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Lumbar instability remodels cartilage endplate to induce intervertebral disc degeneration by recruiting osteoclasts via Hippo-CCL3 signaling

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Bone Research 2024年第3期12卷 555-570页

作者： Hanwen Li Yingchuang Tang Zixiang Liu Kangwu Chen Kai Zhang Sihan Hu Chun Pan Huilin Yang Bin Li Hao Chen Department of Orthopedic Surgery First Affiliated Hospital of Soochow UniversitySuzhouP.R.China Orthopedic Institute Suzhou Medical CollegeSoochow UniversitySuzhouP.R.China Institute of Translational Medicine Medical CollegeYangzhou UniversityYangzhouP.R.China Department of Orthopedic Surgery Affiliated Hospital of Yangzhou UniversityYangzhouP.R.China

Degenerated endplate appears with cheese-like morphology and sensory innervation,contributing to low back pain and subsequently inducing intervertebral disc degeneration in the aged population.1 However,the origin and development mechanism of the cheese-like morphology remain *** in this study,we report lumbar instability induced cartilage endplate remodeling is responsible for this pathological change.

关键词： degeneration cartilage intervertebral

ADAM8 inactivation retards intervertebral disc degeneration in mice

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Genes & Diseases 2024年第3期11卷 91-94页

作者： Zuozhen Tian Frances S.Shofer Mingyue Fan Alec Z.Sandroni Lutian Yao Lin Han Ling Qin Motomi Enomoto-lwamoto Yejia Zhang Department of Physical Medicine&Rehabilitation Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA19146USA Department of Emergency Medicine Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA 19104USA Department of Orthopedic Surgery Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA 19104USA School of Biomedical Engineering Science&Health SystemsDrexel UniversityPhiladelphiaPA 19104USA Department of Orthopedics/Sports Medicine and Joint Surgery the First Hospital of China Medical UniversityShenyangLiaoning 110001China Department of Orthopedics University of Maryland School ofMedicineBaltimoreMD21201USA Section of Rehabilitation Medicine Corporal Michael J.Crescenz Veterans Affairs Medical CenterPhiladelphiaPA 19104USA

ADAM8 has been identified as the fibronectin-cleaving enzyme in human degenerative intervertebral disc(IVD)tissues.^(1)Increase of the active form of ADAM8 and its cleavage product,fibronectin fragment,correlated with an increased degree of IVD degeneration.1 Furthermore,fibronectin fragments have been shown to accelerate the progression of IVD degeneration.^(2)These findings suggest that ADAM8 may play a role in degenerative disc disease,a clinical problem with tremendous socioeconomic burdens in the United States.

关键词： ADAM8 degeneration intervertebral

3D assessment of intervertebral disc degeneration in zebrafish identifies changes in bone density that prime disc disease

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Bone Research 2021年第4期9卷 521-536页

作者： Erika Kague Francesco Turci Elis Newman Yushi Yang Kate Robson Brown Mona S.Aglan Ghada A.Otaify Sarnia A.Temtamy Victor L.Ruiz-Perez Stephen Cross C.Patrick Royall P.Eckhard Witten Chrissy L.Hammond School of Physiology Pharmacology and NeuroscienceBiomedical SciencesUniversity of BristolBristolUK School of Physics HH Wills Physics LaboratoryUniversity of BristolBristolUK Centre for Nanoscience and Quantum Information University of BristolBristolUK Bristol Centre for Functional Nanomaterials University of BristolBristolUK Department of Anthropology and Archaeology University of BristolBristolUK Department of Mechanical Engineering University of BristolBristolUK Clinical Genetics Department Human Genetics and Genome Research DivisionCenter of Excellence for Human GeneticsNational Research CentreCairoEgypt lnstituto de Investigaciones Biomedicas de Madridand Ciber de Enfermedades Raras(CIBERER)MadridSpain Wolfson Bioimaging Facility Biomedical SciencesUniversity of BristolBristolUK School of Chemistry University of BristolBristolUK Evolutionary Developmental Biology Department of BiologyGhent UniversityGhentBelgium

