Pub Date : 2025-06-18DOI: 10.1016/j.jot.2025.06.005
Xiaojie Xu , Dong Wang , Bowei Ni , Hailun Xu , Zixiang Wu , Ting He , Yuejiao Zhang , Xue Hao , Guangyu Ding , Xinyu Zhang , Qing-Jun Meng , Liu Yang
Background
The circadian clock maintains homeostasis in peripheral tissues, including articular cartilage. Cartilage as a highly mechanical loaded tissue experiences diurnal rhythmic mechanical loading activity/rest cycle patterns, which gives external time cue on chondrocytes. Given the cartilage clock driven by loading patterns, we hypothesize that abnormal mechanical loading, a major risk factor for osteoarthritis (OA), can disrupt the cartilage clock, further contributing to OA progression.
Methods
We used both noninvasive in vivo mechanical loading system and PER2Luc reporter mice for ex vivo bioluminescence recording. RNA sequencing was performed in mouse primary chondrocytes treated with 1.0 MPa static compression, and identified core clock molecule REV-ERBα, which was confirmed in human and murine OA cartilage samples. Chondrocytes were treated with Rev-erbα small interfering RNA (si-Rev-erbα), and adeno-associated virus carrying Rev-erbα-specific short hairpin RNA (AAV-shRev-erbα) was injected intra-articularly in mice to knock down Rev-erbα. Relevant signaling pathways regulating REV-ERBα were analyzed by RNA sequencing data. Intraperitoneal injection of SR8278, a specific REV-ERBα antagonist, was performed in mice after mechanical overloading for OA treatment.
Results
Excessive mechanical loading disrupted the circadian rhythm of articular cartilage. The core clock molecule REV-ERBα was increased in OA cartilage and knockdown of Rev-erbαalleviated compression-induced chondrocyte dysfunction. Inhibition of MAPK-MYC pathway by U0126 or SB203580 attenuated compression-induced REV-ERBα up-regulation and cartilage clock disruption. Finally, pharmacological inhibition of REV-ERBα expression by SR8278 restored cartilage clock upon abnormal loading and mitigated OA progression.
Conclusions
REV-ERBα is a key factor in the association between mechanical overloading-induced circadian disruption and OA pathology. This study illustrates the essential mechanism of impaired circadian rhythm under overloading and provides a possibly impactful therapeutic approach for the treatment of OA.
The Translational Potential of this Article
Inhibition REV-ERBα expression by clock-based therapeutic drug SR8278 or MAPK-MYC pathway inhibitors could ameliorate mechanical overloading-induced circadian disruption of cartilage and OA degeneration, indicating a clinical conversion potential for OA treatment.
{"title":"Inhibiting the REV-ERBα expression protects against mechanical overloading-induced cartilage clock disruption and osteoarthritis progression","authors":"Xiaojie Xu , Dong Wang , Bowei Ni , Hailun Xu , Zixiang Wu , Ting He , Yuejiao Zhang , Xue Hao , Guangyu Ding , Xinyu Zhang , Qing-Jun Meng , Liu Yang","doi":"10.1016/j.jot.2025.06.005","DOIUrl":"10.1016/j.jot.2025.06.005","url":null,"abstract":"<div><h3>Background</h3><div>The circadian clock maintains homeostasis in peripheral tissues, including articular cartilage. Cartilage as a highly mechanical loaded tissue experiences diurnal rhythmic mechanical loading activity/rest cycle patterns, which gives external time cue on chondrocytes. Given the cartilage clock driven by loading patterns, we hypothesize that abnormal mechanical loading, a major risk factor for osteoarthritis (OA), can disrupt the cartilage clock, further contributing to OA progression.</div></div><div><h3>Methods</h3><div>We used both noninvasive <em>in vivo</em> mechanical loading system and PER2Luc reporter mice for <em>ex vivo</em> bioluminescence recording. RNA sequencing was performed in mouse primary chondrocytes treated with 1.0 MPa static compression, and identified core clock molecule REV-ERBα, which was confirmed in human and murine OA cartilage samples. Chondrocytes were treated with <em>Rev-erbα</em> small interfering RNA (si-<em>Rev-erbα</em>), and adeno-associated virus carrying <em>Rev-erbα</em>-specific short hairpin RNA (AAV-sh<em>Rev-erbα</em>) was injected intra-articularly in mice to knock down <em>Rev-erbα</em>. Relevant signaling pathways regulating REV-ERBα were analyzed by RNA sequencing data. Intraperitoneal injection of SR8278, a specific REV-ERBα antagonist, was performed in mice after mechanical overloading for OA treatment.</div></div><div><h3>Results</h3><div>Excessive mechanical loading disrupted the circadian rhythm of articular cartilage. The core clock molecule REV-ERBα was increased in OA cartilage and knockdown of <em>Rev-erbα</em>alleviated compression-induced chondrocyte dysfunction. Inhibition of MAPK-MYC pathway by U0126 or SB203580 attenuated compression-induced REV-ERBα up-regulation and cartilage clock disruption. Finally, pharmacological inhibition of REV-ERBα expression by SR8278 restored cartilage clock upon abnormal loading and mitigated OA progression.</div></div><div><h3>Conclusions</h3><div>REV-ERBα is a key factor in the association between mechanical overloading-induced circadian disruption and OA pathology. This study illustrates the essential mechanism of impaired circadian rhythm under overloading and provides a possibly impactful therapeutic approach for the treatment of OA.</div></div><div><h3>The Translational Potential of this Article</h3><div>Inhibition REV-ERBα expression by clock-based therapeutic drug SR8278 or MAPK-MYC pathway inhibitors could ameliorate mechanical overloading-induced circadian disruption of cartilage and OA degeneration, indicating a clinical conversion potential for OA treatment.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"53 ","pages":"Pages 112-125"},"PeriodicalIF":5.9,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144312886","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 : 2025-06-09DOI: 10.1016/j.jot.2025.05.005
Hongyu Jiang , Wei Liu , Jiajie Chen , Yue Tian , Zhibo Jia , Yanbin Wu , Yanjun Guan , Leijia Chen , Wenjing Xu , Haoye Meng , Yingjie Xiong , Jianting Ye , Cheng Huang , Ruichao He , Sice Wang , Yufei Ding , Wei Fan , Yunkang Yang , Jiang Peng , Aiyuan Wang
