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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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Tseranidou S, Segarra-Queralt M, Chemorion FK, Le Maitre CL, Piñero J, Noailly J. Nucleus pulposus cell network modelling in the intervertebral disc. NPJ Syst Biol Appl 2025; 11:13. [PMID: 39890859 PMCID: PMC11785752 DOI: 10.1038/s41540-024-00479-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 12/12/2024] [Indexed: 02/03/2025] Open
Abstract
Intervertebral disc degeneration (IDD) results from an imbalance between anabolic and catabolic processes in the extracellular matrix (ECM). Due to complex biochemical interactions, a comprehensive understanding is needed. This study presents a regulatory network model (RNM) for nucleus pulposus cells (NPC), representing normal intervertebral disc (IVD) conditions. The RNM includes 33 proteins, and 153 interactions based on literature, incorporating key NPC regulatory mechanisms. A semi-quantitative approach calculates the basal steady state, accurately reflecting normal NPC activity. Model validation through published studies replicated pro-catabolic and pro-anabolic shifts, emphasizing the roles of transforming growth factor beta (TGF-β) and interleukin-1 receptor antagonist (IL-1Ra) in ECM regulation. This IVD RNM is a valuable tool for predicting IDD progression, offering insights into ECM degradation mechanisms and guiding experimental research on IVD health and degeneration.
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Affiliation(s)
- Sofia Tseranidou
- Department of Engineering, Universitat Pompeu Fabra, Barcelona, Spain.
| | | | | | - Christine Lyn Le Maitre
- Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, United Kingdom
| | - Janet Piñero
- Hospital del Mar Medical Research Institute, Barcelona, Spain
| | - Jérôme Noailly
- Department of Engineering, Universitat Pompeu Fabra, Barcelona, Spain
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Hong JY, Kim H, Jeon WJ, Yeo C, Kim H, Lee J, Lee YJ, Ha IH. Animal Models of Intervertebral Disc Diseases: Advantages, Limitations, and Future Directions. Neurol Int 2024; 16:1788-1818. [PMID: 39728755 DOI: 10.3390/neurolint16060129] [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: 10/07/2024] [Revised: 11/13/2024] [Accepted: 12/02/2024] [Indexed: 12/28/2024] Open
Abstract
Animal models are valuable tools for studying the underlying mechanisms of and potential treatments for intervertebral disc diseases. In this review, we discuss the advantages and limitations of animal models of disc diseases, focusing on lumbar spinal stenosis, disc herniation, and degeneration, as well as future research directions. The advantages of animal models are that they enable controlled experiments, long-term monitoring to study the natural history of the disease, and the testing of potential treatments. However, they also have limitations, including species differences, ethical concerns, a lack of standardized protocols, and short lifespans. Therefore, ongoing research focuses on improving animal model standardization and incorporating advanced imaging and noninvasive techniques, genetic models, and biomechanical analyses to overcome these limitations. These future directions hold potential for improving our understanding of the underlying mechanisms of disc diseases and for developing new treatments. Overall, although animal models can provide valuable insights into pathophysiology and potential treatments for disc diseases, their limitations should be carefully considered when interpreting findings from animal studies.
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Affiliation(s)
- Jin Young Hong
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul 135-896, Republic of Korea
| | - Hyunseong Kim
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul 135-896, Republic of Korea
| | - Wan-Jin Jeon
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul 135-896, Republic of Korea
| | - Changhwan Yeo
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul 135-896, Republic of Korea
| | - Hyun Kim
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul 135-896, Republic of Korea
| | - Junseon Lee
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul 135-896, Republic of Korea
| | - Yoon Jae Lee
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul 135-896, Republic of Korea
| | - In-Hyuk Ha
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul 135-896, Republic of Korea
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Elmounedi N, Bahloul W, Keskes H. Current Therapeutic Strategies of Intervertebral Disc Regenerative Medicine. Mol Diagn Ther 2024; 28:745-775. [PMID: 39158834 DOI: 10.1007/s40291-024-00729-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/30/2024] [Indexed: 08/20/2024]
Abstract
Intervertebral disc degeneration (IDD) is one of the most frequent causes of low back pain. No treatment is currently available to delay the progression of IDD. Conservative treatment or surgical interventions is only used to target the symptoms of IDD rather than treat the underlying cause. Currently, numerous potential therapeutic strategies are available, including molecular therapy, gene therapy, and cell therapy. However, the hostile environment of degenerated discs is a major problem that has hindered the clinical applicability of such approaches. In this regard, the design of drugs using alternative delivery systems (macro-, micro-, and nano-sized particles) may resolve this problem. These can protect and deliver biomolecules along with helping to improve the therapeutic effect of drugs via concentrating, protecting, and prolonging their presence in the degenerated disc. This review summarizes the research progress of diagnosis and the current options for treating IDD.
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Affiliation(s)
- Najah Elmounedi
- Cell Therapy and Experimental Surgery of Musculoskeletal System LR18SP11 Lab, Sfax Faculty of Medicine, Majida Boulila Road, 3029, Sfax, Tunisia.
| | - Walid Bahloul
- Cell Therapy and Experimental Surgery of Musculoskeletal System LR18SP11 Lab, Sfax Faculty of Medicine, Majida Boulila Road, 3029, Sfax, Tunisia
- Department of Orthopedics and Traumatology, CHU Habib Bourguiba, Sfax, Tunisia
| | - Hassib Keskes
- Cell Therapy and Experimental Surgery of Musculoskeletal System LR18SP11 Lab, Sfax Faculty of Medicine, Majida Boulila Road, 3029, Sfax, Tunisia
- Department of Orthopedics and Traumatology, CHU Habib Bourguiba, Sfax, Tunisia
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McDonnell EE, Ní Néill T, Wilson N, Darwish SL, Butler JS, Buckley CT. In silico modeling the potential clinical effect of growth factor treatment on the metabolism of human nucleus pulposus cells. JOR Spine 2024; 7:e1352. [PMID: 39092165 PMCID: PMC11291302 DOI: 10.1002/jsp2.1352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 06/14/2024] [Accepted: 07/01/2024] [Indexed: 08/04/2024] Open
Abstract
Background While growth factors have the potential to halt degeneration and decrease inflammation in animal models, the literature investigating the effect of dosage on human cells is lacking. Moreover, despite the completion of clinical trials using growth differentiation factor-5 (GDF-5), no results have been publicly released. Aims The overall objective was to quantitatively assess the effect of three clinically relevant concentrations of GDF-5 (0.25, 1, and 2 mg) as a therapeutic for disc regeneration. Materials and methods Firstly, this work experimentally determined the effects of GDF-5 concentration on the metabolic and matrix synthesis rates of human nucleus pulposus (NP) cells. Secondly, in silico modeling was employed to predict the subsequent regenerative effect of different GDF-5 treatments (± cells). Results This study suggests a trend of increased matrix synthesis with 0.25 and 1 mg of GDF-5. However, 2 mg of GDF-5 significantly upregulates oxygen consumption. Despite this, in silico models highlight the potential of growth factors in promoting matrix synthesis compared to cell-only treatments, without significantly perturbing the nutrient microenvironment. Discussion This work elucidates the potential of GDF-5 on human NP cells. Although the results did not reveal statistical differences across all doses, the variability and response among donors is an interesting finding. It highlights the complexity of human response to biological treatments and reinforces the need for further human research and personalized approaches. Furthermore, this study raises a crucial question about whether these potential biologics are more regenerative in nature or better suited as prophylactic therapies for younger patient groups. Conclusion Biological agents exhibit unique characteristics and features, demanding tailored development strategies and individualized assessments rather than a one-size-fits-all approach. Therefore, the journey to realizing the full potential of biological therapies is long and costly. Nonetheless, it holds the promise of revolutionizing spinal healthcare and improving the quality of life for patients suffering from discogenic back pain.
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Affiliation(s)
- Emily E. McDonnell
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College DublinThe University of DublinDublinIreland
- Discipline of Mechanical, Manufacturing and Biomedical Engineering, School of Engineering, Trinity College DublinThe University of DublinDublinIreland
| | - Tara Ní Néill
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College DublinThe University of DublinDublinIreland
- Discipline of Mechanical, Manufacturing and Biomedical Engineering, School of Engineering, Trinity College DublinThe University of DublinDublinIreland
| | - Niamh Wilson
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College DublinThe University of DublinDublinIreland
- Discipline of Mechanical, Manufacturing and Biomedical Engineering, School of Engineering, Trinity College DublinThe University of DublinDublinIreland
| | - Stacey L. Darwish
- National Spinal Injuries UnitMater Misericordiae University HospitalDublinIreland
- School of MedicineUniversity College DublinDublinIreland
- Department of Trauma and OrthopaedicsNational Orthopaedic Hospital, CappaghDublinIreland
- Department of OrthopaedicsSt Vincent's University HospitalDublinIreland
| | - Joseph S. Butler
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College DublinThe University of DublinDublinIreland
- National Spinal Injuries UnitMater Misericordiae University HospitalDublinIreland
- School of MedicineUniversity College DublinDublinIreland
| | - Conor T. Buckley
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College DublinThe University of DublinDublinIreland
- Discipline of Mechanical, Manufacturing and Biomedical Engineering, School of Engineering, Trinity College DublinThe University of DublinDublinIreland
- Advanced Materials and Bioengineering Research (AMBER) Centre, Royal College of Surgeons in Ireland, Trinity College DublinThe University of DublinDublinIreland
- Tissue Engineering Research Group, Department of Anatomy and Regenerative MedicineRoyal College of Surgeons in IrelandDublinIreland
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Tolson JK, Menuet RL, Ly GH, Chanes BA, Bryan EA, Kataria S, Kim J, Ahmadzadeh S, Shekoohi S, Kaye AD. Evolving role of VIADISC for chronic low back and discogenic pain: a narrative review. Expert Opin Emerg Drugs 2024; 29:155-164. [PMID: 38602142 DOI: 10.1080/14728214.2024.2339912] [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: 10/16/2023] [Accepted: 04/03/2024] [Indexed: 04/12/2024]
Abstract
INTRODUCTION Chronic lower back pain is a leading cause of disability and healthcare spending worldwide. Discogenic pain, pain originating from the intervertebral disk, is a common etiology of chronic lower back pain. Currently, accepted treatments for chronic discogenic pain focus only on the management of symptoms, such as pain. There are no approved treatments that stop or reverse degenerating intervertebral discs. Biologic therapies promoting disc regeneration have been developed to expand treatment options. VIADISC™ NP, is a viable disc allograft supplementation that, in a recent trial, demonstrated a significant reduction in pain and increased function in patients suffering from symptomatic degenerative disc disease. AREAS COVERED This manuscript summarizes the epidemiology and etiology of low back pain, the pathophysiology of degenerative disc disease, current treatments, and a need for newer therapies. The rationale behind intradiscal biologics for the treatment of symptomatic degenerative disc disease is also discussed. EXPERT OPINION Characterization of the biology leading to disc degeneration has allowed for the development of intradiscal biologics. They may soon be capable of preventing and reversing disc degeneration. Clinical trials have shown promise, but further research into efficacy and safety is needed before these therapies are widely employed.
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Affiliation(s)
- Jack K Tolson
- School of Medicine, Louisiana State University Health Science Center Shreveport, Shreveport, LA, USA
| | - Robert L Menuet
- School of Medicine, Louisiana State University Health Science Center Shreveport, Shreveport, LA, USA
| | - Gianni H Ly
- School of Medicine, Louisiana State University Health Science Center Shreveport, Shreveport, LA, USA
| | - Benjamin A Chanes
- School of Medicine, Louisiana State University Health Science Center Shreveport, Shreveport, LA, USA
| | - Elizabeth A Bryan
- School of Medicine, Louisiana State University Health Science Center Shreveport, Shreveport, LA, USA
| | - Saurabh Kataria
- Department of Neurology, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, USA
| | - Julian Kim
- Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, USA
| | - Shahab Ahmadzadeh
- Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, USA
| | - Sahar Shekoohi
- Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, USA
| | - Alan D Kaye
- Departments of Anesthesiology and Pharmacology, Toxicology, and Neurosciences, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, USA
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Chekhonatsky VA, Mirzaev KB, Pavlova GV, Usachev DY, Zakharova NB, Chekhonatsky AA, Kuznetsov AV, Gorozhanin AV, Dreval ON. [Genetic factors in degenerative disc disease]. ZHURNAL VOPROSY NEIROKHIRURGII IMENI N. N. BURDENKO 2024; 88:112-118. [PMID: 38549418 DOI: 10.17116/neiro202488021112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2024]
Abstract
OBJECTIVE To analyze available literature data on the role of genetic factors in degenerative disc disease. METHODOLOGY We reviewed the PubMed, MEDLINE, Cohrane Library, e-Library databases using the following keywords: degenerative spine lesions, intervertebral disc herniation, pathogenesis, genetic regulation. RESULTS Searching depth was 2002-2022. We reviewed 84 references. Exclusion criteria: duplicate publications, reviews without detailed description of results, opinions. Finally, we included 43 the most significant studies. CONCLUSION There are literature data on proinflammatory cytokines, growth factors and osteodestructive processes in pathogenesis of degenerative disc disease. However, there is only fragmentary information about the role of genetic regulation of these processes. Some factors, such as microRNA, TGF-b, VEGF, MMP are still poorly understood.
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Affiliation(s)
- V A Chekhonatsky
- Russian Medical Academy of Continuous Postgraduate Education, Moscow, Russia
| | - K B Mirzaev
- Russian Medical Academy of Continuous Postgraduate Education, Moscow, Russia
| | - G V Pavlova
- Burdenko Neurosurgical Center, Moscow, Russia
- Institute of Higher Nervous Activity and Neurophysiology Russian Academy of Sciences, Moscow, Russia
| | - D Yu Usachev
- Russian Medical Academy of Continuous Postgraduate Education, Moscow, Russia
- Burdenko Neurosurgical Center, Moscow, Russia
| | - N B Zakharova
- Razumovsky Saratov State Medical University, Saratov, Russia
| | | | - A V Kuznetsov
- Russian Medical Academy of Continuous Postgraduate Education, Moscow, Russia
| | - A V Gorozhanin
- Russian Medical Academy of Continuous Postgraduate Education, Moscow, Russia
- Botkin Moscow City Clinical Hospital, Moscow, Russia
| | - O N Dreval
- Russian Medical Academy of Continuous Postgraduate Education, Moscow, Russia
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Gurgul AA, Najjar Y, Chee A, An H, Che CT, Park TJ, Warpeha KM. Phenylpropanoid-enriched broccoli seedling extract can reduce inflammatory markers and pain behavior. J Transl Med 2023; 21:922. [PMID: 38115032 PMCID: PMC10731810 DOI: 10.1186/s12967-023-04777-1] [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: 05/11/2023] [Accepted: 11/28/2023] [Indexed: 12/21/2023] Open
Abstract
BACKGROUND Pain is a worldwide problem requiring an effective, affordable, non-addictive therapy. Using the edible plant broccoli, a growth protocol was developed to induce a concentrated combinatorial of potential anti-inflammatories in seedlings. METHODS A growth method was utilized to produce a phenylpropanoid-rich broccoli sprout extract, referred to as Original Extract (OE). OE was concentrated and then resuspended for study of the effects on inflammation events. A rabbit disc model of inflammation and degeneration, and, a mouse model of pain behavior were used for in vivo and in vitro tests. To address aspects of mammalian metabolic processing, the OE was treated with the S9 liver microsome fraction derived from mouse, for use in a mouse in vivo study. Analytical chemistry was performed to identify major chemical species. Continuous variables were analyzed with a number of methods including ANOVA, and two-tailed t tests, as appropriate. RESULTS In a rabbit spine (disc) injury model, inflammatory markers were reduced, and levels of regenerative markers were increased as a result of OE treatment, both in vivo and in vitro. In a mouse pain behavioral model, after treatment with S9 liver microsome fraction, the resultant extract significantly reduced early and late pain behavior in response to a pain stimulus. The OE itself reduced pain behavior in the mouse pain model, but did not achieve the level of significance observed for S9-treated extract. Analytical chemistry undertaken on the extract constituents revealed identities of the chemical species in OE, and how S9 liver microsome fraction treatment altered species identities and proportions. CONCLUSIONS In vitro and in vivo results indicate that the OE, and S9-treated OE broccoli extracts are worthwhile materials to develop a non-opiate inflammation and pain-reducing treatment.
