.I.), Thessaloniki, 10th km Thessaloniki-Thermi Rd, Greece;
| | - Aristeidis Kritis
- School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki (A.U.Th.), Department of Physiology and Pharmacology , Thessaloniki, Greece.,School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki (A.U.Th), cGMP Regenerative Medicine Facility, Department of Physiology and Pharmacology, Thessaloniki, Greece;
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27
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Muresanu C, Somasundaram SG, Vissarionov SV, Gavryushova LV, Nikolenko VN, Mikhaleva LM, Kirkland CE, Aliev G. Hypothetical Role of Growth Factors to Reduce Intervertebral Disc Degeneration Significantly through Trained Biological Transformations. Curr Pharm Des 2021; 27:2221-2230. [PMID: 33076800 DOI: 10.2174/1381612826666201019104201] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 08/11/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Given the evidence of little or no therapeutic benefit of injection-based growth factor therapies, it has been proposed that a naturally triggered uninterrupted blood circulation of the growth factors would be superior. OBJECTIVE We seek to stimulate discussions and more research about the possibility of using the already available growth factors found in the prostate gland and endometrium by starting novel educable physiology, known as biological transformations controlled by the mind. METHODS We summarized the stretch-gated ion channel mechanism of the cell membrane and offer several practical methods that can be applied by anyone, in order to stimulate and enhance the blood circulation of the growth factors from the seminal fluid to sites throughout the body. This study describes, in detail, the practical application of our earlier published studies about biological transformations. RESULTS A previously reported single-patient case study has been extended, adding more from his personal experiences to continually improve this novel physiological training and extending the ideas from our earlier findings in detail. CONCLUSION The biological transformation findings demonstrate the need for additional research to establish the benefits of these natural therapies to repair and rejuvenate tissues affected by various chronic diseases or aging processes.
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Affiliation(s)
- Cristian Muresanu
- Research Center for Applied Biotechnology in Diagnosis and Molecular Therapies (BIODIATECH), Str. Trifoiului nr. 12 G, 400478, Cluj-Napoca, Romania
| | - Siva G Somasundaram
- Department of Biological Sciences, Salem University, Salem, WV 26426, United States
| | - Sergey V Vissarionov
- Department of Spinal Pathology and Neurosurgery, Turner Scientific and Research Institute for Children's Orthopedics, Street Parkovskya 64-68, Pushkin, Saint-Petersburg, 196603, Russian Federation
| | - Liliya V Gavryushova
- Saratov State Medical University named after V.I. Razumovsky, 410012, Saratov, Russian Federation
| | - Vladimir N Nikolenko
- I. M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str., Moscow, 119991, Russian Federation
| | - Liudmila M Mikhaleva
- Federal State Budgetary Institution, Research Institute of Human Morphology, 3, Tsyurupy Str., Moscow, 117418, Russian Federation
| | - Cecil E Kirkland
- Department of Biological Sciences, Salem University, Salem, WV 26426, United States
| | - Gjumrakch Aliev
- I. M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str., Moscow, 119991, Russian Federation
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28
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Zhang Q, Shen Y, Zhao S, Jiang Y, Zhou D, Zhang Y. Exosomes miR-15a promotes nucleus pulposus-mesenchymal stem cells chondrogenic differentiation by targeting MMP-3. Cell Signal 2021; 86:110083. [PMID: 34252537 DOI: 10.1016/j.cellsig.2021.110083] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 06/29/2021] [Accepted: 07/07/2021] [Indexed: 12/27/2022]
Abstract