Back pain is a common condition with a high social impact and represents a global health *** disc disease(IVDD)is one of the major causes of back pain;no therapeutics are currently available to reverse this *** impact of bone mineral density(BMD)on IVDD has been controversial,with some studies suggesting osteoporosis as causative for IVDD and others suggesting it as protective for *** studies to evaluate the influence of genetic components of BMD in IVDD could highlight opportunities for drug development and *** taking a holistic 3D approach,we established an aging zebrafish model for spontaneous *** BMD in aging,detected by automated computational analysis,is caused by bone deformities at the ***,aged zebrafish spines showed changes in bone morphology,microstructure,mineral heterogeneity,and increased fragility that resembled *** of the discs recapitulated IVDD symptoms found in humans:the intervertebral ligament(equivalent to the annulus fibrosus)showed disorganized collagen fibers and herniation,while the disc center(nucleus pulposus equivalent)showed dehydration and cellular *** manipulated BMD in young zebrafish by mutating sp7 and cathepsin K,leading to low and high BMD,***,we detected IVDD in both groups,demonstrating that low BMD does not protect against IVDD,and we found a strong correlation between high BMD and *** learning was applied to high-resolution synchrotron\iCJ image data to analyze osteocyte 3D lacunar distribution and morphology,revealing a role of sp7 in controlling the osteocyte lacunar 3D *** findings suggest potential avenues through which bone quality can be targeted to identify beneficial therapeutics for IVDD.

关键词： intervertebral degeneration protective

A new perspective on intervertebral disc calcification—from bench to bedside

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Bone Research 2024年第1期12卷 50-61页

作者： Emanuel J.Novais Rajkishen Narayanan Jose A.Canseco Koen van de Wetering Christopher K.Kepler Alan S.Hilibrand Alexander R.Vaccaro Makarand V.Risbud Department of Orthopaedic Surgery Sidney Kimmel Medical CollegeThomas Jefferson UniversityPhiladelphiaPAUSA Unidade Local de Saúde do Litoral Alentejano Orthopedic DepartmentSantiago do CacémPortugal Rothman Orthopedic Institute at Thomas Jefferson University PhiladelphiaPAUSA

Disc degeneration primarily contributes to chronic low back and neck ***,there is an urgent need to understand the spectrum of disc degeneration phenotypes such as fibrosis,ectopic calcification,herniation,or mixed *** these phenotypes,disc calcification is the least *** calcification,by definition,is the pathological mineralization of soft tissues,widely studied in the context of conditions that afflict vasculature,skin,and ***,disc calcification is associated with poor surgical outcomes and back pain refractory to conservative *** is frequently seen as a consequence of disc aging and progressive degeneration but exhibits unique molecular and morphological characteristics:hypertrophic chondrocyte-like cell differentiation;TNAP,ENPP1,and ANK upregulation;cell death;altered Pi and PPi homeostasis;and local *** studies in mouse models have provided a better understanding of the mechanisms underlying this *** is essential to recognize that the presentation and nature of mineralization differ between AF,NP,and EP ***,the combination of anatomic location,genetics,and environmental stressors,such as aging or trauma,govern the predisposition to ***,the systemic regulation of calcium and Pi metabolism is less important than the local activity of PPi modulated by the ANK-ENPP1 axis,along with disc cell death and differentiation *** there is limited understanding of this phenotype,understanding the molecular pathways governing local intervertebral disc calcification may lead to developing disease-modifying drugs and better clinical management of degeneration-related pathologies.

关键词： degeneration metabolism intervertebral

Autologous fibroblasts induce fibrosis of the nucleus pulposus to maintain the stability of degenerative intervertebral discs

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Bone Research 2020年第1期8卷 63-75页

作者： Chen Chen Tangjun Zhou Xiaojiang Sun Chen Han Kai Zhang Changqing Zhao Xunlin Li Haijun Tian Xiao Yang Yifan Zhou Zhiqian Chen An Qin Jie Zhao Shanghai Key Laboratory of Orthopaedic Implants Department of Orthopaedic Surgery Shanghai Ninth People’s Hospital Shanghai Jiao Tong University School of Medicine