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Affiliation(s)
- Aleksandra A Gurgul
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, IL, USA
| | - Yahya Najjar
- Department of Biological Sciences, University of Illinois Chicago, 900 S Ashland Ave, M/C 567, Chicago, IL, 60607, USA
| | - Ana Chee
- Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, USA
| | - Howard An
- Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, USA
| | - Chun-Tao Che
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, IL, USA
| | - Thomas J Park
- Department of Biological Sciences, University of Illinois Chicago, 900 S Ashland Ave, M/C 567, Chicago, IL, 60607, USA
| | - Katherine M Warpeha
- Department of Biological Sciences, University of Illinois Chicago, 900 S Ashland Ave, M/C 567, Chicago, IL, 60607, USA.
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Yuan B, Rudeen K, Li J, Williams B, Sumughan S, Lopez G, An HS, Kang-Mieler JJ, Chee AV. Biodegradable Microspheres and Hydrogel Drug Delivery System of Tumor Necrosis Factor (TNF) Inhibitor and Growth Differentiation Factor 5 (GDF5) Reduces Disk Inflammation in the Rabbit Model. Spine (Phila Pa 1976) 2023; 48:E257-E265. [PMID: 37075330 DOI: 10.1097/brs.0000000000004686] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 04/06/2023] [Indexed: 04/21/2023]
Abstract
STUDY DESIGN Preclinical study. OBJECTIVE Develop and test a drug delivery system (DDS) composed of anti-inflammatories and growth factors in the rabbit disk injury model. SUMMARY OF BACKGROUND DATA Biological therapies that inhibit inflammation or enhance cell proliferation can alter intervertebral disk (IVD) homeostasis to favor regeneration. As biological molecules have short half-lives and one molecule may not cover multiple disease pathways, effective treatments may require a combination of growth factors and anti-inflammatory agents delivered in a sustained manner. MATERIALS AND METHODS Biodegradable microspheres were generated separately to encapsulate tumor necrosis factor alpha (TNFα) inhibitors [etanercept (ETN)] or growth differentiation factor 5 (GDF5) and were embedded into a thermoresponsive hydrogel. Release kinetics and activity of ETN and GDF5 were measured in vitro . For in vivo testing, New Zealand White rabbits (n=12) underwent surgery for disk puncture and treatment with blank-DDS, ETN-DDS, or ETN+GDF5-DDS at levels L34, L45, and L56. Radiographic and magnetic resonance images of the spines were obtained. The IVDs were isolated for histologic and gene expression analyses. RESULTS ETN and GDF5 were encapsulated into poly (L-lactide-co-glycolide) microspheres and had average initial bursts of 2.4±0.1 and 11.2±0.7 μg from DDS, respectively. In vitro studies confirmed that ETN-DDS inhibited TNFα-induced cytokine release and GDF5-DDS induced protein phosphorylation. In vivo studies showed that rabbit IVDs treated with ETN+GDF5-DDS had better histologic outcomes, higher levels of extracellular, and lower levels of inflammatory gene expression than IVDs treated with blank-DDS or ETN-DDS. CONCLUSIONS This pilot study demonstrated that DDS can be fabricated to deliver sustained and therapeutic dosages of ETN and GDF5. In addition, ETN+GDF5-DDS may have greater anti-inflammatory and regenerative effects than ETN-DDS alone. Thus, intradiscal injection of controlled release TNF-α inhibitors and growth factors may be a promising treatment to reduce disk inflammation and back pain.
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Affiliation(s)
- Bo Yuan
- Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL
- Department of Orthopaedics, Shanghai Changzheng Hospital, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Kayla Rudeen
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL
| | - Jun Li
- Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Brandon Williams
- Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL
| | - Saurav Sumughan
- Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA
| | - Gregory Lopez
- Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL
| | - Howard S An
- Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL
| | - Jennifer J Kang-Mieler
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL
- Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ
| | - Ana V Chee
- Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL
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Samanta A, Lufkin T, Kraus P. Intervertebral disc degeneration-Current therapeutic options and challenges. Front Public Health 2023; 11:1156749. [PMID: 37483952 PMCID: PMC10359191 DOI: 10.3389/fpubh.2023.1156749] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 06/12/2023] [Indexed: 07/25/2023] Open
Abstract
Degeneration of the intervertebral disc (IVD) is a normal part of aging. Due to the spine's declining function and the development of pain, it may affect one's physical health, mental health, and socioeconomic status. Most of the intervertebral disc degeneration (IVDD) therapies today focus on the symptoms of low back pain rather than the underlying etiology or mechanical function of the disc. The deteriorated disc is typically not restored by conservative or surgical therapies that largely focus on correcting symptoms and structural abnormalities. To enhance the clinical outcome and the quality of life of a patient, several therapeutic modalities have been created. In this review, we discuss genetic and environmental causes of IVDD and describe promising modern endogenous and exogenous therapeutic approaches including their applicability and relevance to the degeneration process.
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Affiliation(s)
| | | | - Petra Kraus
- Department of Biology, Clarkson University, Potsdam, NY, United States
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11
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Multiple nano-drug delivery systems for intervertebral disc degeneration: Current status and future perspectives. Bioact Mater 2023; 23:274-299. [DOI: 10.1016/j.bioactmat.2022.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/16/2022] [Accepted: 11/14/2022] [Indexed: 11/21/2022] Open
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12
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Shnayder NA, Ashkhotov AV, Trefilova VV, Nurgaliev ZA, Novitsky MA, Petrova MM, Narodova EA, Al-Zamil M, Chumakova GA, Garganeeva NP, Nasyrova RF. Molecular Basic of Pharmacotherapy of Cytokine Imbalance as a Component of Intervertebral Disc Degeneration Treatment. Int J Mol Sci 2023; 24:ijms24097692. [PMID: 37175399 PMCID: PMC10178334 DOI: 10.3390/ijms24097692] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 04/17/2023] [Accepted: 04/19/2023] [Indexed: 05/15/2023] Open
Abstract
Intervertebral disc degeneration (IDD) and associated conditions are an important problem in modern medicine. The onset of IDD may be in childhood and adolescence in patients with a genetic predisposition. With age, IDD progresses, leading to spondylosis, spondylarthrosis, herniated disc, spinal canal stenosis. One of the leading mechanisms in the development of IDD and chronic back pain is an imbalance between pro-inflammatory and anti-inflammatory cytokines. However, classical therapeutic strategies for correcting cytokine imbalance in IDD do not give the expected response in more than half of the cases. The purpose of this review is to update knowledge about new and promising therapeutic strategies based on the correction of the molecular mechanisms of cytokine imbalance in patients with IDD. This review demonstrates that knowledge of the molecular mechanisms of the imbalance between pro-inflammatory and anti-inflammatory cytokines may be a new key to finding more effective drugs for the treatment of IDD in the setting of acute and chronic inflammation.
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Affiliation(s)
- Natalia A Shnayder
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
- Shared Core Facilities "Molecular and Cell Technologies", V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia
| | - Azamat V Ashkhotov
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
| | - Vera V Trefilova
- Department of Neurology, Hospital for War Veterans, 193079 Saint Petersburg, Russia
| | - Zaitun A Nurgaliev
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
- Department of Neurology, Hospital for War Veterans, 193079 Saint Petersburg, Russia
| | - Maxim A Novitsky
- Department of Neurology, Hospital for War Veterans, 193079 Saint Petersburg, Russia
| | - Marina M Petrova
- Shared Core Facilities "Molecular and Cell Technologies", V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia
| | - Ekaterina A Narodova
- Shared Core Facilities "Molecular and Cell Technologies", V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia
| | - Mustafa Al-Zamil
- Department of Physiotherapy, Faculty of Continuing Medical Education, Peoples' Friendship University of Russia, 117198 Moscow, Russia
| | - Galina A Chumakova
- Department of Therapy and General Medical Practice with a Course of Postgraduate Professional Education, Altai State Medical University, 656038 Barnaul, Russia
| | - Natalia P Garganeeva
- Department of General Medical Practice and Outpatient Therapy, Siberian State Medical University, 634050 Tomsk, Russia
| | - Regina F Nasyrova
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
- International Centre for Education and Research in Neuropsychiatry, Samara State Medical University, 443016 Samara, Russia
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13
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Kasamkattil J, Gryadunova A, Schmid R, Gay-Dujak MHP, Dasen B, Hilpert M, Pelttari K, Martin I, Schären S, Barbero A, Krupkova O, Mehrkens A. Human 3D nucleus pulposus microtissue model to evaluate the potential of pre-conditioned nasal chondrocytes for the repair of degenerated intervertebral disc. Front Bioeng Biotechnol 2023; 11:1119009. [PMID: 36865027 PMCID: PMC9971624 DOI: 10.3389/fbioe.2023.1119009] [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: 12/08/2022] [Accepted: 01/30/2023] [Indexed: 02/16/2023] Open
Abstract
Introduction: An in vitro model that appropriately recapitulates the degenerative disc disease (DDD) microenvironment is needed to explore clinically relevant cell-based therapeutic strategies for early-stage degenerative disc disease. We developed an advanced 3D nucleus pulposus (NP) microtissues (µT) model generated with cells isolated from human degenerating NP tissue (Pfirrmann grade: 2-3), which were exposed to hypoxia, low glucose, acidity and low-grade inflammation. This model was then used to test the performance of nasal chondrocytes (NC) suspension or spheroids (NCS) after pre-conditioning with drugs known to exert anti-inflammatory or anabolic activities. Methods: NPµTs were formed by i) spheroids generated with NP cells (NPS) alone or in combination with ii) NCS or iii) NC suspension and cultured in healthy or degenerative disc disease condition. Anti-inflammatory and anabolic drugs (amiloride, celecoxib, metformin, IL-1Ra, GDF-5) were used for pre-conditioning of NC/NCS. The effects of pre-conditioning were tested in 2D, 3D, and degenerative NPµT model. Histological, biochemical, and gene expression analysis were performed to assess matrix content (glycosaminoglycans, type I and II collagen), production and release of inflammatory/catabolic factors (IL-6, IL-8, MMP-3, MMP-13) and cell viability (cleaved caspase 3). Results: The degenerative NPµT contained less glycosaminoglycans, collagens, and released higher levels of IL-8 compared to the healthy NPµT. In the degenerative NPµT, NCS performed superior compared to NC cell suspension but still showed lower viability. Among the different compounds tested, only IL-1Ra pre-conditioning inhibited the expression of inflammatory/catabolic mediators and promoted glycosaminoglycan accumulation in NC/NCS in DDD microenvironment. In degenerative NPµT model, preconditioning of NCS with IL-1Ra also provided superior anti-inflammatory/catabolic activity compared to non-preconditioned NCS. Conclusion: The degenerative NPµT model is suitable to study the responses of therapeutic cells to microenvironment mimicking early-stage degenerative disc disease. In particular, we showed that NC in spheroidal organization as compared to NC cell suspension exhibited superior regenerative performance and that IL-1Ra pre-conditioning of NCS could further improve their ability to counteract inflammation/catabolism and support new matrix production within harsh degenerative disc disease microenvironment. Studies in an orthotopic in vivo model are necessary to assess the clinical relevance of our findings in the context of IVD repair.
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Affiliation(s)
- Jesil Kasamkattil
- Spine Surgery, University Hospital Basel, Basel, Switzerland,Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Anna Gryadunova
- Spine Surgery, University Hospital Basel, Basel, Switzerland,Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland,World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Raphael Schmid
- Spine Surgery, University Hospital Basel, Basel, Switzerland,Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Max Hans Peter Gay-Dujak
- Spine Surgery, University Hospital Basel, Basel, Switzerland,Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland,Department of Biomedicine, Institute of Anatomy, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Boris Dasen
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Morgane Hilpert
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Karoliina Pelttari
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Ivan Martin
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Stefan Schären
- Spine Surgery, University Hospital Basel, Basel, Switzerland
| | - Andrea Barbero
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Olga Krupkova
- Spine Surgery, University Hospital Basel, Basel, Switzerland,Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland,*Correspondence: Olga Krupkova,
| | - Arne Mehrkens
- Spine Surgery, University Hospital Basel, Basel, Switzerland,Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
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14
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Hechavarria ME, Richard SA. Elucidating the Focal Immunomodulatory Clues Influencing Mesenchymal Stem Cells in the Milieu of Intervertebral Disc Degeneration. Curr Stem Cell Res Ther 2023; 18:62-75. [PMID: 35450531 DOI: 10.2174/1574888x17666220420134619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 03/21/2022] [Accepted: 03/29/2022] [Indexed: 11/22/2022]
Abstract
The intervertebral discs (IVDs) are a relatively mobile joint that interconnects vertebrae of the spine. Intervertebral disc degeneration (IVDD) is one of the leading causes of low back pain, which is most often related to patient morbidity as well as high medical costs. Patients with chronic IVDD often need surgery that may sometimes lead to biomechanical complications as well as augmented degeneration of the adjacent segments. Moreover, treatment modalities like rigid intervertebral fusion, dynamic instrumentation, as well as other surgical interventions are still controversial. Mesenchymal stem cells (MSCs) have exhibited to have immunomodulatory functions and the ability to differentiate into cartilage, making these cells possibly an epitome for IVD regeneration. Transplanted MSCs were able to repair IVDD back to the normal disc milieu via the activation of the generation of extracellular matrix (ECM) proteins such as aggrecan, proteoglycans and collagen types I and II. IVD milieu clues like, periostin, cluster of differentiation, tumor necrosis factor alpha, interleukins, chemokines, transforming growth factor beta, reactive oxygen species, toll-like receptors, tyrosine protein kinase receptor and disialoganglioside, exosomes are capable of influencing the MSCs during treatment of IVDD. ECM microenvironment clues above have potentials as biomarkers as well as accurate molecular targets for therapeutic intervention in IVDD.
