Pub Date : 2025-07-16DOI: 10.1016/j.jot.2025.06.020
Jingtao Huang , Shicheng Jia , Rongji Liang , Aikang Li , Lin Li , Haojian Wang , Jiayou Chen , Haoxian Tang , Xuan Zhang , Jianjing Lin , Xintao Zhang
Articular cartilage defects caused by trauma or degeneration severely impair patient function. Cartilage repair organoids represent a transformative approach in regenerative medicine to address these challenges. This review focuses on the development and therapeutic potential of such organoids, detailing their role in overcoming limitations of conventional treatments. Central to this progress, bioprinting technology enables precise organoid fabrication by advancing organoid-compatible bioinks and printing techniques. We further examine applications in disease modeling and drug screening, alongside pathways for clinical translation. As organoid engineering matures, it promises to deliver effective, patient-specific solutions for cartilage restoration.
The Translational Potential Statement: The Translational Potential of this Article: 3D-bioprinted cartilage organoids exhibit outstanding efficacy in animal models and hold promise for future clinical trials. The bioinks and printing technologies are distilled to promote basic research toward translation of cartilage repair.
{"title":"Construction of organoids using bioprinting technology: a frontier exploration of cartilage repair","authors":"Jingtao Huang , Shicheng Jia , Rongji Liang , Aikang Li , Lin Li , Haojian Wang , Jiayou Chen , Haoxian Tang , Xuan Zhang , Jianjing Lin , Xintao Zhang","doi":"10.1016/j.jot.2025.06.020","DOIUrl":"10.1016/j.jot.2025.06.020","url":null,"abstract":"<div><div>Articular cartilage defects caused by trauma or degeneration severely impair patient function. Cartilage repair organoids represent a transformative approach in regenerative medicine to address these challenges. This review focuses on the development and therapeutic potential of such organoids, detailing their role in overcoming limitations of conventional treatments. Central to this progress, bioprinting technology enables precise organoid fabrication by advancing organoid-compatible bioinks and printing techniques. We further examine applications in disease modeling and drug screening, alongside pathways for clinical translation. As organoid engineering matures, it promises to deliver effective, patient-specific solutions for cartilage restoration.</div><div>The Translational Potential Statement: The Translational Potential of this Article: 3D-bioprinted cartilage organoids exhibit outstanding efficacy in animal models and hold promise for future clinical trials. The bioinks and printing technologies are distilled to promote basic research toward translation of cartilage repair.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"Pages 37-50"},"PeriodicalIF":5.9,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144634441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-12DOI: 10.1016/j.jot.2025.07.001
Heran Wang , Xiaodong Liu , Xingzhi Jing , Bofei Zhang , Xin Liu , Xiaoyang Liu , Fei Jia , Cheng Su , Wenchao Wang , Xingang Cui
Background
Intervertebral disc degeneration (IDD) is a major cause of low back pain, with cartilaginous endplate (CEP) degeneration playing a critical role. While Yes-associated protein (YAP) and its involvement in CEP degeneration and ferroptosis remain unclear. This study aimed to investigate the regulatory role of YAP in CEP ferroptosis and its underlying mechanisms.
Methods
YAP expression was analyzed in human CEP tissues and mouse LSI models. CEP cells were treated with Verteporfin or YAP-siRNA. Ferroptosis was assessed by measuring iron levels, lipid peroxidation, GSH content, and viability assays. Molecular mechanisms were elucidated using CUT&RUN-qPCR, dual-LUC, and immunofluorescence colocalization. Verteporfin (VP) therapeutic efficacy was evaluated in LSI mice.
Results
YAP knockdown attenuated oxidative stress-induced CEP chondrocyte degeneration and ferroptosis features. Mechanistically, we identified that oxidative stress-induced CEP chondrocyte degeneration involves ferritinophagy, which is regulated by the YAP/TEAD1 signaling axis through transcriptional control of nuclear coactivator 4 (NCOA4). Treatment with verteporfin, a YAP/TEAD1 axis inhibitor, effectively reduced CEP chondrocyte degeneration and IDD progression by targeting NCOA4-mediated ferritinophagy.
Conclusion
Through detailed molecular and cellular analyses, we revealed that the YAP/TEAD1/NCOA4 signaling axis plays a crucial role in regulating CEP chondrocyte ferroptosis and IDD development. These findings not only enhance our understanding of IDD pathogenesis but also suggest that targeting the YAP/TEAD1/NCOA4 axis could be a promising therapeutic strategy for treating IDD.