Lumbar degenerative disc diseases cause low back pain(LBP). The maintenance of the height and stability of the intervertebral disc(IVD) space is an effective treatment for LBP. The following study evaluated the effects of fibroblast injection on intervertebral disc degeneration(IDD) in a preclinical setting. Compared with the IDD group, the fibroblast treatment group demonstrated effective maintenance of IVD height, reduced endplate degeneration, and improved nuclear magnetic resonance signals and overall histological structure. In doing so, fibrotic IVDs maintained the stability and biomechanics of the vertebra. This finding is in agreement with clinical findings that human nucleus pulposus(NP) fibrosis is essential for the maintenance of IVD height and mechanical properties in patients following percutaneous endoscopic lumbar discectomy(PELD). Mechanistically, we demonstrated that injected fibroblasts not only proliferated but also induced NP cells to adopt a fibrotic phenotype via the secretion of TGF-β.Finally, to better mimic human conditions, the efficacy of autologous fibroblast injection in the treatment of IDD was further examined in a nonhuman primate cynomolgus monkey model due to their capacity for upright posture. We showed that the injection of fibroblasts could maintain the IVD height and rescue IVD signals in cynomolgus monkeys. Taken together, the results of our study reveal that autologous fibroblast injection can enhance the natural process of fibrosis during acute and subacute stages of stress-induced IDD. Fibrotic IVDs can maintain the stability, biological activity, and mechanical properties of the intervertebral space, thus providing a new direction for the treatment of intervertebral space-derived lumbar degenerative diseases.

关键词： intervertebral degenerative degeneration

Insights of stem cell-based endogenous repair of intervertebral disc degeneration

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World Journal of Stem Cells 2020年第4期12卷 266-276页

作者： Yang Liu Yan Li Li-Ping Nan Feng Wang Shi-Feng Zhou Xin-Min Feng Hao Liu Liang Zhang Department of Orthopedics West China Hospital of Sichuan UniversityChengdu 610000Sichuan ProvinceChina Department of Orthopedics Dalian Medical UniversityDalian 116000Liaoning ProvinceChina Department of Oncology The Affiliated Cancer HospitalSchool of MedicineUESTCChengdu 610000Sichuan ProvinceChina Department of Orthopedics Clinical Medical College of Yangzhou UniversityYangzhou 225000Jiangsu ProvinceChina

Low back pain has become more prevalent in recent years,causing enormous economic burden for society and *** therapies used in clinics including conservative treatment and surgery can only relieve *** cell-based treatment such as mesenchymal stem cell transplantation poses problems such as short duration of therapeutic effect and ***,the discovery and identification of stem cell niche and stem/progenitor cells in intervertebral disc bring increased attention to endogenous repair ***,we review the studies involving endogenous repair strategy and present the characteristics and current status of this ***,we also discuss the strategy and perspective of endogenous repair strategy in future.

关键词： Low back pain intervertebral disc degeneration Stem cell niche Stem/progenitor cell Endogenous repair strategy Stem cell treatment

Stem cells sources for intervertebral disc regeneration

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World Journal of Stem Cells 2016年第5期8卷 185-201页

作者： Gianluca Vadalà Fabrizio Russo Luca Ambrosio Mattia Loppini Vincenzo Denaro Department of Orthopedic and Trauma Surgery University Campus Bio-Medico of Rome

intervertebral disc regeneration field is rapidly growing since disc disorders represent a major health problem in industrialized countries with very few possible ***, current available therapies are symptomatic, and surgical procedures consist in disc removal and spinal fusion, which is not immune to regardable concerns about possible comorbidities, cost-effectiveness, secondary risks and long-lasting outcomes. This review paper aims to share recent advances in stem cell therapy for the treatment of intervertebral disc degeneration. In literature the potential use of different adult stem cells for intervertebral disc regeneration has already been reported. Bone marrow mesenchymal stromal/stem cells, adipose tissue derived stem cells, synovial stem cells, muscle-derived stem cells, olfactory neural stem cells, induced pluripotent stem cells, hematopoietic stem cells, disc stem cells, and embryonic stem cells have been studied for this purpose either in vitro or in vivo. Moreover, several engineered carriers(e.g., hydrogels), characterized by full biocompatibility and prompt biodegradation, have been designed and combined with different stem cell types in order to optimize the local and controlled delivery of cellular substrates in situ. The paper overviews the literature discussing the current status of our knowledge of the different stem cells types used as a cell-based therapy for disc regeneration.