<div><h3>Objective</h3><div>To investigate the feasibility of constructing cartilaginous organoids (CORGs) using cartilage extracellular matrix microcarriers (CEMMs), evaluate their ectopic chondrogenic potential, and analyze their impact on <em>in situ</em> repair and regeneration of knee cartilage in SD rats.</div></div><div><h3>Methods</h3><div>Cartilage extracellular matrix microcarriers (CEMMs) were created through a combination of decellularization, wet milling, and layered sieving methods. The evaluation of their biological function was conducted through live/dead staining, CCK-8 assay, scratch assay, and Transwell assay in a laboratory setting. The immune microenvironment was confirmed to be influenced by CEMMs through a conditioned culture involving rat macrophages. qRT-PCR and secretory function assays was conducted to evaluate the chondrogenic activity of CORGs. Gene expression profiles throughout the development of CORGs were analyzed using transcriptome sequencing. Immunodeficient mouse subcutaneous model to assess the ectopic chondrogenic capacity of CORGs. CORGs were implanted into the knee joint cartilage defects of SD rats to evaluate their effects on cartilage regeneration.</div></div><div><h3>Results</h3><div>Successfully developed CEMMs with dimensions of 210.4 ± 56.89 um exhibited strong biocompatibility, the capacity to draw in stem cells, stimulate their growth and migration, and encourage macrophages to shift to the M2 type. Functionalized CORGs were successfully constructed based on CEMMs. Transcriptomics showed that CORGs had a gene expression pattern similar to mesodermal to chondrogenic development. CORGs successfully generated cartilaginous tissue subcutaneously in immunodeficient mice. Specifically, at 1 week postoperatively, CORGs were observed to promote M2 polarization of periarticular macrophages. At 6 and 12 weeks post-surgery, gross observation, micro-CT scanning, and histological analyses collectively revealed that CORGs promoted cartilage regeneration.</div></div><div><h3>Conclusions</h3><div>The functionalized CORGs was successfully constructed based on CEMMs, exhibiting robust expression of chondrogenic-related genes and demonstrating the ability to secrete collagen and GAGs. Transcriptomic analysis revealed that CORGs exhibited a gene expression trajectory consistent with the transition from mesodermal to chondrogenic genes, resulting in the successful development of cartilaginous tissues rich in cartilage-specific matrix when implanted subcutaneously in immunodeficient mice. Furthermore, CORGs demonstrated the ability to modulate the immune microenvironment surrounding the knee joint. In SD rat models of knee cartilage defects, CORGs exhibited robust regenerative and repair capacity.</div></div><div><h3>The translational potential of this article</h3><div>This research involved the creation of CORGs utilizing natural biomaterials (ECM) and MSCs, demonstrating significant promise for treating cartilage inj
{"title":"Construction of cartilaginous organoids based on cartilage extracellular matrix microcarriers to promote articular cartilage regeneration through immune regulation","authors":"Hongyu Jiang , Wei Liu , Jiajie Chen , Yue Tian , Zhibo Jia , Yanbin Wu , Yanjun Guan , Leijia Chen , Wenjing Xu , Haoye Meng , Yingjie Xiong , Jianting Ye , Cheng Huang , Ruichao He , Sice Wang , Yufei Ding , Wei Fan , Yunkang Yang , Jiang Peng , Aiyuan Wang","doi":"10.1016/j.jot.2025.05.005","DOIUrl":"10.1016/j.jot.2025.05.005","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate the feasibility of constructing cartilaginous organoids (CORGs) using cartilage extracellular matrix microcarriers (CEMMs), evaluate their ectopic chondrogenic potential, and analyze their impact on <em>in situ</em> repair and regeneration of knee cartilage in SD rats.</div></div><div><h3>Methods</h3><div>Cartilage extracellular matrix microcarriers (CEMMs) were created through a combination of decellularization, wet milling, and layered sieving methods. The evaluation of their biological function was conducted through live/dead staining, CCK-8 assay, scratch assay, and Transwell assay in a laboratory setting. The immune microenvironment was confirmed to be influenced by CEMMs through a conditioned culture involving rat macrophages. qRT-PCR and secretory function assays was conducted to evaluate the chondrogenic activity of CORGs. Gene expression profiles throughout the development of CORGs were analyzed using transcriptome sequencing. Immunodeficient mouse subcutaneous model to assess the ectopic chondrogenic capacity of CORGs. CORGs were implanted into the knee joint cartilage defects of SD rats to evaluate their effects on cartilage regeneration.</div></div><div><h3>Results</h3><div>Successfully developed CEMMs with dimensions of 210.4 ± 56.89 um exhibited strong biocompatibility, the capacity to draw in stem cells, stimulate their growth and migration, and encourage macrophages to shift to the M2 type. Functionalized CORGs were successfully constructed based on CEMMs. Transcriptomics showed that CORGs had a gene expression pattern similar to mesodermal to chondrogenic development. CORGs successfully generated cartilaginous tissue subcutaneously in immunodeficient mice. Specifically, at 1 week postoperatively, CORGs were observed to promote M2 polarization of periarticular macrophages. At 6 and 12 weeks post-surgery, gross observation, micro-CT scanning, and histological analyses collectively revealed that CORGs promoted cartilage regeneration.</div></div><div><h3>Conclusions</h3><div>The functionalized CORGs was successfully constructed based on CEMMs, exhibiting robust expression of chondrogenic-related genes and demonstrating the ability to secrete collagen and GAGs. Transcriptomic analysis revealed that CORGs exhibited a gene expression trajectory consistent with the transition from mesodermal to chondrogenic genes, resulting in the successful development of cartilaginous tissues rich in cartilage-specific matrix when implanted subcutaneously in immunodeficient mice. Furthermore, CORGs demonstrated the ability to modulate the immune microenvironment surrounding the knee joint. In SD rat models of knee cartilage defects, CORGs exhibited robust regenerative and repair capacity.</div></div><div><h3>The translational potential of this article</h3><div>This research involved the creation of CORGs utilizing natural biomaterials (ECM) and MSCs, demonstrating significant promise for treating cartilage inj","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"53 ","pages":"Pages 82-98"},"PeriodicalIF":5.9,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144241333","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 : 2025-06-09DOI: 10.1016/j.jot.2025.05.003
Wang Diaodiao , Tang Miaotian , Ren Pengcheng , Tian Zhuang , Zhang Gang , Liu Yubo , Sun Yuyang , Ye Peng , Sun Wenqiang , Yao Qi
Background
Osteoarthritis (OA) is a chronic disease characterized by degeneration of articular cartilage, affecting over 530 million patients worldwide. Current oral medications such as non-steroidal anti-inflammatory drugs (NSAIDs) can only alleviate symptoms and are associated with numerous adverse effects. Although teriparatide (PTH1-34) exhibits dual functions of chondroprotection and osteogenic effects, its clinical application is significantly limited by its short biological half-life (30–60 min) and accelerated degradation within the inflammatory microenvironment of joint cavities.