The Translational Potential of this Article
This study reveals YAP as a novel therapeutic target for intervertebral disc degeneration by regulating ferroptosis in cartilage endplate cells, which provides a novel strategy in the prevention of IDD.
{"title":"Oxidative stress activates YAP/TEAD1/NCOA4 axis to promote ferroptosis of endplate chondrocytes and aggravate intervertebral disc degeneration","authors":"Heran Wang , Xiaodong Liu , Xingzhi Jing , Bofei Zhang , Xin Liu , Xiaoyang Liu , Fei Jia , Cheng Su , Wenchao Wang , Xingang Cui","doi":"10.1016/j.jot.2025.07.001","DOIUrl":"10.1016/j.jot.2025.07.001","url":null,"abstract":"<div><h3>Background</h3><div>Intervertebral disc degeneration (IDD) is a major cause of low back pain, with cartilaginous endplate (CEP) degeneration playing a critical role. While Yes-associated protein (YAP) and its involvement in CEP degeneration and ferroptosis remain unclear. This study aimed to investigate the regulatory role of YAP in CEP ferroptosis and its underlying mechanisms.</div></div><div><h3>Methods</h3><div>YAP expression was analyzed in human CEP tissues and mouse LSI models. CEP cells were treated with Verteporfin or YAP-siRNA. Ferroptosis was assessed by measuring iron levels, lipid peroxidation, GSH content, and viability assays. Molecular mechanisms were elucidated using CUT&RUN-qPCR, dual-LUC, and immunofluorescence colocalization. Verteporfin (VP) therapeutic efficacy was evaluated in LSI mice.</div></div><div><h3>Results</h3><div>YAP knockdown attenuated oxidative stress-induced CEP chondrocyte degeneration and ferroptosis features. Mechanistically, we identified that oxidative stress-induced CEP chondrocyte degeneration involves ferritinophagy, which is regulated by the YAP/TEAD1 signaling axis through transcriptional control of nuclear coactivator 4 (NCOA4). Treatment with verteporfin, a YAP/TEAD1 axis inhibitor, effectively reduced CEP chondrocyte degeneration and IDD progression by targeting NCOA4-mediated ferritinophagy.</div></div><div><h3>Conclusion</h3><div>Through detailed molecular and cellular analyses, we revealed that the YAP/TEAD1/NCOA4 signaling axis plays a crucial role in regulating CEP chondrocyte ferroptosis and IDD development. These findings not only enhance our understanding of IDD pathogenesis but also suggest that targeting the YAP/TEAD1/NCOA4 axis could be a promising therapeutic strategy for treating IDD.</div></div><div><h3>The Translational Potential of this Article</h3><div>This study reveals YAP as a novel therapeutic target for intervertebral disc degeneration by regulating ferroptosis in cartilage endplate cells, which provides a novel strategy in the prevention of IDD.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"Pages 8-25"},"PeriodicalIF":5.9,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144604130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-10DOI: 10.1016/j.jot.2025.06.019
Xiaodong Li , Frank Asuncion , Michael Ominsky , Qing-Tian Niu , Kristina E. Akesson , Jeffrey Wang , Jay Lieberman , Hua Zhu Ke
Background
Large bone defects are challenging to manage clinically and usually require treatment with bone graft or bone graft substitute. This study evaluated the effect of romosozumab, a sclerostin antibody, in combination with demineralized bone matrix (DBM) on bone regeneration in a critical-size ulnar defect model in nonhuman primates.
Methods
In cynomolgus monkeys (N = 22, male, 10–12 years old), a full-cortex bone defect (0.5 cm long) was created in the left ulnar shaft and filled with DBM. Animals were randomized to receive vehicle (n = 10) or romosozumab (n = 12; 30 mg/kg) subcutaneously, every 2 weeks for 28 weeks. Radiographs of the left ulna were taken every 2 weeks for 28 weeks to monitor bone regeneration response. Ulnae were excised and analyzed by ex-vivo x-ray and micro-computed tomography (micro-CT) to evaluate bone repair, and lumbar vertebrae were excised for bone histomorphometric analysis to evaluate the systemic anabolic response.
Results
In-vivo and ex-vivo x-ray images of surgical ulnae demonstrated that the critical-size ulnar defect fully bridged in 3 romosozumab-treated monkeys at week 28 but not in any vehicle-treated monkey. Micro-CT analysis demonstrated that average new bone volume and new bone area within the defect region were 118 % and 105 % greater, respectively, with romosozumab versus vehicle. Trabecular bone volume per tissue volume and trabecular thickness of lumbar vertebral body were 72 % and 92 % greater, and eroded surface was significantly lower with romosozumab versus vehicle.