关键词： Stem cells intervertebral disc degeneration Spine Tissue engineering Cell therapy

Effect of osteoporosis and intervertebral disc degeneration on endplate cartilage injury in rats

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Asian Pacific Journal of Tropical Medicine 2014年第10期7卷 796-800页

作者： Lei Wang Wei Cui Jean Pierre Kalal Tom Van Hoof Bao-Ge Liu Department of Orthopaedics Beijing Tiantan Hospital affiliated to Capital Medical University Department of Neurosurgery University HospitalUniversity of GhentBelgium Department of Human Anatomy EmbryologyHistology and Medical PhysicsUniversity of GhentBelgium

Objective:To investigate the effect of osteoporosis and intervertebral disc degeneration on the endplate cartilage injury in ***:A total of 48 female Sprague Dawley rats(3 months)were randomly divided into Groups A,B,C and D with 12 rats in each *** and intervertebral disc degeneration composite model,simple degeneration model and simple osteoporosis model were prepared in Groups A,B and C *** modeling,four rats of each group at 12th.18th and 24th week were sacrificed,intervertebral height of cervical vertebra C6/C7 was ***-CT was used to image the endplate of cephalic and caudal cartilage at C6/C7 intervertebral *** area rate of C6 caudal and C7 cephalic cartilage endplate was calculated,and then C6/C7 intervertebral disc was routinely embedded and *** with safranin O to observe histological changes ***:At 12,18 and24 weeks,intervertebral disc height of C6/C7 were(0.58±0.09)mm,(0.53±0.04)mm and(0.04±0.06)mm in Group A rats,(0.55±0.05)mm,(0.52±0.07)mm and(0.07±0.05)mm in Group B *** 24th *** disc height of Group A rats was significantly lower than that of Group B rats(Pintervertebral disc height of Groups A and B rats at each time point were significantly lower than that of Groups C and D(Pintervertebral disc height between Groups C and D(P>0.05).At 12 and 18 weeks,the abraded rate of C6 caudal and C7 cephalic cartilage endplate in Group A rats were significantly higher than that in Groups B.C and D rats(P0.05).Microscopic observation of CT showed that ventral defects in C6caudal or C7 cephalic cartilage endplate in Groups A and B appeared after 12 weeks of modeling;obvious cracks were found in front of the C6 and C7 vertebral body,and cartilage defect shown the trend of"repairing"at 18 and 24 weeks a

关键词： Osteoporosis intervertebral disc degeneration Vertebral bodies Cartilage endplate Damage

Application of Finite Element Analysis for Investigation of intervertebral Disc Degeneration:from Laboratory to Clinic

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Current Medical Science 2019年第1期39卷 7-15页

作者： Bin-wu HU Xiao LV Song-feng CHEN Zeng-wu SHAO Department of Orthopaedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China Department of Orthopaedic Surgery The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China

Due to the ethical concern and inability to detect inner stress distributions of intervertebral disc(IVD),traditional methods for investigation of intervertebral disc degeneration(IVDD)have significant *** researchers have demonstrated that finite element analysis(FEA)is an effective tool for the research of ***,the specific application of FEA for investigation of IVDD has not been systematically elucidated *** the present review,we summarize the current finite element models(FEM)used for the investigation of IVDD,including the poroelastic non linear FEM,difTusive-reactive theory model and cell-activity coupled mechano-electrochemical theory *** further elaborate the use of FEA for the research of IVDD pathogenesis especially for nutrition and biomechanics associated etiology,and the biological,biomechanical and clinical influences of *** addition,the application of FEA for evaluation and exploration of various treatments for IVDD is also *** conclude that FEA is an excellent technique for research of IVDD,which could be used to explore the etiology,biology and biomechanics of *** the future,FEA may help us to achieve the goal of individualized precision therapy.

关键词： finite element analysis intervertebral disc degeneration biomechanics spine