Methods
Porous sustained-release microspheres (M@PTH1-34) were fabricated using FDA-approved poly (lactic-co-glycolic acid) (PLGA) as the matrix, encapsulating PTH1-34 within their multi-channel porous structure. Uniform microsphere preparation and high-efficiency drug loading were achieved through membrane emulsification and temperature-controlled embedding techniques. To systematically evaluate the sustained-release profile and therapeutic outcomes, both in vitro and in vivo OA models were established, enabling comprehensive analysis of cartilage repair efficacy, anti-inflammatory regulation, and immunomodulatory effects.
Results
PTH1-34 could be efficiently loaded into microspheres after self-healing and achieve consistent release over 30 days with biological activity being maintained. In OA model rats, M@PTH1-34 significantly improved behavioral and radiological outcomes, increased cartilage smoothness and thickness, and increased the expression of chondrogenic markers. Additionally, in vitro and in vivo safety tests revealed no significant safety issues. These findings indicate that M@PTH1-34 holds promise as a long-lasting, cost-effective, and safe therapeutic approach for OA.
Conclusion
This study successfully developed a uniform-sized PLGA-based sustained-release microsphere system (M@PTH1-34) that enables continuous drug release for over 30 days following single intra-articular administration. M@PTH1-34 exerts its therapeutic effects on osteoarthritis through the following two ways: (1) Promoting cartilage repair by enhancing the chondrogenic differentiation ability of bone marrow mesenchymal stem cells (BMSCs); (2) Improve the inflammatory microenvironment of joints by inhibiting the expression of inflammatory factors (such as IL-1β) and regulating the polarization state of M1/M2 macrophages.
The translation potential of this article
The system demonstrates prominent clinical translation advantages: (1) Innovative utilization of FDA-approved PLGA carrier combined with membrane emulsification technique ensures precise size control and standardized production; (2) Localized delivery strategy achieves targeted retention within articular
{"title":"Porous PLGA microspheres loaded with PTH1-34 peptide for long-term treatment of OA","authors":"Wang Diaodiao , Tang Miaotian , Ren Pengcheng , Tian Zhuang , Zhang Gang , Liu Yubo , Sun Yuyang , Ye Peng , Sun Wenqiang , Yao Qi","doi":"10.1016/j.jot.2025.05.003","DOIUrl":"10.1016/j.jot.2025.05.003","url":null,"abstract":"<div><h3>Background</h3><div>Osteoarthritis (OA) is a chronic disease characterized by degeneration of articular cartilage, affecting over 530 million patients worldwide. Current oral medications such as non-steroidal anti-inflammatory drugs (NSAIDs) can only alleviate symptoms and are associated with numerous adverse effects. Although teriparatide (PTH<sub>1-34</sub>) exhibits dual functions of chondroprotection and osteogenic effects, its clinical application is significantly limited by its short biological half-life (30–60 min) and accelerated degradation within the inflammatory microenvironment of joint cavities.</div></div><div><h3>Methods</h3><div>Porous sustained-release microspheres (M@PTH<sub>1-34</sub>) were fabricated using FDA-approved poly (lactic-co-glycolic acid) (PLGA) as the matrix, encapsulating PTH<sub>1-34</sub> within their multi-channel porous structure. Uniform microsphere preparation and high-efficiency drug loading were achieved through membrane emulsification and temperature-controlled embedding techniques. To systematically evaluate the sustained-release profile and therapeutic outcomes, both in vitro and in vivo OA models were established, enabling comprehensive analysis of cartilage repair efficacy, anti-inflammatory regulation, and immunomodulatory effects.</div></div><div><h3>Results</h3><div>PTH<sub>1-34</sub> could be efficiently loaded into microspheres after self-healing and achieve consistent release over 30 days with biological activity being maintained. In OA model rats, M@PTH<sub>1-34</sub> significantly improved behavioral and radiological outcomes, increased cartilage smoothness and thickness, and increased the expression of chondrogenic markers. Additionally, in vitro and in vivo safety tests revealed no significant safety issues. These findings indicate that M@PTH<sub>1-34</sub> holds promise as a long-lasting, cost-effective, and safe therapeutic approach for OA.</div></div><div><h3>Conclusion</h3><div>This study successfully developed a uniform-sized PLGA-based sustained-release microsphere system (M@PTH<sub>1-34</sub>) that enables continuous drug release for over 30 days following single intra-articular administration. M@PTH<sub>1-34</sub> exerts its therapeutic effects on osteoarthritis through the following two ways: (1) Promoting cartilage repair by enhancing the chondrogenic differentiation ability of bone marrow mesenchymal stem cells (BMSCs); (2) Improve the inflammatory microenvironment of joints by inhibiting the expression of inflammatory factors (such as IL-1β) and regulating the polarization state of M1/M2 macrophages.</div></div><div><h3>The translation potential of this article</h3><div>The system demonstrates prominent clinical translation advantages: (1) Innovative utilization of FDA-approved PLGA carrier combined with membrane emulsification technique ensures precise size control and standardized production; (2) Localized delivery strategy achieves targeted retention within articular ","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"53 ","pages":"Pages 99-111"},"PeriodicalIF":5.9,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144241635","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 : 2025-06-05DOI: 10.1016/j.jot.2025.04.015
Jingyi Dang , Zhao Zhang , Jun Fu , Liguo Sun , Yubo Shi , Lei Wang , Weidong Tao , Debin Cheng , Xiaohe Wang , Zhenzhou Mi , Dong Liu , Hongbin Fan
<div><h3>Background</h3><div>Chronic tendinopathy with diabetes mellitus (CTDM) poses significant therapeutic challenges due to persistent inflammation and impaired tenogenesis. While the supplementation of tendon stem/progenitor cells (TSPCs) has the potential to facilitate tenogenesis, premature recruitment and proliferation in inflammatory microenvironments risks fibrosis or heterotopic ossification (HO). Consequently, balancing inflammation regulation and tenogenic differentiation is critical for effective healing.</div></div><div><h3>Methods</h3><div>An injectable glucose-responsive dual-drug-sequential delivery hydrogel (GDSH) was developed utilizing oxidized hyaluronic acid-modified dopamine and phenylboronic acid-functionalized carboxymethyl chitosan. Dendritic mesoporous silica nanospheres (DMSNs) encapsulating irisin and connective tissue growth factor (CTGF) were incorporated into the GDSH matrix. A comprehensive characterization of the hydrogel's properties, including rheological, mechanical, adhesive, swelling/degradation, and drug release behaviors, was conducted. In vitro assessments were performed to evaluate cytocompatibility, as well as antioxidant and anti-inflammatory effects, alongside the migration, proliferation, and differentiation of TSPCs. The therapeutic efficacy was further investigated using a collagenase type I/streptozotocin-induced CTDM model in rats, with analyses conducted through histological, biomechanical, and micro-CT methods. Transcriptome sequencing and Western blot analyses were employed to elucidate the involvement of specific signaling pathways in the tissue repair process.