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Affiliation(s)
| | - Seidu A Richard
- Department of Medicine, Princefield University, P. O. Box MA 128, Ho-Volta Region, Ghana, West Africa
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15
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Lv B, Gan W, Cheng Z, Wu J, Chen Y, Zhao K, Zhang Y. Current Insights Into the Maintenance of Structure and Function of Intervertebral Disc: A Review of the Regulatory Role of Growth and Differentiation Factor-5. Front Pharmacol 2022; 13:842525. [PMID: 35754493 PMCID: PMC9213660 DOI: 10.3389/fphar.2022.842525] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 04/08/2022] [Indexed: 11/29/2022] Open
Abstract
Intervertebral disc degeneration (IDD), characterized by conversion of genotypic and phenotypic, is a major etiology of low back pain and disability. In general, this process starts with alteration of metabolic homeostasis leading to ongoing inflammatory process, extracellular matrix degradation and fibrosis, diminished tissue hydration, and impaired structural and mechanical functionality. During the past decades, extensive studies have focused on elucidating the molecular mechanisms of degeneration and shed light on the protective roles of various factors that may have the ability to halt and even reverse the IDD. Mutations of GDF-5 are associated with several human and animal diseases that are characterized by skeletal deformity such as short digits and short limbs. Growth and differentiation factor-5 (GDF-5) has been shown to be a promise biological therapy for IDD. Substantial literature has revealed that GDF-5 can decelerate the progression of IDD on the molecular, cellular, and organ level by altering prolonged imbalance between anabolism and catabolism. GDF family members are the central signaling moleculars in homeostasis of IVD and upregulation of their gene promotes the expression of healthy nucleus pulposus (NP) cell marker genes. In addition, GDF signaling is able to induce mesenchymal stem cells (MSCs) to differentiate into NPCs and mobilize resident cell populations as chemotactic signals. This review will discuss the promising critical role of GDF-5 in maintenance of structure and function of IVDs, and its therapeutic role in IDD endogenous repair.
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Affiliation(s)
- Bin Lv
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weikang Gan
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhangrong Cheng
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Juntao Wu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuhang Chen
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kangchen Zhao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yukun Zhang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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16
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Importance of Matrix Cues on Intervertebral Disc Development, Degeneration, and Regeneration. Int J Mol Sci 2022; 23:ijms23136915. [PMID: 35805921 PMCID: PMC9266338 DOI: 10.3390/ijms23136915] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/17/2022] [Accepted: 06/20/2022] [Indexed: 01/25/2023] Open
Abstract
Back pain is one of the leading causes of disability worldwide and is frequently caused by degeneration of the intervertebral discs. The discs’ development, homeostasis, and degeneration are driven by a complex series of biochemical and physical extracellular matrix cues produced by and transmitted to native cells. Thus, understanding the roles of different cues is essential for designing effective cellular and regenerative therapies. Omics technologies have helped identify many new matrix cues; however, comparatively few matrix molecules have thus far been incorporated into tissue engineered models. These include collagen type I and type II, laminins, glycosaminoglycans, and their biomimetic analogues. Modern biofabrication techniques, such as 3D bioprinting, are also enabling the spatial patterning of matrix molecules and growth factors to direct regional effects. These techniques should now be applied to biochemically, physically, and structurally relevant disc models incorporating disc and stem cells to investigate the drivers of healthy cell phenotype and differentiation. Such research will inform the development of efficacious regenerative therapies and improved clinical outcomes.
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17
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Protective Effects of Growth Differentiation Factor-6 on the Intervertebral Disc: An In Vitro and In Vivo Study. Cells 2022; 11:cells11071174. [PMID: 35406739 PMCID: PMC8998060 DOI: 10.3390/cells11071174] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/21/2022] [Accepted: 03/28/2022] [Indexed: 01/02/2023] Open
Abstract
Growth differentiation factors (GDFs) regulate homeostasis by amplifying extracellular matrix anabolism and inhibiting pro-inflammatory cytokine production in the intervertebral disc (IVD). The aim of this study was to elucidate the effects of GDF-6 on human IVD nucleus pulposus (NP) cells using a three-dimensional culturing system in vitro and on rat tail IVD tissues using a puncture model in vivo. In vitro, Western blotting showed decreased GDF-6 expression with age and degeneration severity in surgically collected human IVD tissues (n = 12). Then, in moderately degenerated human IVD NP cells treated with GDF-6 (100 ng/mL), immunofluorescence demonstrated an increased expression of matrix components including aggrecan and type II collagen. Quantitative polymerase chain reaction analysis also presented GDF-6-induced downregulation of pro-inflammatory tumor necrosis factor (TNF)-α (p = 0.014) and interleukin (IL)-6 (p = 0.016) gene expression stimulated by IL-1β (10 ng/mL). Furthermore, in the mitogen-activated protein kinase pathway, Western blotting displayed GDF-6-induced suppression of p38 phosphorylation (p = 0.041) under IL-1β stimulation. In vivo, intradiscal co-administration of GDF-6 and atelocollagen was effective in alleviating rat tail IVD annular puncture-induced radiologic height loss (p = 0.005), histomorphological degeneration (p < 0.001), matrix metabolism (aggrecan, p < 0.001; type II collagen, p = 0.001), and pro-inflammatory cytokine production (TNF-α, p < 0.001; IL-6, p < 0.001). Consequently, GDF-6 could be a therapeutic growth factor for degenerative IVD disease.
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18
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Platelet-Rich Plasma-Releasate (PRPr) for the Treatment of Discogenic Low Back Pain Patients: Long-Term Follow-Up Survey. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58030428. [PMID: 35334604 PMCID: PMC8952290 DOI: 10.3390/medicina58030428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 03/13/2022] [Accepted: 03/14/2022] [Indexed: 11/29/2022]
Abstract
Background and Objectives: Clinical studies of platelet-rich plasma (PRP) for the treatment of low back pain (LBP) have been reported; however, less is known about its long-term efficiency. Materials and Methods: This study was a long-term follow-up of a previous prospective clinical feasibility study for the use of PRP releasate (PRPr) to treat discogenic LBP patients. Among 14 patients, 11 patients were evaluated for a long-term survey. The efficacy was assessed by a visual analogue scale (VAS) for LBP intensity and the Roland-Morris Disability Questionnaire (RDQ) for LBP-related disability. Radiographic disc height was evaluated for seven patients. Results: Improvements in VAS and RDQ were sustained at an average of 5.9 years after the intradiscal injection of PRPr (p < 0.01 vs. baseline, respectively). Clinically meaningful improvements (more than 30% decrease from baseline) in VAS and RDQ were identified in 91% of patients at final survey. The radiographic measurement of disc height of PRPr-injected discs showed a mild decrease (13.8% decrease compared to baseline) during the average 5.9 years. Conclusions: The results of this study with a small number of patients suggest that the intradiscal injection of PRPr has a safe and efficacious effect on LBP improvement for more than 5 years after treatment. Further large-scale studies would be needed to confirm the clinical evidence for the use of PRPr for the treatment of patients with discogenic LBP.
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19
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Platelet-Rich Plasma Releasate versus Corticosteroid for the Treatment of Discogenic Low Back Pain: A Double-Blind Randomized Controlled Trial. J Clin Med 2022; 11:jcm11020304. [PMID: 35053999 PMCID: PMC8777786 DOI: 10.3390/jcm11020304] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/05/2022] [Accepted: 01/05/2022] [Indexed: 12/15/2022] Open
Abstract
Clinical application of platelet-rich plasma is gaining popularity in treating low back pain (LBP). This study investigated the efficacy and safety of platelet-rich plasma releasate (PRPr) injection into degenerated discs of patients with discogenic LBP. A randomized, double-blind, active-controlled clinical trial was conducted. Sixteen patients with discogenic LBP received an intradiscal injection of either autologous PRPr or corticosteroid (CS). Patients in both groups who wished to have PRPr treatment received an optional injection of PRPr eight weeks later. The primary outcome was change in VAS from baseline at eight weeks. Secondary outcomes were pain, disability, quality of life (QOL), image analyses of disc degeneration, and safety for up to 60 weeks. The VAS change at eight weeks did not significantly differ between the two groups. Fifteen patients received the optional injection. Compared to the CS group, the PRPr group had a significantly improved disability score at 26 weeks and walking ability scores at four and eight weeks. Radiographic disc height and MRI grading score were unchanged from baseline. PRPr caused no clinically important adverse events. PRPr injection showed clinically significant improvements in LBP intensity equal to that of CS. PRPr treatment relieved pain, and improved disability and QOL during 60 weeks of observation.
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20
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Jiang C, Chen Z, Wang X, Zhang Y, Guo X, Xu Z, Yang H, Hao D. The potential mechanisms and application prospects of non-coding RNAs in intervertebral disc degeneration. Front Endocrinol (Lausanne) 2022; 13:1081185. [PMID: 36568075 PMCID: PMC9772433 DOI: 10.3389/fendo.2022.1081185] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 11/23/2022] [Indexed: 12/12/2022] Open
Abstract
Low back pain (LBP) is one of the most common musculoskeletal symptoms and severely affects patient quality of life. The majority of people may suffer from LBP during their life-span, which leading to huge economic burdens to family and society. According to the series of the previous studies, intervertebral disc degeneration (IDD) is considered as the major contributor resulting in LBP. Furthermore, non-coding RNAs (ncRNAs), mainly including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), can regulate diverse cellular processes, which have been found to play pivotal roles in the development of IDD. However, the potential mechanisms of action for ncRNAs in the processes of IDD are still completely unrevealed. Therefore, it is challenging to consider ncRNAs to be used as the potential therapeutic targets for IDD. In this paper, we reviewed the current research progress and findings on ncRNAs in IDD: i). ncRNAs mainly participate in the process of IDD through regulating apoptosis of nucleus pulposus (NP) cells, metabolism of extracellular matrix (ECM) and inflammatory response; ii). the roles of miRNAs/lncRNAs/circRNAs are cross-talk in IDD development, which is similar to the network and can modulate each other; iii). ncRNAs have been attempted to combat the degenerative processes and may be promising as an efficient bio-therapeutic strategy in the future. Hence, this review systematically summarizes the principal pathomechanisms of IDD and shed light on the therapeutic potentials of ncRNAs in IDD.
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Affiliation(s)
- Chao Jiang
- Department of Spine Surgery, Hong Hui Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Zhe Chen
- Department of Spine Surgery, Hong Hui Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Xiaohui Wang
- Department of Spine Surgery, Hong Hui Hospital, Xi’an Jiaotong University, Xi’an, China
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Yongyuan Zhang
- Department of Spine Surgery, Hong Hui Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Xinyu Guo
- Department of Spine Surgery, Hong Hui Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Zhengwei Xu
- Department of Spine Surgery, Hong Hui Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Hao Yang
- Translational Medicine Center, Hong Hui Hospital, Xi’an Jiaotong University, Xi’an, China
- *Correspondence: Hao Yang, ; Dingjun Hao,
| | - Dingjun Hao
- Department of Spine Surgery, Hong Hui Hospital, Xi’an Jiaotong University, Xi’an, China
- *Correspondence: Hao Yang, ; Dingjun Hao,
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21
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Ekram S, Khalid S, Salim A, Khan I. Regulating the fate of stem cells for regenerating the intervertebral disc degeneration. World J Stem Cells 2021; 13:1881-1904. [PMID: 35069988 PMCID: PMC8727226 DOI: 10.4252/wjsc.v13.i12.1881] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/12/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Lower back pain is a leading cause of disability and is one of the reasons for the substantial socioeconomic burden. The etiology of intervertebral disc (IVD) degeneration is complicated, and its mechanism is still not completely understood. Factors such as aging, systemic inflammation, biochemical mediators, toxic environmental factors, physical injuries, and genetic factors are involved in the progression of its pathophysiology. Currently, no therapy for restoring degenerated IVD is available except pain management, reduced physical activities, and surgical intervention. Therefore, it is imperative to establish regenerative medicine-based approaches to heal and repair the injured disc, repopulate the cell types to retain water content, synthesize extracellular matrix, and strengthen the disc to restore normal spine flexion. Cellular therapy has gained attention for IVD management as an alternative therapeutic option. In this review, we present an overview of the anatomical and molecular structure and the surrounding pathophysiology of the IVD. Modern therapeutic approaches, including proteins and growth factors, cellular and gene therapy, and cell fate regulators are reviewed. Similarly, small molecules that modulate the fate of stem cells for their differentiation into chondrocytes and notochordal cell types are highlighted.
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Affiliation(s)
- Sobia Ekram
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Shumaila Khalid
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Asmat Salim
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Irfan Khan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan.
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22
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Kirnaz S, Capadona C, Wong T, Goldberg JL, Medary B, Sommer F, McGrath LB, Härtl R. Fundamentals of Intervertebral Disc Degeneration. World Neurosurg 2021; 157:264-273. [PMID: 34929784 DOI: 10.1016/j.wneu.2021.09.066] [Citation(s) in RCA: 116] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 09/14/2021] [Indexed: 12/16/2022]
Abstract
Lumbar disc degeneration is one of the leading causes of chronic low back pain. The degenerative cascade is often initiated by an imbalance between catabolic and anabolic processes in the intervertebral discs. As a consequence of extracellular matrix degradation, neoinnervation and neovascularization take place. Ultimately, this degenerative process results in disc bulging and loss of nucleus pulposus and water content and subsequent loss of disc height. Most patients respond to conservative management and surgical interventions well initially, yet a significant number of patients continue to suffer from chronic low back pain. Because of the high prevalence of long-term discogenic pain, regenerative biological therapies, including gene therapies, growth factors, cellular-based injections, and tissue-engineered constructs, have attracted significant attention in light of their potential to directly address the degenerative process. Understanding the pathophysiology of degenerative disc disease is important in both refining existing technologies and developing innovative techniques to reverse the degenerative processes in the discs. In this review, we aimed to cover the underlying pathophysiology of degenerative disc disease as well as its associated risk factors and give a comprehensive summary about the developmental, structural, radiological, and biomechanical properties of human intervertebral discs.