Conclusion
High-dose romosozumab in combination with DBM improved bone regeneration in a critical-size ulnar defect model and increased bone mass in non-surgical bone in nonhuman primates.
The translational potential of this article
Clinical management of large bone defect is complex and challenging. More effective management is needed. This paper reports the first nonhuman primate study that evaluated high-dose romosozumab in combination with demineralized bone matrix in a critical-size defect model and provides perspective for the future research evaluating the combination of romosozumab and bone graft or bone graft substitutes in various relevant clinical conditions.
{"title":"High-dose romosozumab promoted bone regeneration of critical-size ulnar defect filled with demineralized bone matrix in nonhuman primates","authors":"Xiaodong Li , Frank Asuncion , Michael Ominsky , Qing-Tian Niu , Kristina E. Akesson , Jeffrey Wang , Jay Lieberman , Hua Zhu Ke","doi":"10.1016/j.jot.2025.06.019","DOIUrl":"10.1016/j.jot.2025.06.019","url":null,"abstract":"<div><h3>Background</h3><div>Large bone defects are challenging to manage clinically and usually require treatment with bone graft or bone graft substitute. This study evaluated the effect of romosozumab, a sclerostin antibody, in combination with demineralized bone matrix (DBM) on bone regeneration in a critical-size ulnar defect model in nonhuman primates.</div></div><div><h3>Methods</h3><div>In cynomolgus monkeys (N = 22, male, 10–12 years old), a full-cortex bone defect (0.5 cm long) was created in the left ulnar shaft and filled with DBM. Animals were randomized to receive vehicle (n = 10) or romosozumab (n = 12; 30 mg/kg) subcutaneously, every 2 weeks for 28 weeks. Radiographs of the left ulna were taken every 2 weeks for 28 weeks to monitor bone regeneration response. Ulnae were excised and analyzed by ex-vivo x-ray and micro-computed tomography (micro-CT) to evaluate bone repair, and lumbar vertebrae were excised for bone histomorphometric analysis to evaluate the systemic anabolic response.</div></div><div><h3>Results</h3><div>In-vivo and ex-vivo x-ray images of surgical ulnae demonstrated that the critical-size ulnar defect fully bridged in 3 romosozumab-treated monkeys at week 28 but not in any vehicle-treated monkey. Micro-CT analysis demonstrated that average new bone volume and new bone area within the defect region were 118 % and 105 % greater, respectively, with romosozumab versus vehicle. Trabecular bone volume per tissue volume and trabecular thickness of lumbar vertebral body were 72 % and 92 % greater, and eroded surface was significantly lower with romosozumab versus vehicle.</div></div><div><h3>Conclusion</h3><div>High-dose romosozumab in combination with DBM improved bone regeneration in a critical-size ulnar defect model and increased bone mass in non-surgical bone in nonhuman primates.</div></div><div><h3>The translational potential of this article</h3><div>Clinical management of large bone defect is complex and challenging. More effective management is needed. This paper reports the first nonhuman primate study that evaluated high-dose romosozumab in combination with demineralized bone matrix in a critical-size defect model and provides perspective for the future research evaluating the combination of romosozumab and bone graft or bone graft substitutes in various relevant clinical conditions.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"54 ","pages":"Pages 1-7"},"PeriodicalIF":5.9,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144588187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01DOI: 10.1016/j.jot.2025.06.011
Yang Hong , Ruiyang Li , Shihao Sheng , Fengjin Zhou , Long Bai , Jiacan Su
Organoids, generated through three-dimensional in vitro culture, are cellular aggregates that accurately mimic the complex microenvironment, cell–cell interactions, and signaling mechanisms of native tissues. These models offer transformative advantages in studying disease mechanisms, drug screening, and personalized medicine. Compared to traditional two-dimensional cell cultures and animal models, organoid systems exhibit higher physiological relevance, effectively mitigating species-specific discrepancies while significantly enhancing clinical translational feasibility. However, current organoid research primarily focuses on soft tissues such as the heart, liver, spleen, lungs, and kidneys, with limited progress in hard tissue organoids, particularly bone organoids. Given the pivotal role of bone tissue in clinical bone repair, disease mechanism elucidation, and drug screening, this field demands further investigation. Based on our previous research, this review introduces a five-stage iterative framework for bone organoid development: 1.0 (physiological model), 2.0 (pathological model), 3.0 (structural model), 4.0 (composite model), and 5.0 (applied model). This paper systematically reviews the technical pathways for bone organoid construction, highlights the core features and scientific value of each model iteration, and explores the current challenges and future directions in this emerging field. The goal is to provide theoretical and technological insights that advance bone organoid research, offering innovative solutions for bone-related disease studies and clinical applications.