</div></div><div><h3>Results</h3><div>The GDSH composite hydrogels possess a range of advantageous properties, including exceptional mechanical strength, optimal adhesiveness, superior biocompatibility, and appropriate swelling and degradation rates, in addition to controllable and sequential drug release capabilities. In vitro investigations revealed that these composite hydrogels exhibit antioxidant and anti-inflammatory effects, while also promoting cell proliferation and migration. Furthermore, they facilitate tenogenic differentiation and simultaneously inhibit the aberrant differentiation of TSPCs. In vivo studies demonstrated that the composite hydrogels significantly improved the morphological and biomechanical properties of injured tendons, reduced inflammation, corrected abnormal differentiation, and displayed favorable biosafety profiles. Transcriptome sequencing and Western blotting analysis indicated that the composite hydrogels repaired CTDM through the MAPK, AMPK, Smad, Hippo and PI3K/AKT signaling pathways.</div></div><div><h3>Conclusion</h3><div>GDSH achieves spatiotemporal control of inflammation resolution and tenogenesis via glucose-responsive sequential delivery of irisin and CTGF. This strategy restores tendon microstructure, biomechanics, and redox homeostasis in CTDM, offering a translatable platform for diabeti
{"title":"Regulating inflammation microenvironment and tenogenic differentiation as sequential therapy promotes tendon healing in diabetic rats","authors":"Jingyi Dang , Zhao Zhang , Jun Fu , Liguo Sun , Yubo Shi , Lei Wang , Weidong Tao , Debin Cheng , Xiaohe Wang , Zhenzhou Mi , Dong Liu , Hongbin Fan","doi":"10.1016/j.jot.2025.04.015","DOIUrl":"10.1016/j.jot.2025.04.015","url":null,"abstract":"<div><h3>Background</h3><div>Chronic tendinopathy with diabetes mellitus (CTDM) poses significant therapeutic challenges due to persistent inflammation and impaired tenogenesis. While the supplementation of tendon stem/progenitor cells (TSPCs) has the potential to facilitate tenogenesis, premature recruitment and proliferation in inflammatory microenvironments risks fibrosis or heterotopic ossification (HO). Consequently, balancing inflammation regulation and tenogenic differentiation is critical for effective healing.</div></div><div><h3>Methods</h3><div>An injectable glucose-responsive dual-drug-sequential delivery hydrogel (GDSH) was developed utilizing oxidized hyaluronic acid-modified dopamine and phenylboronic acid-functionalized carboxymethyl chitosan. Dendritic mesoporous silica nanospheres (DMSNs) encapsulating irisin and connective tissue growth factor (CTGF) were incorporated into the GDSH matrix. A comprehensive characterization of the hydrogel's properties, including rheological, mechanical, adhesive, swelling/degradation, and drug release behaviors, was conducted. In vitro assessments were performed to evaluate cytocompatibility, as well as antioxidant and anti-inflammatory effects, alongside the migration, proliferation, and differentiation of TSPCs. The therapeutic efficacy was further investigated using a collagenase type I/streptozotocin-induced CTDM model in rats, with analyses conducted through histological, biomechanical, and micro-CT methods. Transcriptome sequencing and Western blot analyses were employed to elucidate the involvement of specific signaling pathways in the tissue repair process.</div></div><div><h3>Results</h3><div>The GDSH composite hydrogels possess a range of advantageous properties, including exceptional mechanical strength, optimal adhesiveness, superior biocompatibility, and appropriate swelling and degradation rates, in addition to controllable and sequential drug release capabilities. In vitro investigations revealed that these composite hydrogels exhibit antioxidant and anti-inflammatory effects, while also promoting cell proliferation and migration. Furthermore, they facilitate tenogenic differentiation and simultaneously inhibit the aberrant differentiation of TSPCs. In vivo studies demonstrated that the composite hydrogels significantly improved the morphological and biomechanical properties of injured tendons, reduced inflammation, corrected abnormal differentiation, and displayed favorable biosafety profiles. Transcriptome sequencing and Western blotting analysis indicated that the composite hydrogels repaired CTDM through the MAPK, AMPK, Smad, Hippo and PI3K/AKT signaling pathways.</div></div><div><h3>Conclusion</h3><div>GDSH achieves spatiotemporal control of inflammation resolution and tenogenesis via glucose-responsive sequential delivery of irisin and CTGF. This strategy restores tendon microstructure, biomechanics, and redox homeostasis in CTDM, offering a translatable platform for diabeti","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"53 ","pages":"Pages 63-81"},"PeriodicalIF":5.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144222310","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 : 2025-06-05DOI: 10.1016/j.jot.2025.05.004
Bin Liu , Guanhui Song , Yaosheng Wang , Changheng Song , Yiping Cao , Jinlin Tong , Yuyao Wang , Xinrong Fan , Nannan Shi , Hongyan Zhao , Danping Fan
Intervertebral disc (IVD) degeneration (IDD) is a progressive condition characterized by the deterioration of the intervertebral discs, which serve as cushions between the vertebrae in the spinal column. This degeneration is often associated with aging and can be influenced by various factors, including genetics, mechanical stress, and lifestyle choices. N6-methyladenosine (m6A) modification has emerged as a critical post-transcriptional regulatory mechanism that influences various biological processes, including cellular differentiation, proliferation, and response to stress. Recent studies suggest that m6A modification play significant roles in the pathophysiology of IDD. The dysregulation of m6A methylation is linked to the altered expression of genes involved in inflammation, oxidative stress, extracellular matrix remodeling, regulated cell death including apoptosis, autophagy, pyroptosis and ferroptosis, all of which contribute to the IDD. In this review, we summarize the advanced detection technology of m6A and the roles of m6A in pathological process of IDD, to provide new insights into the molecular mechanisms underlying IDD and identify novel therapeutic targets for intervention.
The translational potential of this article
This work underscores the diagnostic and therapeutic potential of targeting m6A mechanism in IDD. Clinically, m6A regulators may serve as biomarkers for early IDD detection or progression monitoring. Therapeutically, small-molecule modulators of m6A writers/erasers or RNA-based strategies could restore ECM homeostasis, mitigate inflammation, and prevent IVD cell death. Furthermore, advanced m6A mapping technologies may enable personalized interventions by decoding patient-specific epitranscriptomic profiles. These insights bridge molecular mechanisms to clinical innovation, offering novel avenues for IDD treatment and regenerative therapies.