The physiology of the nucleus pulposus (NP) in intervertebral disc degeneration (IVD) has been studied widely. However, interactions involving nucleus pulposus -mesenchymal stem cells (NP-MSCs) are less understood. MicroRNA 15a (miR-15a) is known to target and modulate genes involved in cellular proliferation and apoptosis. This study aimed to understand the interactions and impact of miR-15a and NP-MSCs on chondrogenic differentiation and IVD degeneration. Exosomes secreted by NP cells were purified by differential centrifugation and identified by transmission electron microscopy and exosomal markers. Further, by co-culture these exosomes were re-introduced into the NP-MSC cells, which were confirmed by fluorescence confocal microscopy. NP-MSCs treated with exo-miR-15a increases aggrecan and collagen II mRNA and protein levels while decreasing mRNA and protein levels of ADAMTS4/5 and MMP-3/-13. Toluidine blue staining confirmed that chondrogenic differentiation was increased in NP-MSCs treated with exo-miR-15a. NP-MSCs treated with exo-anti-miR-15a inhibit aggrecan and collagen II expression while increasing ADAMTS4/5 and MMP-3/-13 expression and decreasing chondrogenic differentiation. Dual-luciferase reporter assays revealed that miR-15a directly targets MMP-3 and downregulates its expression. Overexpression of miR-15a increased proliferation and colony formation, whereas combinatorial overexpression with MMP3, suppressed miR-15a's effects. This was also evident through the decreased phosphorylation of PI3K and Akt, upregulation of Wnt3a and β-catenin in the presence of miR-15a, but overexpression of MMP3 indicated an opposite effect. Overall, these data demonstrate that exo-miR-15a promotes NP-MSCs chondrogenic differentiation by downregulating MMP-3 through PI3K/Akt and Wnt3a/β-catenin axis.
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Affiliation(s)
- Qiang Zhang
- Department of Orthopedics, The Affiliated Changzhou No. 2 People's Hospital, Nanjing Medical University, Changzhou, Jiangsu 213003, China
| | - Yifei Shen
- Department of Orthopedics, The Affiliated Changzhou No. 2 People's Hospital, Nanjing Medical University, Changzhou, Jiangsu 213003, China
| | - Shujie Zhao
- Department of Orthopedics, The People's Hospital of Jiangsu Province, Nanjing, Jiangsu 210029, China
| | - Yuqing Jiang
- Department of Orthopedics, The Affiliated Changzhou No. 2 People's Hospital, Nanjing Medical University, Changzhou, Jiangsu 213003, China
| | - Dong Zhou
- Department of Orthopedics, The Affiliated Changzhou No. 2 People's Hospital, Nanjing Medical University, Changzhou, Jiangsu 213003, China.
| | - Yunkun Zhang
- Department of Orthopedics, The Affiliated Changzhou No. 2 People's Hospital, Nanjing Medical University, Changzhou, Jiangsu 213003, China.
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29
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Li J, Xu C, Zhang X, Xi Z, Liu M, Fang Z, Wang N, Xie L, Song Y. TELD with limited foraminoplasty has potential biomechanical advantages over TELD with large annuloplasty: an in-silico study. BMC Musculoskelet Disord 2021; 22:616. [PMID: 34246272 PMCID: PMC8272903 DOI: 10.1186/s12891-021-04504-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 06/17/2021] [Indexed: 02/07/2023] Open
Abstract
Background Facetectomy, an important procedure in the in–out and out–in techniques of transforaminal endoscopic lumbar discectomy (TELD), is related to the deterioration of the postoperative biomechanical environment and poor prognosis. Facetectomy may be avoided in TELD with large annuloplasty, but iatrogenic injury of the annulus and a high grade of nucleotomy have been reported as risk factors influencing poor prognosis. These risk factors may be alleviated in TELD with limited foraminoplasty, and the grade of facetectomy in this surgery can be reduced by using an endoscopic dynamic drill. Methods An intact lumbo-sacral finite element (FE) model and the corresponding model with adjacent segment degeneration were constructed and validated to evaluate the risk of biomechanical deterioration and related postoperative complications of TELD with large annuloplasty and TELD with limited foraminoplasty. Changes in various biomechanical indicators were then computed to evaluate the risk of postoperative complications in the surgical segment. Results Compared with the intact FE models, the model of TELD with limited foraminoplasty demonstrated slight biomechanical deterioration, whereas the model of TELD with large annuloplasty revealed obvious biomechanical deterioration. Degenerative changes in adjacent segments magnified, rather than altered, the overall trends of biomechanical change. Conclusions TELD with limited foraminoplasty presents potential biomechanical advantages over TELD with large annuloplasty. Iatrogenic injury of the annulus and a high grade of nucleotomy are risk factors for postoperative biomechanical deterioration and complications of the surgical segment.