The translational potential of this article: This review provides a systematic overview of bone organoid development, highlighting their remarkable role in orthopaedic research and in clinical practice. Through the incorporation of advanced technologies like artificial intelligence and 3D bioprinting, bone organoids provide novel approaches to the development of regenerative medicine and customized orthopaedic treatments.
{"title":"Bone organoid construction and evolution","authors":"Yang Hong , Ruiyang Li , Shihao Sheng , Fengjin Zhou , Long Bai , Jiacan Su","doi":"10.1016/j.jot.2025.06.011","DOIUrl":"10.1016/j.jot.2025.06.011","url":null,"abstract":"<div><div>Organoids, generated through three-dimensional in vitro culture, are cellular aggregates that accurately mimic the complex microenvironment, cell–cell interactions, and signaling mechanisms of native tissues. These models offer transformative advantages in studying disease mechanisms, drug screening, and personalized medicine. Compared to traditional two-dimensional cell cultures and animal models, organoid systems exhibit higher physiological relevance, effectively mitigating species-specific discrepancies while significantly enhancing clinical translational feasibility. However, current organoid research primarily focuses on soft tissues such as the heart, liver, spleen, lungs, and kidneys, with limited progress in hard tissue organoids, particularly bone organoids. Given the pivotal role of bone tissue in clinical bone repair, disease mechanism elucidation, and drug screening, this field demands further investigation. Based on our previous research, this review introduces a five-stage iterative framework for bone organoid development: 1.0 (physiological model), 2.0 (pathological model), 3.0 (structural model), 4.0 (composite model), and 5.0 (applied model). This paper systematically reviews the technical pathways for bone organoid construction, highlights the core features and scientific value of each model iteration, and explores the current challenges and future directions in this emerging field. The goal is to provide theoretical and technological insights that advance bone organoid research, offering innovative solutions for bone-related disease studies and clinical applications.</div><div>The translational potential of this article: This review provides a systematic overview of bone organoid development, highlighting their remarkable role in orthopaedic research and in clinical practice. Through the incorporation of advanced technologies like artificial intelligence and 3D bioprinting, bone organoids provide novel approaches to the development of regenerative medicine and customized orthopaedic treatments.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"53 ","pages":"Pages 260-273"},"PeriodicalIF":5.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144534722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01DOI: 10.1016/j.jot.2025.05.007
Heng Liu , Tingting Fan , Rui Yuan , Shuai Lu , Dadi Sun , Yong Huan , Maoqi Gong , Honghu Xiao , Chongbin Wei , Hao Wang , Shijie Fan , Yilong He , Jialin Hu , Haoran Zhang , Hao Sun , Qi Gu , Yejun Zha , Xieyuan Jiang
<div><h3>Objective</h3><div>Periprosthetic joint infection (PJI) poses significant challenges to arthroplasty outcomes, necessitating translational animal models for pathogenesis studies and therapeutic development. This study aimed to establish a standardized Beagle PJI model by integrating species-specific 3D-printed femoral prostheses with quantitative bacterial inoculation, while evaluating the dose-dependent effects of <em>Staphylococcus aureus</em> (<em>S. aureus</em>) on infection progression.</div></div><div><h3>Methods</h3><div>Two titanium alloy prostheses were designed using CT-based anatomical data: BFP-C (canine-optimized) and BFP-H (human-derived). Prostheses underwent mechanical compression tests, finite element analysis (FEA) simulating postoperative and osseointegration phases, and <em>in vivo</em> validation in Beagles. The optimized BFP-C was selected for PJI model construction via hemi-hip arthroplasty (HHA), with intraoperative inoculation of <em>S. aureus</em> ranging from 250 to 10^8 colony-forming units (CFU). Longitudinal evaluation included radiography (X-ray/CT), mechanical pull-out tests, histopathology (H&E/Masson/Giemsa staining), bacterial cultures, and mobility assessments using open-field behavioural tracking.</div></div><div><h3>Results</h3><div>BFP-C exhibited superior biomechanical compatibility, with 12.3-fold higher yield strength (6836 ± 157 N vs. 553 ± 49 N) and 97 % reduction in bone strain (0.71 % vs. 20.32 %) compared to BFP-H. All inoculated groups developed PJI with dose-dependent severity: ultra-high-dose (10^8 CFU) groups displayed severe osteolysis (pull-out strength: 24 ± 8 N vs. 924 ± 45 N in controls), biofilm formation, and mobility impairment (74 % reduction in distance travelled, 2003 ± 276 cm vs. 7976 ± 333 cm in controls), whereas low-dose (250 CFU) groups established PJI with milder manifestations, evidenced by sinus tract formation, 55.1 % reduction in pull-out strength (406 ± 15 N vs. 924 ± 45 N in controls), and concordant radiological/histopathological signs of infection. Imaging examinations revealed differential osteolytic patterns corresponding to bacterial loads. Combined wound evaluation and microbiological analyses confirmed consistent infection establishment across all replicates.