{"title":"N6-methyladenosine and intervertebral disc degeneration: Advances in detection and pathological insights","authors":"Bin Liu , Guanhui Song , Yaosheng Wang , Changheng Song , Yiping Cao , Jinlin Tong , Yuyao Wang , Xinrong Fan , Nannan Shi , Hongyan Zhao , Danping Fan","doi":"10.1016/j.jot.2025.05.004","DOIUrl":"10.1016/j.jot.2025.05.004","url":null,"abstract":"<div><div>Intervertebral disc (IVD) degeneration (IDD) is a progressive condition characterized by the deterioration of the intervertebral discs, which serve as cushions between the vertebrae in the spinal column. This degeneration is often associated with aging and can be influenced by various factors, including genetics, mechanical stress, and lifestyle choices. N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) modification has emerged as a critical post-transcriptional regulatory mechanism that influences various biological processes, including cellular differentiation, proliferation, and response to stress. Recent studies suggest that m<sup>6</sup>A modification play significant roles in the pathophysiology of IDD. The dysregulation of m<sup>6</sup>A methylation is linked to the altered expression of genes involved in inflammation, oxidative stress, extracellular matrix remodeling, regulated cell death including apoptosis, autophagy, pyroptosis and ferroptosis, all of which contribute to the IDD. In this review, we summarize the advanced detection technology of m<sup>6</sup>A and the roles of m<sup>6</sup>A in pathological process of IDD, to provide new insights into the molecular mechanisms underlying IDD and identify novel therapeutic targets for intervention.</div></div><div><h3>The translational potential of this article</h3><div>This work underscores the diagnostic and therapeutic potential of targeting m<sup>6</sup>A mechanism in IDD. Clinically, m6A regulators may serve as biomarkers for early IDD detection or progression monitoring. Therapeutically, small-molecule modulators of m<sup>6</sup>A writers/erasers or RNA-based strategies could restore ECM homeostasis, mitigate inflammation, and prevent IVD cell death. Furthermore, advanced m<sup>6</sup>A mapping technologies may enable personalized interventions by decoding patient-specific epitranscriptomic profiles. These insights bridge molecular mechanisms to clinical innovation, offering novel avenues for IDD treatment and regenerative therapies.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"53 ","pages":"Pages 38-51"},"PeriodicalIF":5.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144222843","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 : 2025-06-05DOI: 10.1016/j.jot.2025.04.010
Teng Zhang , Jian Li , Xinyu Li , Xin Pan , Xianlei Gao , Xiaojie Yang , Xiaolin Ma , Hao Li , Shiqing Feng , Zhongjun Liu
<div><h3>Background</h3><div>Corpectomy and bone defects reconstruction is a key surgical technique in spinal diseases treatment. Popular bone defect reconstruction methods include titanium mesh cage (TMC) fixation plate systems and traditional 3D-printed artificial vertebral body (3D-AVB). In our previous study, we conceptualised and created a self-stabilised 3D-printed artificial vertebral body (3D-SAVB) system and tested its clinical safety and efficacy, but have not compared with the conventional implants. This study was designed to compare our innovative 3D-SAVB system with a conventional 3D-AVB system, both mechanically and clinically.</div></div><div><h3>Methods</h3><div>This study included 33 patients with cervical spondylotic myelopathy who underwent single-level ACCF using the TMC, 3D-AVB, and 3D-SAVB systems. The operation time, intraoperative blood loss, neurological function recovery rate, average subsidence length, and cervical lordosis correction (C2-7 Cobb angle change) rates of the TMC, 3D-AVB, and 3D-SAVB groups were tested to compare their performance, and we selected four representative clinical cases with various diseases who underwent 3D-SAVB surgery for follow-up studies to demonstrate the clinical effect. In addition, finite element analysis was used to compare the stability, stress distribution, and artificial vertebral body stress of the 3D-SAVB, 3D-AVB, and TMC systems.</div></div><div><h3>Results</h3><div>The neurological function recovery rates of the TMC (84.8 ± 10.7 %), 3D-AVB (74.3 ± 7.9 %), and SAVB (85.99 ± 13.2 %) groups showed no significant difference (p > 0.05). The mean operation time of the TMC group (119.3 ± 21.5 min) is significant more than the 3D-SAVB (76.1 ± 23.1 mm) and 3D-AVB (82.6 ± 21.3 mm) groups (p < 0.05). The intraoperative blood loss of the TMC group (218.2 ± 51.5 ml) was significantly greater than that of the 3D-SAVB (187.6 ± 43.2 ml) and 3D-AVB groups (195.6 ± 31.3 ml) (p < 0.05). The mean subsidence length of the TMC group (3.5 ± 0.6 mm) was significantly greater than the 3D-AVB (1.3 ± 0.5 mm, p < 0.001) and 3D-SAVB (1.2 ± 1.1 mm, p = 0.002). The lordosis correction (C2-7 Cobb angle change) rate of the 3D-SAVB [(60.38 ± 6.2)%] and 3D-AVB [(61.4 ± 7.9)%] groups was significantly higher than that of the TMC group [(32.35 ± 3.7)%] (p < 0.05). Patients treated with the 3D-SAVB system achieved satisfactory treatment results with no postoperative complications during the follow-up period. The failed TMC fixation plate system underwent revision surgery using 3D-SAVB and demonstrated a superior prognosis. The biomechanical test showed that the 3D-SAVB system had greater longitudinal stability (p < 0.01), better stress distribution (p < 0.01), and less vertebral stress (p < 0.01) than the 3D-AVB and TMC systems.</div></div><div><h3>Conclusion</h3><div>These results demonstrate the mechanical advantages and great clinical application potential of our innovative 3D-SAVB system