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Affiliation(s)
- Sertac Kirnaz
- Department of Neurological Surgery, Weill Cornell Brain and Spine Center, Weill Cornell Medicine, NewYork-Presbyterian Hospital, New York, New York, USA
| | - Charisse Capadona
- Department of Neurological Surgery, Weill Cornell Brain and Spine Center, Weill Cornell Medicine, NewYork-Presbyterian Hospital, New York, New York, USA
| | - Taylor Wong
- Department of Neurological Surgery, Weill Cornell Brain and Spine Center, Weill Cornell Medicine, NewYork-Presbyterian Hospital, New York, New York, USA
| | - Jacob L Goldberg
- Department of Neurological Surgery, Weill Cornell Brain and Spine Center, Weill Cornell Medicine, NewYork-Presbyterian Hospital, New York, New York, USA
| | - Branden Medary
- Department of Neurological Surgery, Weill Cornell Brain and Spine Center, Weill Cornell Medicine, NewYork-Presbyterian Hospital, New York, New York, USA
| | - Fabian Sommer
- Department of Neurological Surgery, Weill Cornell Brain and Spine Center, Weill Cornell Medicine, NewYork-Presbyterian Hospital, New York, New York, USA
| | - Lynn B McGrath
- Department of Neurological Surgery, Weill Cornell Brain and Spine Center, Weill Cornell Medicine, NewYork-Presbyterian Hospital, New York, New York, USA
| | - Roger Härtl
- Department of Neurological Surgery, Weill Cornell Brain and Spine Center, Weill Cornell Medicine, NewYork-Presbyterian Hospital, New York, New York, USA.
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23
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Sudo T, Akeda K, Kawaguchi K, Hasegawa T, Yamada J, Inoue N, Masuda K, Sudo A. Intradiscal injection of monosodium iodoacetate induces intervertebral disc degeneration in an experimental rabbit model. Arthritis Res Ther 2021; 23:297. [PMID: 34876212 PMCID: PMC8653558 DOI: 10.1186/s13075-021-02686-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 11/24/2021] [Indexed: 12/15/2022] Open
Abstract
Background Establishing an optimal animal model for intervertebral disc (IVD) degeneration is essential for developing new IVD therapies. The intra-articular injection of monosodium iodoacetate (MIA), which is commonly used in animal models of osteoarthritis, induces cartilage degeneration and progressive arthritis in a dose- and time-dependent manner. The purpose of this study was to determine the effect of MIA injections into rabbit IVDs on the progression of IVD degeneration evaluated by radiographic, micro-computerized tomography (micro-CT), magnetic resonance imaging (MRI), and histological analyses. Methods In total, 24 New Zealand White (NZW) rabbits were used in this study. Under general anesthesia, lumbar discs from L1–L2 to L4–L5 had a posterolateral percutaneous injection of MIA in contrast agent (CA) (L1–L2: CA only; L2–L3: MIA 0.01 mg; L3–L4: 0.1 mg; L4–L5: 1.0 mg; L5–L6: non-injection (NI) control). Disc height was radiographically monitored biweekly until 12 weeks after injection. Six rabbits were sacrificed at 2, 4, 8, and 12 weeks post-injection and processed for micro-CT, MRI (T2-mapping), and histological analyses. Three-dimensional (3D) disc height in five anatomical zones was evaluated by 3D reconstruction of micro-CT data. Results Disc height of MIA-injected discs (L2–L3 to L4–L5) gradually decreased time-dependently (P < 0.0001). The disc height of MIA 0.01 mg-injected discs was significantly higher than those of MIA 0.1 and 1.0 mg-injected discs (P < 0.01, respectively). 3D micro-CT analysis showed the dose- and time-dependent decrease of 3D disc height of MIA-injected discs predominantly in the posterior annulus fibrosus (AF) zone. MRI T2 values of MIA 0.1 and 1.0 mg-injected discs were significantly decreased compared to those of CA and/or NI controls (P < 0.05). Histological analyses showed progressive time- and dose-degenerative changes in the discs injected with MIA (P < 0.01). MIA induced cell death in the rabbit nucleus pulposus with a high percentage, while the percentage of cell clones was low. Conclusions The results of this study showed, for the first time, that the intradiscal injection of MIA induced degenerative changes of rabbit IVDs in a time- and dose-dependent manner. This study suggests that MIA injection into rabbit IVDs could be used as an animal model of IVD degeneration for developing future treatments.
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Affiliation(s)
- Takao Sudo
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, Japan
| | - Koji Akeda
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, Japan.
| | - Koki Kawaguchi
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, Japan
| | - Takahiro Hasegawa
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, Japan
| | - Junichi Yamada
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, Japan
| | - Nozomu Inoue
- Department of Orthopedic Surgery, Rush Medical College, Chicago, IL, 60612-3833, USA
| | - Koichi Masuda
- Department of Orthopaedic Surgery, University of California, San Diego, 9500 Gilman Dr, La Jolla, 92093-0863, USA
| | - Akihiro Sudo
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, Japan
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Krut Z, Pelled G, Gazit D, Gazit Z. Stem Cells and Exosomes: New Therapies for Intervertebral Disc Degeneration. Cells 2021; 10:cells10092241. [PMID: 34571890 PMCID: PMC8471333 DOI: 10.3390/cells10092241] [Citation(s) in RCA: 105] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/23/2021] [Accepted: 08/25/2021] [Indexed: 12/12/2022] Open
Abstract
Intervertebral disc degeneration (IVDD) occurs as a result of an imbalance of the anabolic and catabolic processes in the intervertebral disc, leading to an alteration in the composition of the extracellular matrix (ECM), loss of nucleus pulposus (NP) cells, excessive oxidative stress and inflammation. Degeneration of the IVD occurs naturally with age, but mechanical trauma, lifestyle factors and certain genetic abnormalities can increase the likelihood of symptomatic disease progression. IVDD, often referred to as degenerative disc disease (DDD), poses an increasingly substantial financial burden due to the aging population and increasing incidence of obesity in the United States. Current treatments for IVDD include pharmacological and surgical interventions, but these lack the ability to stop the progression of disease and restore the functionality of the IVD. Biological therapies have been evaluated but show varying degrees of efficacy in reversing disc degeneration long-term. Stem cell-based therapies have shown promising results in the regeneration of the IVD, but face both biological and ethical limitations. Exosomes play an important role in intercellular communication, and stem cell-derived exosomes have been shown to maintain the therapeutic benefit of their origin cells without the associated risks. This review highlights the current state of research on the use of stem-cell derived exosomes in the treatment of IVDD.
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Affiliation(s)
- Zoe Krut
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Z.K.); (G.P.); (D.G.)
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Gadi Pelled
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Z.K.); (G.P.); (D.G.)
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Dan Gazit
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Z.K.); (G.P.); (D.G.)
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Faculty of Dental Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel
| | - Zulma Gazit
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Z.K.); (G.P.); (D.G.)
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Correspondence:
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Gullbrand SE, Ashinsky BG, Lai A, Gansau J, Crowley J, Cunha C, Engiles JB, Fusellier M, Muehleman C, Pelletier M, Presciutti S, Schol J, Takeoka Y, Yurube T, Zhang Y, Masuda K, Iatridis JC. Development of a standardized histopathology scoring system for intervertebral disc degeneration and regeneration in rabbit models-An initiative of the ORSspine section. JOR Spine 2021; 4:e1147. [PMID: 34337334 PMCID: PMC8313151 DOI: 10.1002/jsp2.1147] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 02/15/2021] [Accepted: 03/25/2021] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND The rabbit lumbar spine is a commonly utilized model for studying intervertebral disc degeneration and for the pre-clinical evaluation of regenerative therapies. Histopathology is the foundation for which alterations to disc morphology and cellularity with degeneration, or following repair or treatment are assessed. Despite this, no standardized histology grading scale has yet been established for the spine field for any of the frequently utilized animal models. AIMS The purpose of this study was to establish a new standardized scoring system to assess disc degeneration and regeneration in the rabbit model. MATERIALS AND METHODS The scoring system was formulated following a review of the literature and a survey of spine researchers. Validation of the scoring system was carried out using images provided by 4 independent laboratories, which were graded by 12 independent graders of varying experience levels. Reliability testing was performed via the computation of intra-class correlation coefficients (ICC) for each category and the total score. The scoring system was then further refined based on the results of the ICC analysis and discussions amongst the authors. RESULTS The final general scoring system involves scoring 7 features (nucleus pulposus shape, area, cellularity and matrix condensation, annulus fibrosus/nucleus pulposus border appearance, annulus fibrosus morphology, and endplate sclerosis/thickening) on a 0 (healthy) to 2 (severe degeneration) scale. ICCs demonstrated overall moderate to good agreement across graders. An addendum to the main scoring system is also included for use in studies evaluating regenerative therapeutics, which involves scoring cell cloning and morphology within the nucleus pulposus and inner annulus fibrosus. DISCUSSION Overall, this new scoring system provides an avenue to improve standardization, allow a more accurate comparison between labs and more robust evaluation of pathophysiology and regenerative treatments across the field. CONCLUSION This study developed a histopathology scoring system for degeneration and regeneration in the rabbit model based on reported practice in the literature, a survey of spine researchers, and validation testing.
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Affiliation(s)
- Sarah E. Gullbrand
- University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Corporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
| | - Beth G. Ashinsky
- University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Corporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
| | - Alon Lai
- Leni and Peter W. May Department of OrthopaedicsIchan School of MedicineNew YorkNew YorkUSA
| | - Jennifer Gansau
- Leni and Peter W. May Department of OrthopaedicsIchan School of MedicineNew YorkNew YorkUSA
| | - James Crowley
- Surgical and Orthopaedic Research Laboratories, Prince of Wales Clinical SchoolUNSWSydneyAustralia
| | - Carla Cunha
- i3S ‐ Instituto de Investigação e Inovação em Saúde, INEB ‐ Instituto de Engenharia BiomédicaPortoPortugal
| | - Julie B. Engiles
- University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of Clinical Studies, New Bolton CenterSchool of Veterinary Medicine, University of Pennsylvania, PhiladelphiaPennsylvaniaUSA
| | - Marion Fusellier
- Inserm, UMR 1229, RMeS, Université de Nantes, ONIRISNantesFrance
| | | | - Matthew Pelletier
- Surgical and Orthopaedic Research Laboratories, Prince of Wales Clinical SchoolUNSWSydneyAustralia
| | | | - Jordy Schol
- Tokai University School of MedicineIseharaJapan
| | | | | | - Yejia Zhang
- University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Corporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
| | | | - James C. Iatridis
- Leni and Peter W. May Department of OrthopaedicsIchan School of MedicineNew YorkNew YorkUSA
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Guo S, Cui L, Xiao C, Wang C, Zhu B, Liu X, Li Y, Liu X, Wang D, Li S. The Mechanisms and Functions of GDF-5 in Intervertebral Disc Degeneration. Orthop Surg 2021; 13:734-741. [PMID: 33817978 PMCID: PMC8126946 DOI: 10.1111/os.12942] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 01/01/2021] [Accepted: 01/01/2021] [Indexed: 01/15/2023] Open
Abstract
Intervertebral disc degeneration (IDD) is widely recognized as the main cause of low back pain, which leads to disability in aging populations and induces great losses both socially and economically worldwide. Unfortunately, current treatments for IDD are aimed at relieving symptoms instead of preserving disc structure and function. Researchers are forged to find new promising biological therapeutics to stop, and even reverse, IVD degeneration. Recently, the injection of growth factors has been shown to be a promising biological therapy for IDD. A number of growth factors have been investigated to modulate the synthesis of the extracellular matrix (ECM) through a variety of pathogenetic biological mechanisms, including suppressing inflammatory process and down-regulating degrading enzymes. However, growth factors, including Transforming Growth Factor-β (TGF-β), Fibroblast Growth Factor (FGF), and Insulin-like Growth Factor-1 (IGF-1), may induce unwanted blood vessel in-growth, which accelerates the process of IDD. On the contrary, studies have demonstrated that injection of GDF-5 into the intervertebral disc of mice can effectively alleviate the degeneration of the intervertebral disc, which elicits their response via BMPRII and will not induce blood vessel in-growth. This finding suggests that GDF-5 is more suitable for use in IDD treatment compared with the three other growth factors. Substantial evidence has suggested that GDF-5 may maintain the structure and function of the intervertebral disc (IVD). GDF-5 plays an important role in IDD and is a very promising therapeutic agent for IDD. This review is focused on the mechanisms and functions of GDF-5 in IDD.
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Affiliation(s)
- Sheng Guo
- Spinal Surgery DepartmentHospital (T.C.M) Affiliated to Southwest Medical UniversityLuzhouChina
| | - Liqiang Cui
- Department of Spine SurgeryMianyang Orthopaedic HospitalMianyangChina
| | - Changming Xiao
- Spinal Surgery DepartmentHospital (T.C.M) Affiliated to Southwest Medical UniversityLuzhouChina
| | - Chenglong Wang
- Spinal Surgery DepartmentHospital (T.C.M) Affiliated to Southwest Medical UniversityLuzhouChina
| | - Bin Zhu
- Institute of Physical EducationSouthwest Medical UniversityLuzhouChina
| | - Xueli Liu
- Institute of Physical EducationSouthwest Medical UniversityLuzhouChina
| | - Yujie Li
- Institute of Physical EducationSouthwest Medical UniversityLuzhouChina
| | - Xinyue Liu
- Institute of Physical EducationSouthwest Medical UniversityLuzhouChina
| | - Dingxuan Wang
- Institute of Physical EducationSouthwest Medical UniversityLuzhouChina
| | - Sen Li
- Spinal Surgery DepartmentHospital (T.C.M) Affiliated to Southwest Medical UniversityLuzhouChina
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Singh S, Patel AA, Singh JR. Intervertebral Disc Degeneration: The Role and Evidence for Non-Stem-Cell-Based Regenerative Therapies. Int J Spine Surg 2021; 15:54-67. [PMID: 34376496 DOI: 10.14444/8055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The use of non-stem-cell-based regenerative medicine therapies for lumbar discogenic pain is an area of growing interest. Although the intervertebral disc is a largely avascular structure, cells located within the nucleus pulposus as well as annulus fibrosis could be targeted for regenerative and restorative treatments. Degenerative disc disease is caused by an imbalance of catabolic and anabolic events within the nucleus pulposus. As catabolic processes overwhelm the environment within the nucleus pulposus, proinflammatory cytokines increase in concentration and lead to further disc degeneration. Non-stem-cell-based therapies, which include growth factor therapy and other proteins, can lead to an increased production of collagen and proteoglycans within the disc.