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Affiliation(s)
- Jingchi Li
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital/West China School of Medicine for Sichuan University, 37# Wuhou Guoxue road, Chengdu, Sichuan Province, 610041, P.R. China
| | - Chen Xu
- Department of Spine Surgery, Changzheng Hospital Affiliated to the Naval Medical University, Shanghai, 200041, China
| | - Xiaoyu Zhang
- Department of Spine Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine for Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, 210028, P.R. China
| | - Zhipeng Xi
- Department of Spine Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine for Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, 210028, P.R. China
| | - Mengnan Liu
- Macau University of Science and Technology, Macau, 999078, China
| | - Zhongxin Fang
- Fluid and Power Machinery Key Laboratory of Ministry of Education, Xihua University, Chengdu, 610039, China
| | - Nan Wang
- Department of Spine Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine for Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, 210028, P.R. China
| | - Lin Xie
- Department of Spine Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine for Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, 210028, P.R. China.
| | - Yueming Song
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital/West China School of Medicine for Sichuan University, 37# Wuhou Guoxue road, Chengdu, Sichuan Province, 610041, P.R. China.
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30
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Xiao L, Ding B, Gao J, Yang B, Wang J, Xu H. Curcumin prevents tension-induced endplate cartilage degeneration by enhancing autophagy. Life Sci 2020; 258:118213. [PMID: 32768583 DOI: 10.1016/j.lfs.2020.118213] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/01/2020] [Accepted: 08/03/2020] [Indexed: 12/16/2022]
Abstract
AIMS Intermittent cyclic tension stimulation(ICMT) was shown to promote degeneration of endplate chondrocytes and induce autophagy. However, enhancing autophagy can alleviate degeneration partly. Studies have shown that curcumin can induce autophagy and protect chondrocytes, we speculated that regulation of autophagy by curcumin might be an effective method to improve the stress resistance of endplate cartilage. In this study, human cervical endplate cartilage specimens were collected, and expression of autophagy markers was detected and compared. MAIN METHODS Human cervical endplate chondrocytes were cultured to establish a tension-induced degeneration model, for which changes of functional metabolism and autophagy levels were detected under different tension loading conditions. Changes in functional metabolism of endplate chondrocytes were observed under high-intensity tension loading in the presence of inhibitors, inducers, and curcumin to regulate the autophagy level of cells. In addition, a rat model of lumbar instability was established to observe the degeneration of lumbar disc after curcumin administration. KEY FINDINGS Through a series of experiments, we found that low-intensity tension stimulation can maintain a stable phenotype of endplate chondrocytes, but high-intensity tension stimulation has a negative effect. Moreover, with increasing tension intensity, the degree of degeneration of endplate chondrocytes was gradually aggravated and the level of autophagy increased. Besides, curcumin upregulated autophagy, inhibited apoptosis, and reduced phenotype loss of endplate chondrocytes induced by high-intensity tension loading, thereby relieving intervertebral disc degeneration induced by mechanical imbalance. SIGNIFICANCE Curcumin mediated autophagy and enhanced the adaptability of endplate chondrocytes to high-intensity tension load, thereby relieving intervertebral disc degeneration.
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Affiliation(s)
- Liang Xiao
- Research center of Spine Surgery, Department of Spine Surgery, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, 241001, PR China
| | - Baiyang Ding
- Research center of Spine Surgery, Department of Spine Surgery, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, 241001, PR China
| | - Jianming Gao
- Research center of Spine Surgery, Department of Spine Surgery, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, 241001, PR China
| | - Bijing Yang
- Research center of Spine Surgery, Department of Spine Surgery, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, 241001, PR China
| | - Jing Wang
- Research center of Spine Surgery, Department of Spine Surgery, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, 241001, PR China
| | - Hongguang Xu
- Research center of Spine Surgery, Department of Spine Surgery, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, 241001, PR China.