背景椎体切除和骨缺损重建是脊柱疾病治疗的关键外科技术。常用的骨缺损重建方法包括钛网笼（TMC）固定钢板系统和传统的3d打印人工椎体（3D-AVB）。在我们之前的研究中，我们概念化并创建了一种自稳定的3d打印人工椎体（3D-SAVB）系统，并测试了其临床安全性和有效性，但尚未与传统植入物进行比较。本研究旨在比较我们创新的3D-SAVB系统与传统的3D-AVB系统在机械和临床方面的差异。方法本研究纳入33例脊髓型颈椎病患者，采用TMC、3D-AVB和3D-SAVB系统行单级ACCF。比较TMC组、3D-AVB组和3D-SAVB组的手术时间、术中出血量、神经功能恢复率、平均下陷长度、颈椎前凸矫正（C2-7 Cobb角变化）率，并选择4例具有代表性的临床病例行3D-SAVB手术进行随访研究，以证明其临床效果。此外，采用有限元分析比较3D-SAVB、3D-AVB和TMC系统的稳定性、应力分布和人工椎体应力。结果TMC组（84.8±10.7%）、3D-AVB组（74.3±7.9%）、SAVB组（85.99±13.2%）的神经功能恢复率差异无统计学意义(p >；0.05)。TMC组平均手术时间（119.3±21.5 min）显著高于3D-SAVB组（76.1±23.1 mm）和3D-AVB组（82.6±21.3 mm） (p <；0.05)。TMC组术中出血量（218.2±51.5 ml）明显大于3D-SAVB组（187.6±43.2 ml）和3D-AVB组（195.6±31.3 ml） (p <；0.05)。TMC组的平均下陷长度（3.5±0.6 mm）显著大于3D-AVB组（1.3±0.5 mm）， p <；0.001)和3D-SAVB（1.2±1.1 mm, p = 0.002）。3D-SAVB组前凸矫正（C2-7 Cobb角改变）率[(60.38±6.2)%]和3D-AVB组[(61.4±7.9)%]显著高于TMC组[(32.35±3.7)%](p <；0.05)。3D-SAVB系统治疗的患者在随访期间均取得满意的治疗效果，无术后并发症发生。失败的TMC固定钢板系统采用3D-SAVB进行翻修手术，预后良好。生物力学试验表明，3D-SAVB系统具有更大的纵向稳定性(p <；0.01)，应力分布较好(p <；0.01)，椎体应力较小(p <；0.01)，高于3D-AVB和TMC系统。结论本发明的3D-SAVB系统在具有挑战性的脊柱手术中具有机械优势和巨大的临床应用潜力。3D-SAVB系统消除了对辅助固定钢板的需要，减少了手术并发症，如下沉，并改善了颈椎前凸矫正。其生物力学优势和临床疗效支持其作为下一代脊柱植入物的采用。
{"title":"An innovative self-stabilised 3D-printed artificial vertebral body designed for clinical application and comparison with the conventional implants","authors":"Teng Zhang , Jian Li , Xinyu Li , Xin Pan , Xianlei Gao , Xiaojie Yang , Xiaolin Ma , Hao Li , Shiqing Feng , Zhongjun Liu","doi":"10.1016/j.jot.2025.04.010","DOIUrl":"10.1016/j.jot.2025.04.010","url":null,"abstract":"<div><h3>Background</h3><div>Corpectomy and bone defects reconstruction is a key surgical technique in spinal diseases treatment. Popular bone defect reconstruction methods include titanium mesh cage (TMC) fixation plate systems and traditional 3D-printed artificial vertebral body (3D-AVB). In our previous study, we conceptualised and created a self-stabilised 3D-printed artificial vertebral body (3D-SAVB) system and tested its clinical safety and efficacy, but have not compared with the conventional implants. This study was designed to compare our innovative 3D-SAVB system with a conventional 3D-AVB system, both mechanically and clinically.</div></div><div><h3>Methods</h3><div>This study included 33 patients with cervical spondylotic myelopathy who underwent single-level ACCF using the TMC, 3D-AVB, and 3D-SAVB systems. The operation time, intraoperative blood loss, neurological function recovery rate, average subsidence length, and cervical lordosis correction (C2-7 Cobb angle change) rates of the TMC, 3D-AVB, and 3D-SAVB groups were tested to compare their performance, and we selected four representative clinical cases with various diseases who underwent 3D-SAVB surgery for follow-up studies to demonstrate the clinical effect. In addition, finite element analysis was used to compare the stability, stress distribution, and artificial vertebral body stress of the 3D-SAVB, 3D-AVB, and TMC systems.</div></div><div><h3>Results</h3><div>The neurological function recovery rates of the TMC (84.8 ± 10.7 %), 3D-AVB (74.3 ± 7.9 %), and SAVB (85.99 ± 13.2 %) groups showed no significant difference (p > 0.05). The mean operation time of the TMC group (119.3 ± 21.5 min) is significant more than the 3D-SAVB (76.1 ± 23.1 mm) and 3D-AVB (82.6 ± 21.3 mm) groups (p < 0.05). The intraoperative blood loss of the TMC group (218.2 ± 51.5 ml) was significantly greater than that of the 3D-SAVB (187.6 ± 43.2 ml) and 3D-AVB groups (195.6 ± 31.3 ml) (p < 0.05). The mean subsidence length of the TMC group (3.5 ± 0.6 mm) was significantly greater than the 3D-AVB (1.3 ± 0.5 mm, p < 0.001) and 3D-SAVB (1.2 ± 1.1 mm, p = 0.002). The lordosis correction (C2-7 Cobb angle change) rate of the 3D-SAVB [(60.38 ± 6.2)%] and 3D-AVB [(61.4 ± 7.9)%] groups was significantly higher than that of the TMC group [(32.35 ± 3.7)%] (p < 0.05). Patients treated with the 3D-SAVB system achieved satisfactory treatment results with no postoperative complications during the follow-up period. The failed TMC fixation plate system underwent revision surgery using 3D-SAVB and demonstrated a superior prognosis. The biomechanical test showed that the 3D-SAVB system had greater longitudinal stability (p < 0.01), better stress distribution (p < 0.01), and less vertebral stress (p < 0.01) than the 3D-AVB and TMC systems.</div></div><div><h3>Conclusion</h3><div>These results demonstrate the mechanical advantages and great clinical application potential of our innovative 3D-SAVB system ","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"53 ","pages":"Pages 52-62"},"PeriodicalIF":5.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144222925","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 : 2025-06-04DOI: 10.1016/j.jot.2025.05.009
Yining Liu , Xiaolei Ji , Jinge Zhang , Jinhong Lu , Boyang Liu , Haijian Sun , Dengshun Miao
{"title":"Corrigendum to “Chk2 deletion rescues bone loss and cellular senescence induced by Bmi1 deficiency via regulation of Cyp1a1” [J Orthop Translat, 52 (2025) 360–375 /doi.org/10.1016/j.jot.2025.04.014]","authors":"Yining Liu , Xiaolei Ji , Jinge Zhang , Jinhong Lu , Boyang Liu , Haijian Sun , Dengshun Miao","doi":"10.1016/j.jot.2025.05.009","DOIUrl":"10.1016/j.jot.2025.05.009","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"53 ","pages":"Page 37"},"PeriodicalIF":5.9,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144211907","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 : 2025-06-03DOI: 10.1016/j.jot.2025.05.008
Mingkai Wang , Ruiyang Li , Shihao Sheng , Zhenglin Dong , Long Bai , Xiuhui Wang , Jianhua Wang , Yuxiao Lai , Xiao Chen , Jie Gao , Chongru He , Han Liu , Jiacan Su
Background
Inflammatory bowel disease (IBD) with osteoporosis (OP) exhibits a clinically significant comorbidity, for which no effective treatment is currently available. Intestinal organoids (IOs), engineered through three-dimensional (3D) coculture systems, demonstrated intrinsic regenerative potentials. Additionally, extracellular vesicles derived from IOs (IOEVs) have been identified as potent nanoscale mediators capable of modulating intestinal inflammation.