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Affiliation(s)
- Saarang Singh
- Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York
| | - Ankur A Patel
- Department of Physical Medicine and Rehabilitation, New York-Presbyterian Hospital, Columbia University Medical Center, New York, New York
| | - Jaspal R Singh
- Department of Rehabilitation Medicine, Weill Cornell Medical Center, New York, New York
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Huang X, Zheng C, Wang W, Ye X, Lin CY, Wu Z. The Effect and Possible Mechanism of Intradiscal Injection of Simvastatin in the Treatment of Discogenic Pain in Rats. Front Neurosci 2021; 15:642436. [PMID: 33815046 PMCID: PMC8010318 DOI: 10.3389/fnins.2021.642436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 02/10/2021] [Indexed: 11/21/2022] Open
Abstract
To study the effect of intradiscal injection of simvastatin on discogenic pain in rats and its possible mechanism, 30 adult female rats were used in this experiment. Twenty rats were randomly divided into sham operation group (Control group), intervertebral disk degeneration group (DDD group), intervertebral disk degeneration + hydrogel group (DDD + GEL group), and intervertebral disk degeneration + simvastatin group (DDD + SIM group). The mechanical pain threshold and cold sensation in rats were measured. The contents of NF-kappa B1, RelA, GAP43, SP, CGRP, TRPM 8, IL-1β, and TNF-α in the intervertebral disk (IVD), the corresponding contents of dorsal root ganglion (DRG) and plantar skin GAP43 and TRPM 8 were quantitatively detected by PCR. The corresponding IVDs were stained to detect their degeneration. There was no significant difference in the mechanical pain threshold between the groups at each time point. From the first day to the 8th week after surgery, the cold-sensing response of the DDD group was significantly higher than that of the Control group (P < 0.05). At 7 and 8 weeks postoperatively, the cold-sensing response of the DDD + SIM group was significantly lower than that of the DDD + GEL group (P < 0.05). The levels of NF-κB1, RelA, GAP43, SP, CGRP, TRPM8, IL-1β, and TNF-α in the IVD of DDD + SIM group were significantly lower than those in DDD group (P < 0.05). The content of GAP43 and TRPM8 in rat plantar skin decreased significantly and TRPM8 in DRG decreased significantly (P < 0.05).
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Affiliation(s)
- Xiaodong Huang
- Department of Orthopedics, The Third Affiliated Hospital of Guangzhou Medical University, Guangdong, China
- Department of Orthopaedic Surgery, College of Medicine, University of Cincinnati, Cincinnati, OH, United States
- Department of Orthopaedics, Shanghai Changzheng Hospital, Shanghai, China
| | - Changkun Zheng
- Department of Orthopaedics, Fuzhou Second Hospital Affiliated to Xiamen University, Fujian, China
| | - Weiheng Wang
- Department of Orthopaedics, Shanghai Changzheng Hospital, Shanghai, China
| | - Xiaojian Ye
- Department of Orthopaedics, Shanghai Changzheng Hospital, Shanghai, China
| | - Chia-Ying Lin
- Department of Orthopaedic Surgery, College of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Zenghui Wu
- Department of Orthopedics, The Third Affiliated Hospital of Guangzhou Medical University, Guangdong, China
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Roh EJ, Darai A, Kyung JW, Choi H, Kwon SY, Bhujel B, Kim KT, Han I. Genetic Therapy for Intervertebral Disc Degeneration. Int J Mol Sci 2021; 22:ijms22041579. [PMID: 33557287 PMCID: PMC7914740 DOI: 10.3390/ijms22041579] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 01/30/2021] [Accepted: 02/01/2021] [Indexed: 02/06/2023] Open
Abstract
Intervertebral disc (IVD) degeneration can cause chronic lower back pain (LBP), leading to disability. Despite significant advances in the treatment of discogenic LBP, the limitations of current treatments have sparked interest in biological approaches, including growth factor and stem cell injection, as new treatment options for patients with chronic LBP due to IVD degeneration (IVDD). Gene therapy represents exciting new possibilities for IVDD treatment, but treatment is still in its infancy. Literature searches were conducted using PubMed and Google Scholar to provide an overview of the principles and current state of gene therapy for IVDD. Gene transfer to degenerated disc cells in vitro and in animal models is reviewed. In addition, this review describes the use of gene silencing by RNA interference (RNAi) and gene editing by the clustered regularly interspaced short palindromic repeats (CRISPR) system, as well as the mammalian target of rapamycin (mTOR) signaling in vitro and in animal models. Significant technological advances in recent years have opened the door to a new generation of intradiscal gene therapy for the treatment of chronic discogenic LBP.
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Affiliation(s)
- Eun Ji Roh
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si 13496, Korea; (E.J.R.); (A.D.); (J.W.K.); (H.C.); (S.Y.K.); (B.B.)
- Department of Biomedical Science, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si 13496, Korea
| | - Anjani Darai
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si 13496, Korea; (E.J.R.); (A.D.); (J.W.K.); (H.C.); (S.Y.K.); (B.B.)
- Department of Biomedical Science, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si 13496, Korea
| | - Jae Won Kyung
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si 13496, Korea; (E.J.R.); (A.D.); (J.W.K.); (H.C.); (S.Y.K.); (B.B.)
| | - Hyemin Choi
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si 13496, Korea; (E.J.R.); (A.D.); (J.W.K.); (H.C.); (S.Y.K.); (B.B.)
| | - Su Yeon Kwon
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si 13496, Korea; (E.J.R.); (A.D.); (J.W.K.); (H.C.); (S.Y.K.); (B.B.)
| | - Basanta Bhujel
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si 13496, Korea; (E.J.R.); (A.D.); (J.W.K.); (H.C.); (S.Y.K.); (B.B.)
- Department of Biomedical Science, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si 13496, Korea
| | - Kyoung Tae Kim
- School of Medicine, Department of Neurosurgery, Kyungpook National University, Daegu 41944, Korea;
- Department of Neurosurgery, Kyungpook National University Hospital, Daegu 41944, Korea
| | - Inbo Han
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si 13496, Korea; (E.J.R.); (A.D.); (J.W.K.); (H.C.); (S.Y.K.); (B.B.)
- Correspondence:
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30
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Tsiapalis D, Kearns S, Kelly JL, Zeugolis DI. Growth factor and macromolecular crowding supplementation in human tenocyte culture. BIOMATERIALS AND BIOSYSTEMS 2021; 1:100009. [PMID: 36825160 PMCID: PMC9934496 DOI: 10.1016/j.bbiosy.2021.100009] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 11/18/2020] [Accepted: 01/22/2021] [Indexed: 01/20/2023] Open
Abstract
Cell-assembled tissue engineering strategies hold great potential in regenerative medicine, as three-dimensional tissue-like modules can be produced, even from a patient's own cells. However, the development of such implantable devices requires prolonged in vitro culture time, which is associated with cell phenotypic drift. Considering that the cells in vivo are subjected to numerous stimuli, multifactorial approaches are continuously gaining pace towards controlling cell fate during in vitro expansion. Herein, we assessed the synergistic effect of simultaneous and serial growth factor supplementation (insulin growth factor-1, platelet-derived growth factor ββ, growth differentiation factor 5 and transforming growth factor β3) to macromolecular crowding (carrageenan) in human tenocyte function; collagen synthesis and deposition; and gene expression. TGFβ3 supplementation (without/with carrageenan) induced the highest (among all groups) DNA content. In all cases, tenocyte proliferation was significantly increased as a function of time in culture, whilst metabolic activity was not affected. Carrageenan supplementation induced significantly higher collagen deposition than groups without carrageenan (without/with any growth factor). Of all the growth factors used, TGFβ3 induced the highest collagen deposition when used together with carrageenan in both simultaneous and serial fashion. At day 13, gene expression analysis revealed that TGFβ3 in serial supplementation to carrageenan upregulated the most and downregulated the least collagen- and tendon- related genes and upregulated the least and downregulated the most osteo-, chondro-, fibrosis- and adipose- related trans-differentiation genes. Collectively, these data clearly advocate the beneficial effects of multifactorial approaches (in this case, growth factor and macromolecular crowding supplementation) in the development of functional cell-assembled tissue surrogates.
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Affiliation(s)
- Dimitrios Tsiapalis
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | | | | | - Dimitrios I. Zeugolis
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Faculty of Biomedical Sciences, Università della Svizzera Italiana (USI), Lugano, Switzerland
- Corresponding authors.
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31
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Baumgartner L, Wuertz-Kozak K, Le Maitre CL, Wignall F, Richardson SM, Hoyland J, Ruiz Wills C, González Ballester MA, Neidlin M, Alexopoulos LG, Noailly J. Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research. Int J Mol Sci 2021; 22:E703. [PMID: 33445782 PMCID: PMC7828304 DOI: 10.3390/ijms22020703] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/22/2020] [Accepted: 12/24/2020] [Indexed: 12/17/2022] Open
Abstract
Intervertebral disc (IVD) degeneration is a major risk factor of low back pain. It is defined by a progressive loss of the IVD structure and functionality, leading to severe impairments with restricted treatment options due to the highly demanding mechanical exposure of the IVD. Degenerative changes in the IVD usually increase with age but at an accelerated rate in some individuals. To understand the initiation and progression of this disease, it is crucial to identify key top-down and bottom-up regulations' processes, across the cell, tissue, and organ levels, in health and disease. Owing to unremitting investigation of experimental research, the comprehension of detailed cell signaling pathways and their effect on matrix turnover significantly rose. Likewise, in silico research substantially contributed to a holistic understanding of spatiotemporal effects and complex, multifactorial interactions within the IVD. Together with important achievements in the research of biomaterials, manifold promising approaches for regenerative treatment options were presented over the last years. This review provides an integrative analysis of the current knowledge about (1) the multiscale function and regulation of the IVD in health and disease, (2) the possible regenerative strategies, and (3) the in silico models that shall eventually support the development of advanced therapies.
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Affiliation(s)
- Laura Baumgartner
- BCN MedTech, Department of Information and Communication Technologies, Universitat Pompeu Fabra, 08018 Barcelona, Spain; (L.B.); (C.R.W.); (M.A.G.B.)
| | - Karin Wuertz-Kozak
- Department of Biomedical Engineering, Rochester Institute of Technology (RIT), Rochester, NY 14623, USA;
- Schön Clinic Munich Harlaching, Spine Center, Academic Teaching Hospital and Spine Research Institute of the Paracelsus Medical University Salzburg (Austria), 81547 Munich, Germany
| | - Christine L. Le Maitre
- Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield S1 1WB, UK;
| | - Francis Wignall
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Oxford Road, Manchester M13 9PT, UK; (F.W.); (S.M.R.); (J.H.)
| | - Stephen M. Richardson
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Oxford Road, Manchester M13 9PT, UK; (F.W.); (S.M.R.); (J.H.)
| | - Judith Hoyland
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Oxford Road, Manchester M13 9PT, UK; (F.W.); (S.M.R.); (J.H.)
| | - Carlos Ruiz Wills
- BCN MedTech, Department of Information and Communication Technologies, Universitat Pompeu Fabra, 08018 Barcelona, Spain; (L.B.); (C.R.W.); (M.A.G.B.)
| | - Miguel A. González Ballester
- BCN MedTech, Department of Information and Communication Technologies, Universitat Pompeu Fabra, 08018 Barcelona, Spain; (L.B.); (C.R.W.); (M.A.G.B.)
- Catalan Institution for Research and Advanced Studies (ICREA), Pg. Lluis Companys 23, 08010 Barcelona, Spain
| | - Michael Neidlin
- Department of Mechanical Engineering, National Technical University of Athens, 15780 Athens, Greece; (M.N.); (L.G.A.)
| | - Leonidas G. Alexopoulos
- Department of Mechanical Engineering, National Technical University of Athens, 15780 Athens, Greece; (M.N.); (L.G.A.)
| | - Jérôme Noailly
- BCN MedTech, Department of Information and Communication Technologies, Universitat Pompeu Fabra, 08018 Barcelona, Spain; (L.B.); (C.R.W.); (M.A.G.B.)
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Chou PH, Chee A, Shi P, Lin CL, Zhao Y, Zhang L, An HS. Small molecule antagonist of C-C chemokine receptor 1 (CCR1) reduces disc inflammation in the rabbit model. Spine J 2020; 20:2025-2036. [PMID: 32673730 DOI: 10.1016/j.spinee.2020.07.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 06/22/2020] [Accepted: 07/08/2020] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Targeting chemokines or chemokine receptors is a promising treatment strategy for diseases with chronic inflammation such as rheumatoid arthritis and discogenic pain. Identifying specific molecules and determining their effectiveness in animal models are the first steps in developing these treatments. Macrophage markers have been detected in the intervertebral disc tissues of patients with disc degenerative disease and discogenic pain and in different animal models. Macrophage recruitment into the disc may play a role in initiation of inflammation and if unresolved may lead to chronic inflammation and subsequent back pain. PURPOSE The objectives of these studies are to (1) identify chemokine receptor antagonists that can block macrophage migration induced by disc cells in vitro and (2) determine if intradiscal treatment with these antagonists can reduce disc inflammation and degeneration in vivo. STUDY DESIGN In vitro migration assays were used to test effectiveness of chemokine receptor antagonists to block macrophage migration induced by disc cells. The rabbit annular puncture model was used to test for anti-inflammatory and regenerative effects of chemokine receptor antagonist treatment in vivo. METHODS In vitro - THP-1 human monocytic cell line and freshly isolated rabbit primary splenocytes were assayed for migration using 3 µm Corning Transwell inserts with conditioned media of interleukin (IL)-1β treated human or rabbit disc cells. Inhibition of macrophage migration was evaluated using different concentrations of small molecule antagonists of C-C chemokine receptor (CCR)1 and CCR2. In vivo - New Zealand White rabbits (n=40) underwent disc puncture and intradiscal treatment with saline, CCR1 or CCR2 antagonists within the same procedure. X-ray and magnetic resonance (MR) images and serum samples were taken for disc height, MRI grade and IL-8 serum level analyses. Intervertebral discs were isolated for RNA analysis of inflammatory and disc phenotypic markers and for immunohistochemical analysis of macrophage marker, RAM11. The outcome measures were compared between the three treatment groups. These studies were funded by a research grant from AO Foundation, Switzerland (Project no S-14-86A; 120000 CHF). CCR1 and CCR2 antagonists were kindly provided by ChemoCentryx (Mountain View, CA). RESULTS In vitro migration assays showed that THP-1 migration induced by disc cells was blocked by CCR2 antagonist more effectively than CCR1 antagonist, while rabbit splenocyte migration was inhibited by CCR1 antagonist and not the other. In the rabbit annular puncture model, rabbit discs treated with CCR1 antagonist had significantly better MRI grades than those treated with CCR2 antagonist at 6 weeks post-treatment. Gene expression studies demonstrate that discs treated with CCR1 or CCR2 antagonists expressed less inflammatory markers than saline-treated discs at 3 weeks post-treatment. Although CCR2 antagonist treatment did not reduce inflammatory marker expression at 6 weeks, discs treated with CCR1 antagonist expressed less inflammatory markers and also a higher ratio of collagen type 2 to collagen type 1 genes indicating favorable disc matrix production. There were no significant differences between all three treatment groups in regards to disc height indexes, IL-8 serum levels or macrophage marker detection. CONCLUSIONS These studies have identified that small molecule antagonists against CCR2 and CCR1 were respectively effective in blocking THP-1 and rabbit splenocyte migration induced by disc cells in vitro. Further, both CCR2 and CCR1 antagonist intradiscal treatments were effective in reducing disc inflammation at an early time point of 3 weeks. Lastly, only CCR1 antagonist demonstrated anti-inflammatory effects and better MRI grades at 6 weeks. CLINICAL SIGNIFICANCE Our preclinical studies demonstrate that CCR1 and CCR2 antagonist delivery through intradiscal injection is sufficient to reduce disc inflammation at early time points, whereas CCR1 antagonists had longer term anti-inflammatory effects. Clinical studies have found that CCR1 antagonist was safe, tolerable and clinically active in reducing inflammation in rheumatoid arthritis patients. These studies suggest that CCR1 antagonist may be a promising biological treatment to reduce disc inflammation that translates to back pain relief.