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Kupka J, Kohler A, El Bagdadi K, Bostelmann R, Brenneis M, Fleege C, Chan D, Zaucke F, Meurer A, Rickert M, Jenei-Lanzl Z. Adrenoceptor Expression during Intervertebral Disc Degeneration. Int J Mol Sci 2020; 21:ijms21062085. [PMID: 32197418 PMCID: PMC7139977 DOI: 10.3390/ijms21062085] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 02/27/2020] [Accepted: 03/07/2020] [Indexed: 12/12/2022] Open
Abstract
Healthy and degenerating intervertebral discs (IVDs) are innervated by sympathetic nerves, however, adrenoceptor (AR) expression and functionality have never been investigated systematically. Therefore, AR gene expression was analyzed in both tissue and isolated cells from degenerated human IVDs. Furthermore, human IVD samples and spine sections of wildtype mice (WT) and of a mouse line that develops spontaneous IVD degeneration (IVDD, in SM/J mice) were stained for ARs and extracellular matrix (ECM) components. In IVD homogenates and cells α1a-, α1b-, α2a-, α2b-, α2c-, β1-, and β2-AR genes were expressed. In human sections, β2-AR was detectable, and its localization parallels with ECM alterations. Similarly, in IVDs of WT mice, only β2-AR was expressed, and in IVDs of SM/J mice, β2AR expression was stronger accompanied by increased collagen II, collagen XII, decorin as well as decreased cartilage oligomeric matrix protein expression. In addition, norepinephrine stimulation of isolated human IVD cells induced intracellular signaling via ERK1/2 and PKA. For the first time, the existence and functionality of ARs were demonstrated in IVD tissue samples, suggesting that the sympathicus might play a role in IVDD. Further studies will address relevant cellular mechanisms and thereby help to develop novel therapeutic options for IVDD.
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Affiliation(s)
- Johannes Kupka
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital Friedrichsheim gGmbH, 60528 Frankfurt/Main, Germany (A.K.); (K.E.B.); (M.B.); (F.Z.); (A.M.); (M.R.)
| | - Annika Kohler
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital Friedrichsheim gGmbH, 60528 Frankfurt/Main, Germany (A.K.); (K.E.B.); (M.B.); (F.Z.); (A.M.); (M.R.)
| | - Karima El Bagdadi
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital Friedrichsheim gGmbH, 60528 Frankfurt/Main, Germany (A.K.); (K.E.B.); (M.B.); (F.Z.); (A.M.); (M.R.)
| | - Richard Bostelmann
- Clinic of Neurosurgery, Heinrich Heine University, 40225 Duesseldorf, Germany;
| | - Marco Brenneis
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital Friedrichsheim gGmbH, 60528 Frankfurt/Main, Germany (A.K.); (K.E.B.); (M.B.); (F.Z.); (A.M.); (M.R.)
| | - Christoph Fleege
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital Friedrichsheim gGmbH, 60528 Frankfurt/Main, Germany (A.K.); (K.E.B.); (M.B.); (F.Z.); (A.M.); (M.R.)
| | - Danny Chan
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China;
| | - Frank Zaucke
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital Friedrichsheim gGmbH, 60528 Frankfurt/Main, Germany (A.K.); (K.E.B.); (M.B.); (F.Z.); (A.M.); (M.R.)
| | - Andrea Meurer
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital Friedrichsheim gGmbH, 60528 Frankfurt/Main, Germany (A.K.); (K.E.B.); (M.B.); (F.Z.); (A.M.); (M.R.)
| | - Marcus Rickert
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital Friedrichsheim gGmbH, 60528 Frankfurt/Main, Germany (A.K.); (K.E.B.); (M.B.); (F.Z.); (A.M.); (M.R.)
| | - Zsuzsa Jenei-Lanzl
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital Friedrichsheim gGmbH, 60528 Frankfurt/Main, Germany (A.K.); (K.E.B.); (M.B.); (F.Z.); (A.M.); (M.R.)