Methods
In this study, we successfully established IOs and isolated IOEVs. miRNA sequencing in IOEVs revealed IBD-associated miRNAs, which may alleviate inflammatory response and have osteogenic effects. An in vitro model of IBD was established using lipopolysaccharide (LPS) to induce inflammation. Additionally, the dextran sulfate sodium (DSS)-induced IBD mouse model was employed to evaluate in vivo effects.
Results
In the LPS-induced in vitro model, treatment with IOs and IOEVs resulted in reduced cell necrosis and apoptosis. In DSS-induced IBD mouse models, treatment led to restoration of body weight and colon morphology. Histological assessment revealed an increase in intestinal crypts and normalization of tissue architecture. Immunological analyses showed upregulation of ZO-1 and Ki67 and downregulation of Caspase-3, suggesting enhanced mucosal barrier integrity and cellular proliferation with decreased apoptosis. Cytokine profiling showed downregulation of pro-inflammatory cytokines TNF-α, IL-1β, IL-6 and upregulation of anti-inflammatory cytokine IL-10. Importantly, the combination of IOs and IOEVs reversed osteoporosis progression in IBD, improving bone mass and quality.
Conclusion
Collectively, these multimodal findings establish a novel paradigm for gut–bone axis modulation through organoid-derived biologics, offering a promising therapeutic strategy for managing IBD-associated osteoporosis.
The translational potential of this article
This study highlights the translational potential of intestinal organoids and their extracellular vesicles as a dual-action biologic therapy that alleviates intestinal inflammation and reverses bone loss in IBD-associated osteoporosis. The identification of functional miRNAs within IOEVs supports their development as minimally invasive, cell-free therapeutics for systemic complications in inflammatory disease.
{"title":"Combination therapy using intestinal organoids and their extracellular vesicles for inflammatory bowel disease complicated with osteoporosis","authors":"Mingkai Wang , Ruiyang Li , Shihao Sheng , Zhenglin Dong , Long Bai , Xiuhui Wang , Jianhua Wang , Yuxiao Lai , Xiao Chen , Jie Gao , Chongru He , Han Liu , Jiacan Su","doi":"10.1016/j.jot.2025.05.008","DOIUrl":"10.1016/j.jot.2025.05.008","url":null,"abstract":"<div><h3>Background</h3><div>Inflammatory bowel disease (IBD) with osteoporosis (OP) exhibits a clinically significant comorbidity, for which no effective treatment is currently available. Intestinal organoids (IOs), engineered through three-dimensional (3D) coculture systems, demonstrated intrinsic regenerative potentials. Additionally, extracellular vesicles derived from IOs (IOEVs) have been identified as potent nanoscale mediators capable of modulating intestinal inflammation.</div></div><div><h3>Methods</h3><div>In this study, we successfully established IOs and isolated IOEVs. miRNA sequencing in IOEVs revealed IBD-associated miRNAs, which may alleviate inflammatory response and have osteogenic effects. An in vitro model of IBD was established using lipopolysaccharide (LPS) to induce inflammation. Additionally, the dextran sulfate sodium (DSS)-induced IBD mouse model was employed to evaluate in vivo effects.</div></div><div><h3>Results</h3><div>In the LPS-induced in vitro model, treatment with IOs and IOEVs resulted in reduced cell necrosis and apoptosis. In DSS-induced IBD mouse models, treatment led to restoration of body weight and colon morphology. Histological assessment revealed an increase in intestinal crypts and normalization of tissue architecture. Immunological analyses showed upregulation of ZO-1 and Ki67 and downregulation of Caspase-3, suggesting enhanced mucosal barrier integrity and cellular proliferation with decreased apoptosis. Cytokine profiling showed downregulation of pro-inflammatory cytokines TNF-α, IL-1β, IL-6 and upregulation of anti-inflammatory cytokine IL-10. Importantly, the combination of IOs and IOEVs reversed osteoporosis progression in IBD, improving bone mass and quality.</div></div><div><h3>Conclusion</h3><div>Collectively, these multimodal findings establish a novel paradigm for gut–bone axis modulation through organoid-derived biologics, offering a promising therapeutic strategy for managing IBD-associated osteoporosis.</div></div><div><h3>The translational potential of this article</h3><div>This study highlights the translational potential of intestinal organoids and their extracellular vesicles as a dual-action biologic therapy that alleviates intestinal inflammation and reverses bone loss in IBD-associated osteoporosis. The identification of functional miRNAs within IOEVs supports their development as minimally invasive, cell-free therapeutics for systemic complications in inflammatory disease.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"53 ","pages":"Pages 26-36"},"PeriodicalIF":5.9,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144196329","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 : 2025-06-02DOI: 10.1016/j.jot.2025.05.010
Tianyu Qin , Ming Shi , Yongheng Xie , Naibo Feng , Chungeng Liu , Ke Chen , Yining Chen , Wanli Zheng , Mingxi Zhu , Songlin Peng , Guozhi Xiao , Houqing Long
Background
Intervertebral disc degeneration (IDD) is a major cause of chronic low back pain, involving lipid dysregulation and cellular senescence in nucleus pulposus (NP) cells. However, the relationship between lipid accumulation and cellular senescence in IDD remain unclear. This study aims to investigate whether lipid accumulation promotes NP cell senescence and explore the role of LAMP1-mediated lipophagy in mitigating these effects.
Methods
Human and rat NP tissue samples were analyzed for lipid levels and senescence markers, including p16, p21 and p53. NP cells were treated with palmitic acid (PA) to induce lipid accumulation. Multi-omics analysis and machine learning were used to identify LAMP1 as a key regulator of lipid metabolism in NP cells. The effects of LAMP1 overexpression on lipid clearance and cellular senescence were evaluated in vitro. The natural compound sulforaphane (SFN) was applied to stimulate LAMP1-mediated lipophagy. LAMP1 knockdown was used to assess the role of LAMP1 in SFN-induced lipophagy and its impact on lipid accumulation and senescence. In vivo, SFN treatment was administered to rats with IDD induced by needle puncture. MRI, X-ray, and histological analysis were performed to evaluate the effects of SFN on disc degeneration, lipid accumulation, and senescence in NP tissue.
Results
Excessive lipid accumulation in degenerated NP tissues was observed, along with increased expression of senescence markers. Further experiments demonstrated that LAMP1 overexpression reduced lipid accumulation and senescence in NP cells. Notably, the natural compound sulforaphane enhanced LAMP1-mediated lipophagy, promoting lipid clearance and reducing senescence. In vivo, sulforaphane treatment in a rat IDD model reduced lipid accumulation and delayed IDD.