</div></div><div><h3>Conclusion</h3><div>This Beagle PJI model successfully recapitulates clinical infection dynamics, emphasizing the critical role of species-specific prosthesis design and standardized bacterial quantification. The integrated multimodal evaluation system (imaging, biomechanical, and behavioural analyses) demonstrated both the reliability of the model and its sensitivity in detecting infection progression. Its modular design supports customization for studying biofilm-resistant implants or antibiotic delivery systems. These findings not only provide a critical tool for mechanistic PJI research but also establish a theoretical foundation for clinical translation, with the quantitativ
{"title":"Establishment of a clinically relevant beagle model for periprosthetic joint infection with 3D-printed prostheses and multimodal evaluation","authors":"Heng Liu , Tingting Fan , Rui Yuan , Shuai Lu , Dadi Sun , Yong Huan , Maoqi Gong , Honghu Xiao , Chongbin Wei , Hao Wang , Shijie Fan , Yilong He , Jialin Hu , Haoran Zhang , Hao Sun , Qi Gu , Yejun Zha , Xieyuan Jiang","doi":"10.1016/j.jot.2025.05.007","DOIUrl":"10.1016/j.jot.2025.05.007","url":null,"abstract":"<div><h3>Objective</h3><div>Periprosthetic joint infection (PJI) poses significant challenges to arthroplasty outcomes, necessitating translational animal models for pathogenesis studies and therapeutic development. This study aimed to establish a standardized Beagle PJI model by integrating species-specific 3D-printed femoral prostheses with quantitative bacterial inoculation, while evaluating the dose-dependent effects of <em>Staphylococcus aureus</em> (<em>S. aureus</em>) on infection progression.</div></div><div><h3>Methods</h3><div>Two titanium alloy prostheses were designed using CT-based anatomical data: BFP-C (canine-optimized) and BFP-H (human-derived). Prostheses underwent mechanical compression tests, finite element analysis (FEA) simulating postoperative and osseointegration phases, and <em>in vivo</em> validation in Beagles. The optimized BFP-C was selected for PJI model construction via hemi-hip arthroplasty (HHA), with intraoperative inoculation of <em>S. aureus</em> ranging from 250 to 10^8 colony-forming units (CFU). Longitudinal evaluation included radiography (X-ray/CT), mechanical pull-out tests, histopathology (H&E/Masson/Giemsa staining), bacterial cultures, and mobility assessments using open-field behavioural tracking.</div></div><div><h3>Results</h3><div>BFP-C exhibited superior biomechanical compatibility, with 12.3-fold higher yield strength (6836 ± 157 N vs. 553 ± 49 N) and 97 % reduction in bone strain (0.71 % vs. 20.32 %) compared to BFP-H. All inoculated groups developed PJI with dose-dependent severity: ultra-high-dose (10^8 CFU) groups displayed severe osteolysis (pull-out strength: 24 ± 8 N vs. 924 ± 45 N in controls), biofilm formation, and mobility impairment (74 % reduction in distance travelled, 2003 ± 276 cm vs. 7976 ± 333 cm in controls), whereas low-dose (250 CFU) groups established PJI with milder manifestations, evidenced by sinus tract formation, 55.1 % reduction in pull-out strength (406 ± 15 N vs. 924 ± 45 N in controls), and concordant radiological/histopathological signs of infection. Imaging examinations revealed differential osteolytic patterns corresponding to bacterial loads. Combined wound evaluation and microbiological analyses confirmed consistent infection establishment across all replicates.</div></div><div><h3>Conclusion</h3><div>This Beagle PJI model successfully recapitulates clinical infection dynamics, emphasizing the critical role of species-specific prosthesis design and standardized bacterial quantification. The integrated multimodal evaluation system (imaging, biomechanical, and behavioural analyses) demonstrated both the reliability of the model and its sensitivity in detecting infection progression. Its modular design supports customization for studying biofilm-resistant implants or antibiotic delivery systems. These findings not only provide a critical tool for mechanistic PJI research but also establish a theoretical foundation for clinical translation, with the quantitativ","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"53 ","pages":"Pages 274-285"},"PeriodicalIF":5.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144548857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01DOI: 10.1016/j.jot.2025.06.003
Raed H. Ogaili , Ahmed Alassal , Nurul Fariha Za'aba , Izzat Zulkiflee , Isma Liza Mohd Isa