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Affiliation(s)
- Po-Hsin Chou
- Department of Orthopedic Surgery, Rush University Medical Center, 1611 W Harrison Street, Suite 300, Chicago, IL 60612, USA; Department of Orthopedic and Traumatology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd, Beitou District, Taipei City, Taiwan 11217, ROC; School of Medicine, National Yang-Ming University, No.155, Sec. 2, Linong St, Beitou District, Taipei City, Taiwan 112, ROC
| | - Ana Chee
- Department of Orthopedic Surgery, Rush University Medical Center, 1611 W Harrison Street, Suite 300, Chicago, IL 60612, USA
| | - Peng Shi
- Department of Orthopedic Surgery, Rush University Medical Center, 1611 W Harrison Street, Suite 300, Chicago, IL 60612, USA; Tufts University School of Dental Medicine, 1 Kneeland St, Boston, MA 02111, USA
| | - Cheng-Li Lin
- Department of Orthopedic Surgery, Rush University Medical Center, 1611 W Harrison Street, Suite 300, Chicago, IL 60612, USA; Department of Orthopedic Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, No.138, Sheng-Li Rd, 70428, Tainan City, Taiwan 704, ROC
| | - Yibo Zhao
- Department of Orthopedic Surgery, Rush University Medical Center, 1611 W Harrison Street, Suite 300, Chicago, IL 60612, USA; Department of Orthopedics, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Rd, Taiyuan, Shanxi, 030001 China
| | - Li Zhang
- Department of Orthopedic Surgery, Rush University Medical Center, 1611 W Harrison Street, Suite 300, Chicago, IL 60612, USA; Department of Orthopedics, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, No. 99, Longcheng St, Taiyuan, Shanxi, 030032 China
| | - Howard S An
- Department of Orthopedic Surgery, Rush University Medical Center, 1611 W Harrison Street, Suite 300, Chicago, IL 60612, USA.
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Mern DS, Walsen T, Beierfuß A, Thomé C. Animal models of regenerative medicine for biological treatment approaches of degenerative disc diseases. Exp Biol Med (Maywood) 2020; 246:483-512. [PMID: 33175609 DOI: 10.1177/1535370220969123] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Degenerative disc disease (DDD) is a painful, chronic and progressive disease, which is characterized by inflammation, structural and biological deterioration of the intervertebral disc (IVD) tissues. DDD is specified as cell-, age-, and genetic-dependent degenerative process that can be accelerated by environmental factors. It is one of the major causes of chronic back pain and disability affecting millions of people globally. Current treatment options, such as physical rehabilitation, pain management, and surgical intervention, can provide only temporary pain relief. Different animal models have been used to study the process of IVD degeneration and develop therapeutic options that may restore the structure and function of degenerative discs. Several research works have depicted considerable progress in understanding the biological basis of disc degeneration and the therapeutic potentials of cell transplantation, gene therapy, applications of supporting biomaterials and bioactive factors, or a combination thereof. Since animal models play increasingly significant roles in treatment approaches of DDD, we conducted an electronic database search on Medline through June 2020 to identify, compare, and discuss publications regarding biological therapeutic approaches of DDD that based on intradiscal treatment strategies. We provide an up-to-date overview of biological treatment strategies in animal models including mouse, rat, rabbit, porcine, bovine, ovine, caprine, canine, and primate models. Although no animal model could profoundly reproduce the clinical conditions in humans; animal models have played important roles in specifying our knowledge about the pathophysiology of DDD. They are crucial for developing new therapy approaches for clinical applications.
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Affiliation(s)
| | - Tanja Walsen
- Department of Neurosurgery, Medical University of Innsbruck, Innsbruck A-6020, Austria
| | - Anja Beierfuß
- Laboratory Animal Facility, Medical University of Innsbruck, Innsbruck A-6020, Austria
| | - Claudius Thomé
- Department of Neurosurgery, Medical University of Innsbruck, Innsbruck A-6020, Austria
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Drug delivery in intervertebral disc degeneration and osteoarthritis: Selecting the optimal platform for the delivery of disease-modifying agents. J Control Release 2020; 328:985-999. [PMID: 32860929 DOI: 10.1016/j.jconrel.2020.08.041] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 08/21/2020] [Accepted: 08/21/2020] [Indexed: 12/16/2022]
Abstract
Osteoarthritis (OA) and intervertebral disc degeneration (IVDD) as major cause of chronic low back pain represent the most common degenerative joint pathologies and are leading causes of pain and disability in adults. Articular cartilage (AC) and intervertebral discs are cartilaginous tissues with a similar biochemical composition and pathophysiological aspects of degeneration. Although treatments directed at reversing these conditions are yet to be developed, many promising disease-modifying drug candidates are currently under investigation. Given the localized nature of these chronic diseases, drug delivery systems have the potential to enhance therapeutic outcomes by providing controlled and targeted release of bioactives, minimizing the number of injections needed and increasing drug concentration in the affected areas. This review provides a comprehensive overview of the currently most promising disease-modifying drugs as well as potential drug delivery systems for OA and IVDD therapy.
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Hu ZL, Li HY, Chang X, Li YY, Liu CH, Gao XX, Zhai Y, Chen YX, Li CQ. Exosomes derived from stem cells as an emerging therapeutic strategy for intervertebral disc degeneration. World J Stem Cells 2020; 12:803-813. [PMID: 32952860 PMCID: PMC7477652 DOI: 10.4252/wjsc.v12.i8.803] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 06/09/2020] [Accepted: 07/05/2020] [Indexed: 02/06/2023] Open
Abstract
Intervertebral disc (IVD) degenerative diseases are a common problem in the world, and they cause substantial social and economic burdens for people. The current methods for treating IVD degenerative diseases mainly include surgery and conservative treatment, which cannot fundamentally restore the normal structure of the disc. With continuous research on the mechanism of degeneration and the development of regenerative medicine, rapid progress has been made in the field of regenerative medicine regarding the use of stem cell-derived exosomes, which are active biological substances used in intercellular communication, because they show a strong effect in promoting tissue regeneration. The study of exosomes in the field of IVD degeneration has just begun, and many surprising achievements have been made. This paper mainly reviews the biological characteristics of exosomes and highlights the current status of exosomes in the field of IVD degeneration, as well as future developments regarding exosomes.
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Affiliation(s)
- Zhi-Lei Hu
- Department of Orthopedics, Xinqiao Hospital, Army Military Medical University, Chongqing 400037, China
| | - Hai-Yin Li
- Department of Orthopedics, Xinqiao Hospital, Army Military Medical University, Chongqing 400037, China
| | - Xian Chang
- Department of Orthopedics, Xinqiao Hospital, Army Military Medical University, Chongqing 400037, China
| | - Yue-Yang Li
- Department of Orthopedics, Xinqiao Hospital, Army Military Medical University, Chongqing 400037, China
| | - Chen-Hao Liu
- Department of Orthopedics, Xinqiao Hospital, Army Military Medical University, Chongqing 400037, China
| | - Xiao-Xin Gao
- Department of Orthopedics, Xinqiao Hospital, Army Military Medical University, Chongqing 400037, China
| | - Yu Zhai
- Department of Orthopedics, Xinqiao Hospital, Army Military Medical University, Chongqing 400037, China
| | - Yu-Xuan Chen
- Center of Traumatic Orthopedics, People's Liberation Army 990 Hospital, Xinyang 46400, Henan Province, China
| | - Chang-Qing Li
- Department of Orthopedics, Xinqiao Hospital, Army Military Medical University, Chongqing 400037, China
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Szwedowski D, Szczepanek J, Paczesny Ł, Pękała P, Zabrzyński J, Kruczyński J. Genetics in Cartilage Lesions: Basic Science and Therapy Approaches. Int J Mol Sci 2020; 21:E5430. [PMID: 32751537 PMCID: PMC7432875 DOI: 10.3390/ijms21155430] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/24/2020] [Accepted: 07/27/2020] [Indexed: 12/31/2022] Open
Abstract
Cartilage lesions have a multifactorial nature, and genetic factors are their strongest determinants. As biochemical and genetic studies have dramatically progressed over the past decade, the molecular basis of cartilage pathologies has become clearer. Several homeostasis abnormalities within cartilaginous tissue have been found, including various structural changes, differential gene expression patterns, as well as altered epigenetic regulation. However, the efficient treatment of cartilage pathologies represents a substantial challenge. Understanding the complex genetic background pertaining to cartilage pathologies is useful primarily in the context of seeking new pathways leading to disease progression as well as in developing new targeted therapies. A technology utilizing gene transfer to deliver therapeutic genes to the site of injury is quickly becoming an emerging approach in cartilage renewal. The goal of this work is to provide an overview of the genetic basis of chondral lesions and the different approaches of the most recent systems exploiting therapeutic gene transfer in cartilage repair. The integration of tissue engineering with viral gene vectors is a novel and active area of research. However, despite promising preclinical data, this therapeutic concept needs to be supported by the growing body of clinical trials.
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Affiliation(s)
- Dawid Szwedowski
- Orthopedic Arthroscopic Surgery International (O.A.S.I.) Bioresearch Foundation, Gobbi N.P.O., 20133 Milan, Italy;
- Department of Orthopaedics and Trauma Surgery, Provincial Polyclinical Hospital, 87100 Torun, Poland
| | - Joanna Szczepanek
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, 87100 Torun, Poland
| | - Łukasz Paczesny
- Orvit Clinic, Citomed Healthcare Center, 87100 Torun, Poland; (Ł.P.); (J.Z.)
| | - Przemysław Pękała
- Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, 30705 Krakow, Poland;
| | - Jan Zabrzyński
- Orvit Clinic, Citomed Healthcare Center, 87100 Torun, Poland; (Ł.P.); (J.Z.)
| | - Jacek Kruczyński
- Department of General Orthopaedics, Musculoskeletal Oncology and Trauma Surgery, Poznan University of Medical Sciences, 60512 Poznań, Poland;
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A Meta-analysis Assessing the Association Between COL11A1 and GDF5 Genetic Variants and Intervertebral Disc Degeneration Susceptibility. Spine (Phila Pa 1976) 2020; 45:E616-E623. [PMID: 31923126 DOI: 10.1097/brs.0000000000003371] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN Meta-analysis to collect relevant studies to assess the association between COL11A1 and GDF5 genetic variants and susceptibility to IDD. OBJECTIVE The aim of this study was to assess whether or not COL11A1 and GDF5 genetic variants were associated with susceptibility to IDD. SUMMARY OF BACKGROUND DATA IDD or LDH is a major public health problem. There have been several studies evaluating the relationship between COL11A1 and GDF5 genetic variants with risk of intervertebral disc degeneration (IDD). However, the studies were limited in discrete outcome and sample size, and some of the results were contradictory. METHODS We systematically searched the relevant publications in electronic databases. Eligible studies were included based on the defined criteria. The pooled odds ratios (ORs) with its 95% confidence intervals (CIs) were received using STATA 15. Subgroup analysis, sensitivity analysis, publication bias, and the "Trim and fill" method were performed in the meta-analysis. RESULTS A total of 3287 IDD cases and 5115 controls were incorporated into the meta-analysis. Our results demonstrated that COL11A1 rs1676486 was significantly associated with increased IDD susceptibility under all genetic models (allele model T vs. C: OR = 1.40, 95% CI 1.23-1.59, P = 0.000; homozygote model TT vs. CC: OR = 1.89, 95%CI 1.40-2.56, P = 0.000; dominant model TT+TC vs. CC: OR = 1.52, 95% CI 1.29-1.80, P = 0.000; recessive model TT vs. TC + CC: OR = 1.58, 95% CI 1.18-2.12, P = 0.002). However, GDF5 rs143383 was not (allele model T vs. C: OR = 1.15, 95% CI 0.91-1.44, P = 0.244; homozygote model TT vs. CC: OR = 1.22, 95% CI 0.75-2.00, P = 0.429; dominant model TT vs. CC+CT: OR = 1.22, 95% CI 0.95-1.57, P = 0.112; recessive model TC + TT vs. CC: OR = 1.12, 95% CI 0.73-1.73, P = 0.594). Subgroup analysis indicated ethnicity was not the source of heterogeneity. Sensitivity analysis, publication bias, and the "Trim and fill" method demonstrated the meta-analysis was of reliability. CONCLUSION Our results suggested that COL11A1 rs1676486 was significantly associated with IDD and the T allele was a risky factor. However, GDF5 rs143383 was not. LEVEL OF EVIDENCE 1.
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Cazzanelli P, Wuertz-Kozak K. MicroRNAs in Intervertebral Disc Degeneration, Apoptosis, Inflammation, and Mechanobiology. Int J Mol Sci 2020; 21:ijms21103601. [PMID: 32443722 PMCID: PMC7279351 DOI: 10.3390/ijms21103601] [Citation(s) in RCA: 164] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/16/2020] [Accepted: 05/18/2020] [Indexed: 12/12/2022] Open
Abstract
Intervertebral disc (IVD) degeneration is a multifactorial pathological process associated with low back pain, the leading cause of years lived in disability worldwide. Key characteristics of the pathological changes connected with degenerative disc disease (DDD) are the degradation of the extracellular matrix (ECM), apoptosis and senescence, as well as inflammation. The impact of nonphysiological mechanical stresses on IVD degeneration and inflammation, the mechanisms of mechanotransduction, and the role of mechanosensitive miRNAs are of increasing interest. As post-transcriptional regulators, miRNAs are known to affect the expression of 30% of proteincoding genes and numerous intracellular processes. The dysregulation of miRNAs is therefore associated with various pathologies, including degenerative diseases such as DDD. This review aims to give an overview of the current status of miRNA research in degenerative disc pathology, with a special focus on the involvement of miRNAs in ECM degradation, apoptosis, and inflammation, as well as mechanobiology.