- Correspondence: ; Tel.: +49-69-6705-408
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Molladavoodi S, McMorran J, Gregory D. Mechanobiology of annulus fibrosus and nucleus pulposus cells in intervertebral discs. Cell Tissue Res 2019; 379:429-444. [PMID: 31844969 DOI: 10.1007/s00441-019-03136-1] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 11/03/2019] [Indexed: 02/07/2023]
Abstract
Low back pain (LBP) is a chronic condition that can affect up to 80% of the global population. It is the number one cause of disability worldwide and has enormous socioeconomic consequences. One of the main causes of this condition is intervertebral disc (IVD) degeneration. IVD degenerative processes and inflammation associated with it has been the subject of many studies in both tissue and cell level. It is believed that the phenotype of the resident cells within the IVD directly affects homeostasis of the tissue. At the same time, IVDs located between vertebral bodies of spine are under various mechanical loading conditions in vivo. Therefore, investigating how mechanical loading can affect the behaviour of IVD cells has been a subject of many research articles. In this review paper, following a brief explanation of the anatomy of the IVD and its resident cells, we compiled mechanobiological studies of IVD cells (specifically, annulus fibrosus and nucleus pulposus cells) and synthesized and discussed the key findings of the field.
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Affiliation(s)
- Sara Molladavoodi
- Department of Kinesiology and Physical Education, Wilfrid Laurier University, Waterloo, ON, Canada.,Department of Health Sciences, Wilfrid Laurier University, Waterloo, ON, Canada
| | - John McMorran
- Department of Kinesiology and Physical Education, Wilfrid Laurier University, Waterloo, ON, Canada
| | - Diane Gregory
- Department of Kinesiology and Physical Education, Wilfrid Laurier University, Waterloo, ON, Canada. .,Department of Health Sciences, Wilfrid Laurier University, Waterloo, ON, Canada.
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Sun Z, Luo ZJ. Osteoporosis therapies might lead to intervertebral disc degeneration via affecting cartilage endplate. Med Hypotheses 2019; 125:5-7. [PMID: 30902151 DOI: 10.1016/j.mehy.2019.02.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 01/01/2019] [Accepted: 02/01/2019] [Indexed: 02/07/2023]
Abstract
Osteoporosis and intervertebral disc degeneration (IDD) are both age-related diseases of the musculoskeletal system. With the average life expectancy longer than ever, the morbidity caused by these two diseases is increasing. Nowadays, treatment strategies for osteoporosis are mainly aimed at increasing the mineral density of the bone. Some of these therapies, including vitamin D, calcium, bisphosphonates, Wnt signal activators and parathyroid hormone regulators, have been suggested to be capable of causing calcification of the cartilage endplate in the intervertebral disc. This alteration could block nutrient and oxygen transportation to the center part of the disc, thus lead to intervertebral disc degeneration. Consequently, we hypothesize that osteoporosis therapies might be a potential risk for IDD. This assumption indicates that we should take the alterations of the cartilage endplate into consideration in further osteoporosis treatment to avoid IDD in the patient.
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Affiliation(s)
- Zhen Sun
- Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, West Changle Road, Xi'an, 710032, China
| | - Zhuo-Jing Luo
- Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, West Changle Road, Xi'an, 710032, China.
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Pekala PA, Henry BM, Taterra D, Piwowar M, Vikse J, Tubbs RS, Tomaszewski KA. FokI as a genetic factor of intervertebral disc degeneration: A PRISMA-compliant systematic review of overlapping meta-analyses. J Clin Neurosci 2018; 60:36-43. [PMID: 30309807 DOI: 10.1016/j.jocn.2018.09.028] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 09/26/2018] [Indexed: 01/08/2023]
Abstract
The association of FokI (rs2228570), a polymorphism of the vitamin D receptor gene, with intervertebral disc degeneration (IDD) has been investigated in a multitude of studies. However, conflicting results of these studies led to emergence of several meta-analyses over the past few years. Despite the increased statistical power, these meta-analyses have failed to provide uniform and conclusive data on the relationship of FokI with IDD. The aim of this study was to present a comprehensive review based on the most up-to-date meta-analyses on the association of FokI with IDD. A comprehensive search of all major databases was conducted to identify meta-analyses investigating relation between FokI and IDD. No date or language restrictions were applied. The Jadad decision algorithm was utilized to evaluate included meta-analyses and identify the one providing the best evidence. A total of 7 meta-analyses (n = 2580 original patients), that included six to ten case control studies, analyzed the association of FokI polymorphism with IDD. The meta-analysis of the highest quality supported the notion that overall there is no statistically significant association between FokI polymorphism and IDD. However, the authors showed that Caucasians have a reduced risk of IDD and Hispanics have an increased risk of IDD in the dominant and dominant/homozygous/heterozygous models of FokI polymorphism. While currently there is no evidence of an association between FokI polymorphism and IDD in the general population, ethnic predisposition has been shown.