Conclusion
Our findings suggest that LAMP1-mediated lipophagy plays a crucial role in inhibiting NP cell senescence and that sulforaphane can slow the progression of IDD by activating LAMP1.
The translational potential of this article
This study indicates that the therapeutic effects of sulforaphane in mitigating lipid accumulation and senescence can provide an effective treatment strategy for delaying the progression of IDD in the future.
{"title":"Activation of LAMP1-mediated lipophagy by sulforaphane inhibits cellular senescence and intervertebral disc degeneration","authors":"Tianyu Qin , Ming Shi , Yongheng Xie , Naibo Feng , Chungeng Liu , Ke Chen , Yining Chen , Wanli Zheng , Mingxi Zhu , Songlin Peng , Guozhi Xiao , Houqing Long","doi":"10.1016/j.jot.2025.05.010","DOIUrl":"10.1016/j.jot.2025.05.010","url":null,"abstract":"<div><h3>Background</h3><div>Intervertebral disc degeneration (IDD) is a major cause of chronic low back pain, involving lipid dysregulation and cellular senescence in nucleus pulposus (NP) cells. However, the relationship between lipid accumulation and cellular senescence in IDD remain unclear. This study aims to investigate whether lipid accumulation promotes NP cell senescence and explore the role of LAMP1-mediated lipophagy in mitigating these effects.</div></div><div><h3>Methods</h3><div>Human and rat NP tissue samples were analyzed for lipid levels and senescence markers, including p16, p21 and p53. NP cells were treated with palmitic acid (PA) to induce lipid accumulation. Multi-omics analysis and machine learning were used to identify LAMP1 as a key regulator of lipid metabolism in NP cells. The effects of LAMP1 overexpression on lipid clearance and cellular senescence were evaluated in vitro. The natural compound sulforaphane (SFN) was applied to stimulate LAMP1-mediated lipophagy. LAMP1 knockdown was used to assess the role of LAMP1 in SFN-induced lipophagy and its impact on lipid accumulation and senescence. In vivo, SFN treatment was administered to rats with IDD induced by needle puncture. MRI, X-ray, and histological analysis were performed to evaluate the effects of SFN on disc degeneration, lipid accumulation, and senescence in NP tissue.</div></div><div><h3>Results</h3><div>Excessive lipid accumulation in degenerated NP tissues was observed, along with increased expression of senescence markers. Further experiments demonstrated that LAMP1 overexpression reduced lipid accumulation and senescence in NP cells. Notably, the natural compound sulforaphane enhanced LAMP1-mediated lipophagy, promoting lipid clearance and reducing senescence. In vivo, sulforaphane treatment in a rat IDD model reduced lipid accumulation and delayed IDD.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that LAMP1-mediated lipophagy plays a crucial role in inhibiting NP cell senescence and that sulforaphane can slow the progression of IDD by activating LAMP1.</div></div><div><h3>The translational potential of this article</h3><div>This study indicates that the therapeutic effects of sulforaphane in mitigating lipid accumulation and senescence can provide an effective treatment strategy for delaying the progression of IDD in the future.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"53 ","pages":"Pages 12-25"},"PeriodicalIF":5.9,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144196328","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 : 2025-05-28DOI: 10.1016/j.jot.2025.05.001
Qiuyuan Wang , Moli Huang , Jiong Jiong Guo
Single-cell RNA sequencing (scRNA-seq) technology hold significant potential for advancing orthopedic research. This review examines the impact of ScRNA-seq on the future development of orthopedic research and practice. In the study of osteoarthritis, scRNA-seq can finely characterize the changes in the subsets of chondrocytes and their role in disease progression. In rheumatoid arthritis, this technique reveals the complex heterogeneity and cell-to-cell interactions between fibroblasts and immune cells. ScRNA-seq offers insights into the heterogeneity of nucleus pulposus, annulus fibrosus, and endplate cells, providing a novel perspective on the pathological mechanisms of intervertebral disc degeneration. Single-cell analysis in osteosarcoma research has uncovered the complexity of the tumor microenvironment and mechanisms of immunosuppression. Through these studies, scRNA-seq enhances insights into disease pathogenesis and offers innoviate approaches for precision medicine and personalized treatment strategies.
The Translational Potential of this Article
This article systematically reviews the cellular heterogeneity, molecular mechanisms and immune microenvironment of orthopedic diseases (such as osteoarthritis, rheumatoid arthritis, intervertebral disc degeneration, osteosarcoma) by single-cell RNA sequencing (scRNA-seq), which provides a theoretical basis for accurate diagnosis, new therapeutic target discovery (such as TRPV1, CXCR4) and individualized treatment strategies. The combination of multi-omics and spatial transcriptome technology is expected to accelerate clinical translation and optimize the diagnosis and treatment system of orthopedic diseases.
{"title":"From cells to clinic: Single-cell transcriptomics shaping the future of orthopedics","authors":"Qiuyuan Wang , Moli Huang , Jiong Jiong Guo","doi":"10.1016/j.jot.2025.05.001","DOIUrl":"10.1016/j.jot.2025.05.001","url":null,"abstract":"<div><div>Single-cell RNA sequencing (scRNA-seq) technology hold significant potential for advancing orthopedic research. This review examines the impact of ScRNA-seq on the future development of orthopedic research and practice. In the study of osteoarthritis, scRNA-seq can finely characterize the changes in the subsets of chondrocytes and their role in disease progression. In rheumatoid arthritis, this technique reveals the complex heterogeneity and cell-to-cell interactions between fibroblasts and immune cells. ScRNA-seq offers insights into the heterogeneity of nucleus pulposus, annulus fibrosus, and endplate cells, providing a novel perspective on the pathological mechanisms of intervertebral disc degeneration. Single-cell analysis in osteosarcoma research has uncovered the complexity of the tumor microenvironment and mechanisms of immunosuppression. Through these studies, scRNA-seq enhances insights into disease pathogenesis and offers innoviate approaches for precision medicine and personalized treatment strategies.</div></div><div><h3>The Translational Potential of this Article</h3><div>This article systematically reviews the cellular heterogeneity, molecular mechanisms and immune microenvironment of orthopedic diseases (such as osteoarthritis, rheumatoid arthritis, intervertebral disc degeneration, osteosarcoma) by single-cell RNA sequencing (scRNA-seq), which provides a theoretical basis for accurate diagnosis, new therapeutic target discovery (such as TRPV1, CXCR4) and individualized treatment strategies. The combination of multi-omics and spatial transcriptome technology is expected to accelerate clinical translation and optimize the diagnosis and treatment system of orthopedic diseases.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"53 ","pages":"Pages 1-11"},"PeriodicalIF":5.9,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144155084","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}
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