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Affiliation(s)
- Petra Cazzanelli
- Department of Biomedical Engineering, Rochester Institute of Technology (RIT), Rochester, NY 14623, USA;
| | - Karin Wuertz-Kozak
- Department of Biomedical Engineering, Rochester Institute of Technology (RIT), Rochester, NY 14623, USA;
- Schön Clinic Munich Harlaching, Spine Center, Academic Teaching Hospital and Spine Research Institute of the Paracelsus Medical University Salzburg (Austria), 81547 Munich, Germany
- Correspondence: ; Tel.: +1-585-475-7355
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Frapin L, Clouet J, Chédeville C, Moraru C, Samarut E, Henry N, André M, Bord E, Halgand B, Lesoeur J, Fusellier M, Guicheux J, Le Visage C. Controlled release of biological factors for endogenous progenitor cell migration and intervertebral disc extracellular matrix remodelling. Biomaterials 2020; 253:120107. [PMID: 32450408 DOI: 10.1016/j.biomaterials.2020.120107] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 04/20/2020] [Accepted: 05/06/2020] [Indexed: 02/06/2023]
Abstract
The recent description of resident stem/progenitor cells in degenerated intervertebral discs (IVDs) supports the notion that their regenerative capacities could be harnessed to stimulate endogenous repair of the nucleus pulposus (NP). In this study, we developed a delivery system based on pullulan microbeads (PMBs) for sequential release of the chemokine CCL-5 to recruit these disc stem/progenitor cells to the NP tissue, followed by the release of the growth factors TGF-β1 and GDF-5 to induce the synthesis of a collagen type II- and aggrecan-rich extracellular matrix (ECM). Bioactivity of released CCL5 on human adipose-derived stem cells (hASCs), selected to mimic disc stem/progenitors, was demonstrated using a Transwell® chemotaxis assay. The regenerative effects of loaded PMBs were investigated in ex vivo spontaneously degenerated ovine IVDs. Fluorescent hASCs were seeded on the top cartilaginous endplates (CEPs); the degenerated NPs were injected with PMBs loaded with CCL5, TGF-β1, and GDF-5; and the IVDs were then cultured for 3, 7, and 28 days to allow for cell migration and disc regeneration. The PMBs exhibited sustained release of biological factors for 21 days. Ex vivo migration of seeded hASCs from the CEP toward the NP was demonstrated, with the cells migrating a significantly greater distance when loaded PMBs were injected (5.8 ± 1.3 mm vs. 3.5 ± 1.8 mm with no injection of PMBs). In ovine IVDs, the overall NP cellularity, the collagen type II and the aggrecan staining intensities, and the Tie2+ progenitor cell density in the NP were increased at day 28 compared to the control groups. Considered together, PMBs loaded with CCL5/TGF-β1/GDF-5 constitute an innovative and promising strategy for controlled release of growth factors to promote cell recruitment and extracellular matrix remodelling.
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Affiliation(s)
- Leslie Frapin
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France; Université de Nantes, UFR Odontologie, Nantes, F-44042, France
| | - Johann Clouet
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France; Université de Nantes, UFR Odontologie, Nantes, F-44042, France; CHU Nantes, Pharmacie Centrale, PHU 11, Nantes, F-44093, France; Université de Nantes, UFR Sciences Biologiques et Pharmaceutiques, Nantes, F-44035, France
| | - Claire Chédeville
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France; Université de Nantes, UFR Odontologie, Nantes, F-44042, France
| | - Constantin Moraru
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France; Université de Nantes, UFR Odontologie, Nantes, F-44042, France; CHU Nantes, Service de Neurotraumatologie, PHU4 OTONN, Nantes, F-44093, France
| | - Edouard Samarut
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France; Université de Nantes, UFR Odontologie, Nantes, F-44042, France; CHU Nantes, Service de Neurotraumatologie, PHU4 OTONN, Nantes, F-44093, France
| | - Nina Henry
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France; Université de Nantes, UFR Odontologie, Nantes, F-44042, France
| | - Manon André
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France; Université de Nantes, UFR Odontologie, Nantes, F-44042, France; SC3M -"Electron Microscopy, Microcharacterization, and Functional Morphohistology Imaging" Core Facility, Structure Fédérative de Recherche François Bonamy, INSERM - UMS016, CNRS 3556, CHU Nantes, Université de Nantes, Nantes, Nantes, F-04402, France
| | - Eric Bord
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France; Université de Nantes, UFR Odontologie, Nantes, F-44042, France; CHU Nantes, Service de Neurotraumatologie, PHU4 OTONN, Nantes, F-44093, France
| | - Boris Halgand
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France; Université de Nantes, UFR Odontologie, Nantes, F-44042, France; CHU Nantes, PHU4 OTONN, Nantes, F-44093, France
| | - Julie Lesoeur
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France; Université de Nantes, UFR Odontologie, Nantes, F-44042, France; SC3M -"Electron Microscopy, Microcharacterization, and Functional Morphohistology Imaging" Core Facility, Structure Fédérative de Recherche François Bonamy, INSERM - UMS016, CNRS 3556, CHU Nantes, Université de Nantes, Nantes, Nantes, F-04402, France
| | - Marion Fusellier
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France; Université de Nantes, UFR Odontologie, Nantes, F-44042, France; Department of Diagnostic Imaging, CRIP, National Veterinary School (ONIRIS), Nantes, F-44307, France
| | - Jérôme Guicheux
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France; Université de Nantes, UFR Odontologie, Nantes, F-44042, France; SC3M -"Electron Microscopy, Microcharacterization, and Functional Morphohistology Imaging" Core Facility, Structure Fédérative de Recherche François Bonamy, INSERM - UMS016, CNRS 3556, CHU Nantes, Université de Nantes, Nantes, Nantes, F-04402, France; CHU Nantes, PHU4 OTONN, Nantes, F-44093, France.
| | - Catherine Le Visage
- Inserm, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France; Université de Nantes, UFR Odontologie, Nantes, F-44042, France.
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Abstract
STUDY DESIGN Review article. OBJECTIVE A review of the literature on current strategies utilized in intervertebral regeneration and repair efforts. METHODS A review of the literature and analysis of the data to provide an updated review on current concepts of intervertebral disc repair and regeneration efforts. RESULTS Multiple regenerative strategies for intervertebral disc regeneration are being employed to reduce pain and improve quality of life. Current promising strategies include molecular therapy, gene therapy, cell-based therapy, and augmentation with biomaterials. Multiple clinical trials studying biologic, cell-based, and scaffold-based injectable therapies are currently being investigated. CONCLUSION Low back pain due to intervertebral disc disease represents a significant health and societal burden. Current promising strategies include molecular therapy, gene therapy, cell-based therapy, and augmentation with biomaterials. To date, there are no Food and Drug Administration-approved intradiscal therapies for discogenic back pain, and there are no large randomized trials that have shown clinically significant improvement with any investigational regenerative treatment. Multiple clinical trials studying biologic, cell-based, or scaffold-based injectable therapies are being currently investigated.
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Affiliation(s)
- Derek G. Ju
- Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | | - Hyun W. Bae
- Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Degeneration of Lumbar Intervertebral Discs: Characterization of Anulus Fibrosus Tissue and Cells of Different Degeneration Grades. Int J Mol Sci 2020; 21:ijms21062165. [PMID: 32245213 PMCID: PMC7139657 DOI: 10.3390/ijms21062165] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 03/18/2020] [Accepted: 03/19/2020] [Indexed: 01/16/2023] Open
Abstract
Intervertebral disc (IVD) herniation and degeneration is a major source of back pain. In order to regenerate a herniated and degenerated disc, closure of the anulus fibrosus (AF) is of crucial importance. For molecular characterization of AF, genome-wide Affymetrix HG-U133plus2.0 microarrays of native AF and cultured cells were investigated. To evaluate if cells derived from degenerated AF are able to initiate gene expression of a regenerative pattern of extracellular matrix (ECM) molecules, cultivated cells were stimulated with bone morphogenetic protein 2 (BMP2), transforming growth factor β1 (TGFβ1) or tumor necrosis factor-α (TNFα) for 24 h. Comparative microarray analysis of native AF tissues showed 788 genes with a significantly different gene expression with 213 genes more highly expressed in mild and 575 genes in severe degenerated AF tissue. Mild degenerated native AF tissues showed a higher gene expression of common cartilage ECM genes, whereas severe degenerated AF tissues expressed genes known from degenerative processes, including matrix metalloproteinases (MMP) and bone associated genes. During monolayer cultivation, only 164 differentially expressed genes were found. The cells dedifferentiated and altered their gene expression profile. RTD-PCR analyses of BMP2- and TGFβ1-stimulated cells from mild and severe degenerated AF tissue after 24 h showed an increased expression of cartilage associated genes. TNFα stimulation increased MMP1, 3, and 13 expression. Cells derived from mild and severe degenerated tissues could be stimulated to a comparable extent. These results give hope that regeneration of mildly but also strongly degenerated disc tissue is possible.
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Intervertebral Disc Diseases PART 2: A Review of the Current Diagnostic and Treatment Strategies for Intervertebral Disc Disease. Int J Mol Sci 2020; 21:ijms21062135. [PMID: 32244936 PMCID: PMC7139690 DOI: 10.3390/ijms21062135] [Citation(s) in RCA: 138] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 03/12/2020] [Accepted: 03/18/2020] [Indexed: 12/25/2022] Open
Abstract
With an aging population, there is a proportional increase in the prevalence of intervertebral disc diseases. Intervertebral disc diseases are the leading cause of lower back pain and disability. With a high prevalence of asymptomatic intervertebral disc diseases, there is a need for accurate diagnosis, which is key to management. A thorough understanding of the pathophysiology and clinical manifestation aids in understanding the natural history of these conditions. Recent developments in radiological and biomarker investigations have potential to provide noninvasive alternatives to the gold standard, invasive discogram. There is a large volume of literature on the management of intervertebral disc diseases, which we categorized into five headings: (a) Relief of pain by conservative management, (b) restorative treatment by molecular therapy, (c) reconstructive treatment by percutaneous intervertebral disc techniques, (d) relieving compression and replacement surgery, and (e) rigid fusion surgery. This review article aims to provide an overview on various current diagnostic and treatment options and discuss the interplay between each arms of these scientific and treatment advancements, hence providing an outlook of their potential future developments and collaborations in the management of intervertebral disc diseases.
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Barakat AH, Elwell VA, Lam KS. Stem cell therapy in discogenic back pain. JOURNAL OF SPINE SURGERY (HONG KONG) 2019; 5:561-583. [PMID: 32043007 PMCID: PMC6989932 DOI: 10.21037/jss.2019.09.22] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 09/09/2019] [Indexed: 04/23/2023]
Abstract
Chronic low back pain has both substantial social and economic impacts on patients and healthcare budgets. Adding to the magnitude of the problem is the difficulty in identifying the exact causes of disc degeneration with modern day diagnostic and imaging techniques. With that said, current non-operative and surgical treatment modalities for discogenic low back pain fails to meet the expectations in many patients and hence the challenge. The objective for newly emerging stem cell regenerative therapy is to treat degenerative disc disease (DDD) by restoring the disc's cellularity and modulating the inflammatory response. Appropriate patient selection is crucial for the success of stem cell therapy. Regenerative modalities for discogenic pain currently focus on the use of either primary cells harvested from the intervertebral discs or stem cells from other sources whether autogenic or allogenic. The microenvironment in which stem cells are being cultured has been recognized to play a crucial role in directing or maintaining the production of the desired phenotypes and may enhance their regenerative potential. This has led to a more specific focus on innovating more effective culturing techniques, delivery vehicles and scaffolds for stem cell application. Although stem cell therapy might offer an attractive alternative treatment option, more clinical studies are still needed to establish on the safety and feasibility of such therapy. In this literature review, we aim to present the most recent in vivo and in vitro studies related to the use of stem cell therapy in the treatment of discogenic low back pain.
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Affiliation(s)
- Ahmed H. Barakat
- Brighton and Sussex University Hospitals NHS Trust, Brighton, UK
| | - Vivian A. Elwell
- Brighton and Sussex University Hospitals NHS Trust, Brighton, UK
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Luo TD, Marquez-Lara A, Zabarsky ZK, Vines JB, Mowry KC, Jinnah AH, Ma X, Berwick BW, Willey JS, Li Z, Smith TL, O'Gara TJ. A percutaneous, minimally invasive annulus fibrosus needle puncture model of intervertebral disc degeneration in rabbits. J Orthop Surg (Hong Kong) 2019; 26:2309499018792715. [PMID: 30114959 DOI: 10.1177/2309499018792715] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
PURPOSE Various animal models have been proposed to mimic the pathophysiologic process of intervertebral disc degeneration, a leading cause of back pain. The purpose of this study is to describe a minimally invasive technique via percutaneous needle puncture of the annulus fibrosus in New Zealand white rabbits. METHODS Under fluoroscopic guidance, an 18-gauge spinal needle was inserted 2 cm lateral to the midline spinous process. The needle was slowly advanced at approximately 45° angle until it was adjacent to the L5/L6 disc space. Lateral and anteroposterior views were used to verify correct needle position before advancing into the nucleus pulposus. The rabbits underwent weekly X-rays for 4 weeks to assess disc height index. MRI T2 relaxation was evaluated at week four to assess morphological changes. Discs were histologically graded on a 12-point scale to assess degeneration and compared to discs obtained from uninjured rabbits. RESULTS There were no complications associated with the percutaneous needle puncture procedure. All animals survived the duration of the experiment. Four weeks after injury, the disc height had progressively narrowed to approximately 50% of baseline. MRI assessment at the 4-week time point demonstrated a mean T2 relaxation time at the L5/L6 level that was 20.9% of the T2 relaxation time at the uninjured L4/L5 disc level ( p < 0.001). Histological analysis demonstrated lamellar disorganization of the annulus and decreased cellularity and proteoglycan content within the injured nucleus compared to uninjured control discs. CONCLUSION The present study demonstrated a reliable technique of inducing an annular tear via a percutaneous needle puncture. Compared to open surgical approaches, the percutaneous model produces similar progressive disc degeneration while minimizing harm to the animal subjects. CLINICAL RELEVANCE The present study establishes a technique for the introduction of novel therapeutic agents to treat disc degeneration that may translate to future clinical trials.