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Affiliation(s)
- Przemysław A Pekala
- International Evidence-Based Anatomy Working Group, Krakow, Poland; Department of Anatomy, Jagiellonian University Medical College, Krakow, Poland.
| | - Brandon Michael Henry
- International Evidence-Based Anatomy Working Group, Krakow, Poland; Department of Anatomy, Jagiellonian University Medical College, Krakow, Poland
| | - Dominik Taterra
- International Evidence-Based Anatomy Working Group, Krakow, Poland; Department of Anatomy, Jagiellonian University Medical College, Krakow, Poland
| | - Monika Piwowar
- Department of Bioinformatics and Telemedicine, Jagiellonian University Medical College, Krakow, Poland
| | - Jens Vikse
- International Evidence-Based Anatomy Working Group, Krakow, Poland; Department of Surgery, Stavanger University Hospital, Stavanger, Norway
| | | | - Krzysztof A Tomaszewski
- International Evidence-Based Anatomy Working Group, Krakow, Poland; Department of Anatomy, Jagiellonian University Medical College, Krakow, Poland
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Wang Y, Yi XD, Li CD. The influence of artificial nucleus pulposus replacement on stress distribution in the cartilaginous endplate in a 3-dimensional finite element model of the lumbar intervertebral disc. Medicine (Baltimore) 2017; 96:e9149. [PMID: 29390319 PMCID: PMC5815731 DOI: 10.1097/md.0000000000009149] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE This study aimed to investigate the effects involved with the artificial nucleus pulposus (NP) replacement on stress distribution of the cartilaginous endplate (CEP) in a 3-dimensional lumbar intervertebral disc (IVD) model using a finite element (FE) analysis. METHODS A healthy male volunteer was recruited for the purposes of the study and a spiral computed tomography scan was subsequently conducted to obtain the data information in relation to the L4/5 motion segment. An FE model of the L4/5 motion segment constructed, on the basis of which degenerative IVD, IVD with NP removal, and IVD with NP replacement were in turn built. The stress distribution of the CEP and bulging of IVD were estimated using various motion states, including axial loading, forward flexion, backward extension, left axial rotation, and right axial rotation. RESULTS Under different motion states, the vertebral stress was higher in the degenerative IVD, the IVD with NP removal, and the IVD with NP replacement, in comparison to that of the normal IVD. Furthermore, a higher vertebral stress was detected in the degenerative IVD than the IVD with NP removal and the IVD with NP replacement. An even distribution of vertebral stress was observed in the IVD model with an artificial NP replacement, while the vertebral stress and bulging displacement were lower than after NP removal. Our findings provided confirmation that stress of the CEP was consistent with the vertebral stress. CONCLUSION This study provided evidence suggesting that NP replacement, vertebral stress, and bulging displacement are lower than that of degenerative IVD and IVD with NP removal under different motion states.