Low back pain (LBP) is a global health problem, primarily caused by intervertebral disc (IVD) degeneration. Current treatments focus on symptom relief without addressing the underlying degenerative mechanisms. Regenerative strategies have emerged as promising therapies through the use of functional biomaterials and stem cells capable of modulating key signalling pathways to promote tissue regeneration. However, challenges such as efficient delivery systems, long-term survival of transplanted cells, and hostile disc microenvironment remain. This review focuses on recent advances in regenerative approaches using biomaterials, cells, and therapeutic agents of exosomes, and genes to restore IVD structure and function. We discuss the current understanding of IVD anatomy, physiology and degeneration pathophysiology followed by current treatments. We highlight the rationale for regenerative therapy in halting the degenerative hallmarks tailored to mild, moderate to severe IVD degeneration. Our review emphasizes on the functional biomaterials designed for advanced delivery system, therapeutic intervention and IVD tissue engineering. We discuss the cell-based therapy, highlighting various cell sources, therapeutic effects, clinical trials and its obstacles. We discuss the use of therapeutic agents such as the genes and exosome therapies in IVD regeneration. The clinical translational potential of regenerative therapy is vast and promising, driven by advances in cellular therapies, biomaterials, and cell-free approaches like exosomes, which offer new avenues for regenerating degenerative IVDs. While significant progress has been made in developing safe, effective, and scalable treatments, challenges remain in immune compatibility, manufacturing, and regulatory pathways. Emerging innovations in gene editing, 3D bioprinting, and personalized approaches are poised to accelerate the translation of these therapies into mainstream medicine, with interdisciplinary collaboration and global efforts playing a crucial role in overcoming current bottlenecks and realizing the full potential of regenerative medicine to transform patient care. This article offers a comprehensive framework to guide preclinical research and future clinical translation of effective regenerative therapies, aiming at reducing the global burden of LBP and improving long-term patient outcomes.
{"title":"Regenerative strategies for intervertebral disc degeneration","authors":"Raed H. Ogaili , Ahmed Alassal , Nurul Fariha Za'aba , Izzat Zulkiflee , Isma Liza Mohd Isa","doi":"10.1016/j.jot.2025.06.003","DOIUrl":"10.1016/j.jot.2025.06.003","url":null,"abstract":"<div><div>Low back pain (LBP) is a global health problem, primarily caused by intervertebral disc (IVD) degeneration. Current treatments focus on symptom relief without addressing the underlying degenerative mechanisms. Regenerative strategies have emerged as promising therapies through the use of functional biomaterials and stem cells capable of modulating key signalling pathways to promote tissue regeneration. However, challenges such as efficient delivery systems, long-term survival of transplanted cells, and hostile disc microenvironment remain. This review focuses on recent advances in regenerative approaches using biomaterials, cells, and therapeutic agents of exosomes, and genes to restore IVD structure and function. We discuss the current understanding of IVD anatomy, physiology and degeneration pathophysiology followed by current treatments. We highlight the rationale for regenerative therapy in halting the degenerative hallmarks tailored to mild, moderate to severe IVD degeneration. Our review emphasizes on the functional biomaterials designed for advanced delivery system, therapeutic intervention and IVD tissue engineering. We discuss the cell-based therapy, highlighting various cell sources, therapeutic effects, clinical trials and its obstacles. We discuss the use of therapeutic agents such as the genes and exosome therapies in IVD regeneration. The clinical translational potential of regenerative therapy is vast and promising, driven by advances in cellular therapies, biomaterials, and cell-free approaches like exosomes, which offer new avenues for regenerating degenerative IVDs. While significant progress has been made in developing safe, effective, and scalable treatments, challenges remain in immune compatibility, manufacturing, and regulatory pathways. Emerging innovations in gene editing, 3D bioprinting, and personalized approaches are poised to accelerate the translation of these therapies into mainstream medicine, with interdisciplinary collaboration and global efforts playing a crucial role in overcoming current bottlenecks and realizing the full potential of regenerative medicine to transform patient care. This article offers a comprehensive framework to guide preclinical research and future clinical translation of effective regenerative therapies, aiming at reducing the global burden of LBP and improving long-term patient outcomes.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"53 ","pages":"Pages 286-308"},"PeriodicalIF":5.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144548856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01DOI: 10.1016/j.jot.2025.07.009