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Affiliation(s)
- T David Luo
- 1 Department of Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Alejandro Marquez-Lara
- 1 Department of Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Zachary K Zabarsky
- 1 Department of Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Jeremy B Vines
- 2 Organogenesis Surgical and Sports Medicine, Birmingham, AL, USA
| | - Katie C Mowry
- 2 Organogenesis Surgical and Sports Medicine, Birmingham, AL, USA
| | - Alexander H Jinnah
- 1 Department of Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Xue Ma
- 1 Department of Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Benjamin W Berwick
- 1 Department of Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Jeffrey S Willey
- 1 Department of Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.,3 Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Zhongyu Li
- 1 Department of Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Thomas L Smith
- 1 Department of Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Tadhg J O'Gara
- 1 Department of Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
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Imanishi T, Akeda K, Murata K, Sudo A. Effect of diminished flow in rabbit lumbar arteries on intervertebral disc matrix changes using MRI T2-mapping and histology. BMC Musculoskelet Disord 2019; 20:347. [PMID: 31351455 PMCID: PMC6661094 DOI: 10.1186/s12891-019-2721-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 07/15/2019] [Indexed: 12/17/2022] Open
Abstract
Background Impaired lumbar artery flow has been reported in clinical and epidemiological studies to be associated with low back pain and lumbar disc degeneration. However, it has not been experimentally demonstrated that impaired lumbar artery flow directly induces intervertebral disc (IVD) degeneration by affecting IVD matrix metabolism. The purpose of this study was to evaluate whether ligation of the lumbar artery can affect degenerative changes in the rabbit IVD. Methods New Zealand White rabbits (n = 20) were used in this study. Under general anesthesia, the third and fourth lumbar arteries were double-ligated using vascular clips. The blood flow to the L3/L4 disc (cranial disc) was reduced by ligation of the third lumbar artery and that of the L5/L6 disc (caudal disc) by ligation of the fourth lumbar artery. The blood flow to the L4/L5 disc (bilateral disc) was decreased by ligation of both the third and fourth lumbar arteries. The L2/L3 disc was used as the control. Disc height was radiographically monitored biweekly until 12 weeks after surgery. The rabbits were sacrificed at 4, 8, and 12 weeks after surgery and magnetic resonance imaging (MRI) T2-mapping, histology and immunohistochemistry were assessed. Results Lumbar artery ligation did not induce significant changes in disc height between control and ischemic discs (cranial, bilateral and caudal discs) during the 12-week experimental period. T2-values of ischemic discs had no significant trend to be lower than those of the control L2/L3 discs. Histologically, Safranin-O staining changed following ligation of corresponding IVD lumbar arteries. Histological grading scores for disc degeneration, which correlated significantly with MRI T2-values, had significant changes after the surgery. Immunohistochemical analysis showed that the ligation of lumbar arteries significantly affected a change in the percentage of HIF-1α immunoreactive cells of ischemia discs compared to that of control discs four weeks after the surgery (p < 0.05). Conclusions The MRI and histology results suggest that diminished flow in lumbar arteries induce mild changes in the extracellular matrix metabolism of rabbit IVDs. These matrix changes, however, were not progressive and differed from the degenerative disc changes seen in the process of human IVD degeneration.
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Affiliation(s)
- Takao Imanishi
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, Japan
| | - Koji Akeda
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, Japan.
| | - Koichiro Murata
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, Japan
| | - Akihiro Sudo
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, Japan
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Tendulkar G, Chen T, Ehnert S, Kaps HP, Nüssler AK. Intervertebral Disc Nucleus Repair: Hype or Hope? Int J Mol Sci 2019; 20:3622. [PMID: 31344903 PMCID: PMC6696292 DOI: 10.3390/ijms20153622] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 07/19/2019] [Accepted: 07/20/2019] [Indexed: 12/28/2022] Open
Abstract
Chronic back pain is a common disability, which is often accredited to intervertebral disc degeneration. Gold standard interventions such as spinal fusion, which are mainly designed to mechanically seal the defect, frequently fail to restore the native biomechanics. Moreover, artificial implants have limited success as a repair strategy, as they do not alter the underlying disease and fail to promote tissue integration and subsequent native biomechanics. The reported high rates of spinal fusion and artificial disc implant failure have pushed intervertebral disc degeneration research in recent years towards repair strategies. Intervertebral disc repair utilizing principles of tissue engineering should theoretically be successful, overcoming the inadequacies of artificial implants. For instance, advances in the development of scaffolds aided with cells and growth factors have opened up new possibilities for repair strategies. However, none has reached the stage of clinical trials in humans. In this review, we describe the hitches encountered in the musculoskeletal field and summarize recent advances in designing tissue-engineered constructs for promoting nucleus pulposus repair. Additionally, the review focuses on the effect of biomaterial aided with cells and growth factors on achieving effective functional reparative potency, highlighting the ways to enhance the efficacy of these treatments.
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Affiliation(s)
- Gauri Tendulkar
- Siegfried Weller Institute for Trauma Research at the BG Unfallklinik Tübingen, Eberhard Karls Universität Tübingen, Schnarrenbergstrasse 95, 72076 Tübingen, Germany
| | - Tao Chen
- Siegfried Weller Institute for Trauma Research at the BG Unfallklinik Tübingen, Eberhard Karls Universität Tübingen, Schnarrenbergstrasse 95, 72076 Tübingen, Germany
| | - Sabrina Ehnert
- Siegfried Weller Institute for Trauma Research at the BG Unfallklinik Tübingen, Eberhard Karls Universität Tübingen, Schnarrenbergstrasse 95, 72076 Tübingen, Germany
| | - Hans-Peter Kaps
- Siegfried Weller Institute for Trauma Research at the BG Unfallklinik Tübingen, Eberhard Karls Universität Tübingen, Schnarrenbergstrasse 95, 72076 Tübingen, Germany
| | - Andreas K Nüssler
- Siegfried Weller Institute for Trauma Research at the BG Unfallklinik Tübingen, Eberhard Karls Universität Tübingen, Schnarrenbergstrasse 95, 72076 Tübingen, Germany.
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Clouet J, Fusellier M, Camus A, Le Visage C, Guicheux J. Intervertebral disc regeneration: From cell therapy to the development of novel bioinspired endogenous repair strategies. Adv Drug Deliv Rev 2019; 146:306-324. [PMID: 29705378 DOI: 10.1016/j.addr.2018.04.017] [Citation(s) in RCA: 141] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Revised: 03/29/2018] [Accepted: 04/24/2018] [Indexed: 12/15/2022]
Abstract
Low back pain (LBP), frequently associated with intervertebral disc (IVD) degeneration, is a major public health concern. LBP is currently managed by pharmacological treatments and, if unsuccessful, by invasive surgical procedures, which do not counteract the degenerative process. Considering that IVD cell depletion is critical in the degenerative process, the supplementation of IVD with reparative cells, associated or not with biomaterials, has been contemplated. Recently, the discovery of reparative stem/progenitor cells in the IVD has led to increased interest in the potential of endogenous repair strategies. Recruitment of these cells by specific signals might constitute an alternative strategy to cell transplantation. Here, we review the status of cell-based therapies for treating IVD degeneration and emphasize the current concept of endogenous repair as well as future perspectives. This review also highlights the challenges of the mobilization/differentiation of reparative progenitor cells through the delivery of biologics factors to stimulate IVD regeneration.
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Affiliation(s)
- Johann Clouet
- INSERM, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes F-44042, France; CHU Nantes, Pharmacie Centrale, PHU 11, Nantes F-44093, France; Université de Nantes, UFR Sciences Biologiques et Pharmaceutiques, Nantes F-44035, France; Université de Nantes, UFR Odontologie, Nantes F-44042, France
| | - Marion Fusellier
- INSERM, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes F-44042, France; Department of Diagnostic Imaging, CRIP, National Veterinary School (ONIRIS), Nantes F-44307, France
| | - Anne Camus
- INSERM, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes F-44042, France; Université de Nantes, UFR Odontologie, Nantes F-44042, France
| | - Catherine Le Visage
- INSERM, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes F-44042, France; Université de Nantes, UFR Odontologie, Nantes F-44042, France
| | - Jérôme Guicheux
- INSERM, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes F-44042, France; Université de Nantes, UFR Odontologie, Nantes F-44042, France; CHU Nantes, PHU4 OTONN, Nantes, F-44093, France.
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Hodgkinson T, Shen B, Diwan A, Hoyland JA, Richardson SM. Therapeutic potential of growth differentiation factors in the treatment of degenerative disc diseases. JOR Spine 2019; 2:e1045. [PMID: 31463459 PMCID: PMC6686806 DOI: 10.1002/jsp2.1045] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 01/16/2019] [Accepted: 02/04/2019] [Indexed: 02/06/2023] Open
Abstract
Intervertebral disc (IVD) degeneration is a major contributing factor to chronic low back pain and disability, leading to imbalance between anabolic and catabolic processes, altered extracellular matrix composition, loss of tissue hydration, inflammation, and impaired mechanical functionality. Current treatments aim to manage symptoms rather than treat underlying pathology. Therefore, IVD degeneration is a target for regenerative medicine strategies. Research has focused on understanding the molecular process of degeneration and the identification of various factors that may have the ability to halt and even reverse the degenerative process. One such family of growth factors, the growth differentiation factor (GDF) family, have shown particular promise for disc regeneration in in vitro and in vivo models of IVD degeneration. This review outlines our current understanding of IVD degeneration, and in this context, aims to discuss recent advancements in the use of GDF family members as anabolic factors for disc regeneration. An increasing body of evidence indicates that GDF family members are central to IVD homeostatic processes and are able to upregulate healthy nucleus pulposus cell marker genes in degenerative cells, induce mesenchymal stem cells to differentiate into nucleus pulposus cells and even act as chemotactic signals mobilizing resident cell populations during disc injury repair. The understanding of GDF signaling and its interplay with inflammatory and catabolic processes may be critical for the future development of effective IVD regeneration therapies.
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Affiliation(s)
- Tom Hodgkinson
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of ManchesterManchester Academic Health Sciences CentreManchesterUK
- Centre for the Cellular Microenvironment, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life SciencesUniversity of GlasgowGlasgowUK
| | - Bojiang Shen
- St. George Clinical SchoolUniversity of New South WalesSydneyNew South WalesAustralia
| | - Ashish Diwan
- St. George Clinical SchoolUniversity of New South WalesSydneyNew South WalesAustralia
| | - Judith A. Hoyland
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of ManchesterManchester Academic Health Sciences CentreManchesterUK
- NIHR Manchester Biomedical Research Centre, Manchester University Foundation TrustManchester Academic Health Sciences CentreManchesterUK
| | - Stephen M. Richardson
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of ManchesterManchester Academic Health Sciences CentreManchesterUK
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Gelalis ID, Christoforou G, Charchanti A, Gkiatas I, Pakos E, Papadopoulos D, Ploumis A, Korompilias A. Autologous platelet-rich plasma (PRP) effect on intervertebral disc restoration: an experimental rabbit model. EUROPEAN JOURNAL OF ORTHOPAEDIC SURGERY AND TRAUMATOLOGY 2018; 29:545-551. [PMID: 30370433 DOI: 10.1007/s00590-018-2337-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 10/22/2018] [Indexed: 12/12/2022]
Abstract
PURPOSE Platelet-rich plasma (PRP) treatment for intervertebral disc (IVD) repair and tissue engineering technologies have been the target of intense research with promising results. The purpose of this study was to investigate the effect of only one intradiscal injection of PRP in the degenerated rabbit IVD and to assess the restoration process over a 6-week follow-up period. METHODS The L3-L4 and L4-L5 discs of 18 adult female rabbits were injured, according to an established degenerative model, with an 18-gauge needle, and classified into two groups: In the discs of group A rabbits, after needle puncture, an intradiscal injection of autologous PRP growth factors was performed, using a 27-gauge needle, and in the discs of the control group (group B), the same procedure was followed by intradiscal injection of normal saline. The PRP preparation was carried out aseptically, after blood collection from the same rabbit. RESULTS During the 6 weeks, there was a noteworthy progression of degeneration process in group B, whereas the grade of degeneration was significantly lower in group A, both for annulus fibrosus (AF) and for nucleus pulposus (NP). The intervertebral disc regeneration and reversal process of the lesions are obvious on 45 days after the injury, in group A. The hematoxylin and eosin histology grading score and the expression of collagen type II in NP and inner layer of AF were the markers better mirroring the degeneration and restoration process. CONCLUSION PRP intradiscal treatment in degenerative disc disease provokes the maintenance of the disc's basic morphological characteristics with restoration being evident early after injury.
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Affiliation(s)
- Ioannis D Gelalis
- Deparment of Orthopaedic Surgery, School of Medicine, University of Ioannina, 45110, Ioannina, Greece
| | - Georgios Christoforou
- Deparment of Orthopaedic Surgery, School of Medicine, University of Ioannina, 45110, Ioannina, Greece
| | - Antonia Charchanti
- Deparment of Orthopaedic Surgery, School of Medicine, University of Ioannina, 45110, Ioannina, Greece
| | - Ioannis Gkiatas
- Deparment of Orthopaedic Surgery, School of Medicine, University of Ioannina, 45110, Ioannina, Greece.
| | - Emilios Pakos
- Deparment of Orthopaedic Surgery, School of Medicine, University of Ioannina, 45110, Ioannina, Greece
| | - Dimitrios Papadopoulos
- Deparment of Orthopaedic Surgery, School of Medicine, University of Ioannina, 45110, Ioannina, Greece
| | - Avraam Ploumis
- Deparment of Orthopaedic Surgery, School of Medicine, University of Ioannina, 45110, Ioannina, Greece
| | - Anastasios Korompilias
- Deparment of Orthopaedic Surgery, School of Medicine, University of Ioannina, 45110, Ioannina, Greece
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Huang X, Zhang W, Shao Z. Association between GDF5 rs143383 genetic polymorphism and musculoskeletal degenerative diseases susceptibility: a meta-analysis. BMC MEDICAL GENETICS 2018; 19:169. [PMID: 30217184 PMCID: PMC6137727 DOI: 10.1186/s12881-018-0685-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 09/09/2018] [Indexed: 11/10/2022]
Abstract
BACKGROUND Several studies have assessed the association between GDF5 rs143383 polymorphism and the susceptibility of musculoskeletal degenerative diseases, such as intervertebral disc degeneration (IDD) and osteoarthritis (OA), but the results are inconsistent. The aim of our study was to evaluate the association between them comprehensively. METHODS A systematical search was conducted on PubMed, Scopus, Web of Science (WOS), Embase, and the Cochrane Library databases updated to April 20, 2018. Eligible studies about polymorphisms in GDF5 gene and risk of IDD or OA were included. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were utilized. RESULTS Fifteen studies with a total of 5915 cases and 12,252 controls were finally included in our study. Meta-analysis of GDF5 rs143383 polymorphism was statistically associated with increased risk of musculoskeletal degenerative diseases under each genetic model (allele model: OR = 1.32, 95% CI 1.19-1.48, P = 0.000; homozygote model: OR = 1.80, 95%CI 1.49-2.16, P = 0.000; heterozygote model: OR = 1.37, 95%CI 1.21-1.55, P = 0.000; dominant model: OR = 1.56, 95%CI 1.39-1.75, P = 0.000; recessive model: OR = 1.39, 95%CI 1.20-1.60, P = 0.000). Stratified analyses based on disease type showed a significant association between the GDF5 rs143383 polymorphism and increased risk of IDD and OA under all genetic models studied. When stratified with ethnicity, pooled outcomes revealed that this polymorphism was significantly related with increased risk of musculoskeletal degenerative diseases in both Asian and Caucasian populations under all genetic models studied. CONCLUSIONS The present study suggested that GDF5 rs143383 polymorphism was significantly associated with susceptibility to musculoskeletal degenerative diseases.
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Affiliation(s)
- Xin Huang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Weiyue Zhang
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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