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Validation of the intervertebral disc histological degeneration score in cervical intervertebral discs and their end plates. Spine J 2017; 17:738-745. [PMID: 28104459 DOI: 10.1016/j.spinee.2017.01.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2016] [Revised: 12/08/2016] [Accepted: 01/12/2017] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Vertebral joints consist of intervertebral discs (IVDs) and cartilaginous end plates (EP) that lie superiorly and inferiorly to the IVDs and separate them from the adjacent vertebral bodies. With aging, both IVDs and EPs undergo degeneration. The Histologic Degeneration Score (HDS) is a grading system that microscopically evaluates the degree of degeneration in lumbar discs and predicts it with high accuracy basing on several histological markers of IVD and EP. There is currently a lack of validated histologic grading schemes for cervical spine degeneration. PURPOSE The aim of our study was to describe the changes in cervical IVDs and EPs with degeneration and to test the validity of the HDS in the cervical spine. STUDY DESIGN A histological study on degenerative changes in cervical IVDs and EPs was conducted. METHODS Thirty human cadavers were dissected to obtain 60 cervical IVDs from the lower half of C4 to the level of the upper half of C6. The IVDs were carefully excised along with EPs and then sectioned to obtain midsagittal samples for macroscopic examination according to a five-grade classification system. The samples were further dissected, fixed, and stained for histological examination according to HDS. RESULTS Thirty C4-C5 IVDs and thirty C5-C6 IVDs were macroscopically examined for degeneration. The averaged Thompson's grade was found to be 2.9±1.3. The mean HDS for IVDs was 13.1±5.8 and for EP was 10.2±5.2. The interrater reliability estimates indicated excellent reliability (κ values>0.81, percentage agreement 86.1%-96.1%). Spearman's rank correlation coefficients for IVD and EP scores showed good consistency in predicting macroscopic degeneration. No significant differences were found between the values for cervical IVDs and EPs in the present study and those for lumbar discs derived in previous studies. CONCLUSIONS The HDS was confirmed to be as accurate in predicting the degree of degeneration in the cervical spine as in the lumbar region. To our best knowledge, this is the first reported and validated histological classification system intended for assessing histological degeneration in the cervical spine. Therefore, HDS can be recommended for academic and pathologic purposes in cervical disc degeneration.
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Rim DC. Quantitative Pfirrmann Disc Degeneration Grading System to Overcome the Limitation of Pfirrmann Disc Degeneration Grade. KOREAN JOURNAL OF SPINE 2016; 13:1-8. [PMID: 27123023 PMCID: PMC4844654 DOI: 10.14245/kjs.2016.13.1.1] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 01/06/2016] [Accepted: 01/07/2016] [Indexed: 12/15/2022]
Abstract
Objective Pfirrmann disc degeneration grade is one of morphologic disc degeneration grading system and it was reliable on routine T2-weighted magnetic resonance (MR) images. The purpose of this study was to evaluate the agreement of Pfirrmann disc degeneration grade, and check the alternative technique of disc degeneration grading system. Methods Fifteen volunteers (4 medical doctors related to spinal disease, 2 medical doctors not related to spinal disease, 6 nurses in spinal hospital, and 3 para-medicines) were included in this study. Three different digitalized MR images were provided all volunteers, and they checked Pfirrmann disc degeneration grade of each disc levels after careful listening to explanation. Indeed, all volunteers checked the signal intensity of disc degeneration at the points of nucleus pulposus (NP), disc membrane, ligaments, fat, and air to modify the quantitative Pfirrmann disc degeneration grade. Results Total 225 grade results of Pfirrmann disc degeneration grade and 405 signal intensity results of quantitative Pfirrmann disc degeneration grade were analyzed. Average interobserver agreement was "moderate (mean±standard deviation, 0.575±0.251)" from poor to excellent. Completely agreed levels of Pfirrmann disc degeneration grade were only 4 levels (26.67%), and the disagreement levels were observed in 11 levels; two different grades in 8 levels (53.33%) and three different grades in 3 levels (20%). Quantitative Pfirrmann disc degeneration showed relatively cluster distribution with the interobserver deviations of 0.41-1.56 at the ratio of NP and disc membrane, and it showed relatively good cluster and distribution indicating that the proposed grading system has good discrimination ability. Conclusion Pfirrmann disc degeneration grade showed the limitation of different interobserver results, but this limitation could be overcome by using quantitative techniques of MR signal intensity. Further evaluation is needed to access its advantage and reliabilities.
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Affiliation(s)
- Dae Cheol Rim
- Department of Neurosurgery, Kim Young Soo Spine & Joint Hospital, Seoul, Korea
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