Sien Lin , Gang Li
{"title":"Editorial: From molecular insights to innovative implants in degenerative skeletal disorders","authors":"Sien Lin , Gang Li","doi":"10.1016/j.jot.2025.07.009","DOIUrl":"10.1016/j.jot.2025.07.009","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"53 ","pages":"Pages A1-A2"},"PeriodicalIF":5.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144771557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01DOI: 10.1016/j.jot.2025.05.006
Xuefei Zhao , Hanting Xia , Yiwen Yang , Tianyou Ma , Yichen Lu , Zhefei Xie , Xing Zhou , Jiangyuan Liu , Zhengsheng Bao , Huihui Xu , Jinjin Ma , Houfu Ling , Shuyan Zhang , Taotao Xu , Peijian Tong , Hongting Jin
Background/objective
Cartilage defects (CDs) present a significant challenge in orthopaedic medicine. Owing to the inherently limited regenerative capacity of cartilaginous tissue, defects usually do not heal via natural repair processes. Consequently, damaged tissue is replaced by fibrocartilage-like tissues instead of the original hyaline cartilage. Therefore, inhibiting fibrocartilage formation while promoting hyalinisation may represent a novel strategy for CD therapy. Although studies have explored the role of interleukin (IL)-17A and ferroptosis in the fibrosis of visceral organs, such as the liver, lungs, and kidneys, their implication in cartilage fibrosis and fibrocartilage formation remains unclear. Herein, we aimed to determine whether IL-17A and ferroptosis are collectively involved in the process of cartilage fibrosis and to investigate the effects of amygdalin (AMD) and magnesium ions (Mg2+) in cartilage regeneration and the potential molecular mechanisms underlying these effects.
Methods
Cartilage samples were collected from patients with osteoarthritis and subjected to immunohistochemistry analysis to assess fibrocartilage formation indicators within the degenerated areas. Quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry analyses were employed to assess changes in cartilage anabolism and expression of fibrocartilage markers after treatment with different concentrations of AMD. We also treated chondrocytes with an IL-17A/RA antagonist, a ferroptosis inhibitor, a ferroptosis inducer, and AMD, and measured the changes in fibrocartilage-, ferroptosis-, and IL-17 signalling-associated factors. Finally, mice with microfracture (MF)-induced CDs were administered intra-articular injections of either saline, AMD (10 μmol/L), MgCl2 (0.5 mmol/L), or AMD (10 μmol/mL) plus MgCl2 (0.5 mmol/L) twice a week. After 4 and 8 weeks, chondral repair was assessed through histological and immunohistochemical analyses in each group.
Results
IL-17A activated lipid peroxidation, leading to chondrocyte ferroptosis, while AMD suppressed IL-17 signalling, thereby mitigating the decrease in glutathione peroxidase 4 (GPX4) expression induced by IL-17A or erastin. In mice with MF surgery-induced CD, the combination of AMD and Mg2+ mitigated oxidative stress, thereby enhancing the positive effects of Mg2+. This combination led to a significant improvement in chondrogenesis, activation of anabolic processes, and reduction of catabolic activity in the articular cartilage, ultimately supporting cartilage repair and regeneration.
Conclusions
AMD targets IL-17 signalling to inhibit chondrocyte ferroptosis. Furthermore, the combination of AMD and Mg2+ suppresses IL-17A/GPX4 signalling, suppressing fibrocartilage formation and fostering hyaline cartilage regenera
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Pub Date : 2025-07-01DOI: 10.1016/j.jot.2025.06.015
Xinyi Cheng , Yida Chen , Xichao Zhou , Qiaoli Gu , Huan Zhao , Chao Wan , Mimi Chen , Huilin Yang , Qin Shi
Osteoporosis (OP) is a serious public health problem affecting the elderly worldwide. The immune system is well-known to play an important role in bone metabolism and formation. However, immunosenescence, defined as the gradual deterioration of immune system function with aging, has become one of the key factors that drive OP, referred to as immunoporosis. Immune cells may experience substantial functional and phenotypic alterations with aging, disturbing the intricate balance between bone formation and resorption, ultimately leading to bone loss and fragility. These alterations promote osteoclastogenesis and impair osteogenesis through the release of senescence-associated secretory phenotype (SASP) factors and other signaling pathways, a phenomenon referred to as “inflammaging”. Accordingly, the present review summarizes the latest findings on the interplay between immunosenescence and bone biology, with a purpose to shed light on the molecular and cellular processes that drive the development of OP. This study is anticipated to provide potential reference for developing innovative therapeutic strategies targeting immunosenescence to rescue bone fragility and enhance skeletal health in older adults.
The Translational potential statement: This review highlights the role of immunosenescence in the development of OP and suggests it as a possible treatment target. We summarize the mechanisms of senescent immune cells affecting bone metabolism balance and removing these cells or blocking their secretions [e.g., SASPs] in reducing bone loss. Several preclinical studies have shown that drugs targeting immunosenescence can improve bone health in animal models. Recent clinical studies also report links between immunosenescence markers (e.g., CD4+ CD28- T cells, TNF-α, and IL 6) and low bone mineral density. These findings support the idea of using immunosenescence features to identify high risk patients and guide early treatment. By combining basic research with clinical data, this review may provide valuable insights for future immune based therapies for OP.
骨质疏松症（Osteoporosis， OP）是困扰全球老年人的严重公共卫生问题。众所周知，免疫系统在骨代谢和形成中起着重要作用。然而，免疫衰老，即免疫系统功能随着年龄的增长而逐渐恶化，已成为OP的关键驱动因素之一，称为免疫疏松症。随着年龄的增长，免疫细胞可能经历实质性的功能和表型改变，扰乱骨形成和骨吸收之间的复杂平衡，最终导致骨丢失和脆弱。这些改变通过释放衰老相关分泌表型（SASP）因子和其他信号通路促进破骨细胞生成并损害骨生成，这种现象被称为“炎症”。因此，本文综述了免疫衰老与骨生物学相互作用的最新研究成果，旨在揭示驱动op发展的分子和细胞过程，为开发针对免疫衰老的创新治疗策略提供潜在的参考，以挽救老年人骨骼脆弱性，增强骨骼健康。翻译潜力声明：这篇综述强调了免疫衰老在OP发展中的作用，并建议它作为一个可能的治疗靶点。我们总结了衰老免疫细胞影响骨代谢平衡的机制，并清除这些细胞或阻断其分泌[例如，sasp]以减少骨质流失。一些临床前研究表明，靶向免疫衰老的药物可以改善动物模型的骨骼健康。最近的临床研究也报告了免疫衰老标志物（如CD4+ CD28- T 细胞、TNF-α和IL - 6）与低骨密度之间的联系。这些发现支持使用免疫衰老特征来识别高风险患者并指导早期治疗的想法。通过将基础研究与临床数据相结合，本综述可能为未来OP的免疫治疗提供有价值的见解。
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Pub Date : 2025-07-01DOI: 10.1016/j.jot.2025.06.014
Yidan Pang , Dongjing Jia , Fang Ye , Fei Liu , Jiaqi Li , Siyuan Zhu , Bingqi Wang , Meng Yao , Lin Du , Chunying Yang , Guoji Guo , Cunxiang Ju , Lufeng Yao , Changqing Zhang , Junjie Gao , Hao Qi
Objective
Alzheimer's disease (AD) is marked by amyloid β (Aβ) accumulation, neuroinflammation, and cognitive decline. While neuroinflammation is a key feature of AD, the potential involvement of bone marrow-derived cells in its pathology remains unclear. This study aimed to investigate the role of bone marrow-derived myeloid cells in driving neuroinflammation in AD.
Methods
We developed a transgenic mouse model (FAD4T) by overexpressing human APPSwe/Ind and PSEN1 M146L/L286V on a C57BL/6J background. FAD4T mice were characterized for hallmark AD features, including amyloid deposition, glial activation, and cognitive deficits. Additionally, single-cell transcriptomic analysis was performed to profile bone marrow and brain myeloid cells. Bone marrow transplantation experiments were conducted to assess the contribution of bone marrow-derived macrophages to neuroinflammation in AD.
Results
FAD4T mice exhibited hallmark AD phenotypes such as amyloid deposition, glial activation, and cognitive impairment, alongside osteoporosis-like changes. Single-cell transcriptomic analysis identified a significant increase in bone marrow-derived macrophages in the brains of FAD4T mice. These cells showed upregulation of AD-related genes, including Cst7 and Ctsd, suggesting their active role in neuroinflammation. Bone marrow transplantation experiments further confirmed that bone marrow-derived macrophages contributed to the inflammatory processes in the AD brain.
Conclusion
Our findings demonstrate that bone marrow-derived myeloid cells infiltrate the brain and might play a critical role in driving neuroinflammation in AD. Targeting these cells may represent a novel therapeutic strategy for mitigating inflammation and disease progression in AD.
The translational potential of this article
Our findings suggest that bone marrow-derived inflammation play a critical role in AD-associated inflammation, offering potential targets for therapeutic intervention such as Cst7 and Ctsd in bone marrow-derived myeloid cells.
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