Pub Date : 2025-05-01DOI: 10.1016/j.jot.2025.03.008
Chinese Orthopedic Association, Yu Zhao , Yan Zhao , Sheng Lu , Qiang Yang , Liang Chen , Xinlong Ma , Guixing Qiu
{"title":"Corrigendum to ‘Guideline for adolescent scoliosis screening in China (Public Version 2024)’ [J Orthop Translation, Volume 50, January 2025, Pages 364-372]","authors":"Chinese Orthopedic Association, Yu Zhao , Yan Zhao , Sheng Lu , Qiang Yang , Liang Chen , Xinlong Ma , Guixing Qiu","doi":"10.1016/j.jot.2025.03.008","DOIUrl":"10.1016/j.jot.2025.03.008","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Page 492"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144632104","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 : 2025-05-01DOI: 10.1016/j.jot.2025.04.018
Zeyuan Zhang , Fuming Cao , Dingfa Liang , Meng Pan , William W. Lu , Houchen Lyu , Yong Xie , Licheng Zhang , Peifu Tang
The musculoskeletal system, the primary load-bearing structure of the human body, plays a crucial role in mechanotransduction, a process comprising mechanosensation, mechanotransduction, and mechanical effect. Aging leads to loss of ability of mechanosensitive cells to sense mechanical stimuli, disruption of transduction pathways, SASP and adiposity accumulation. At the mesoscopic level, bone, cartilage, and muscle differentiation decline, while adipogenesis increases, leading to extracellular matrix and structural aging, ultimately manifesting as macroscopic musculoskeletal degeneration. This review explores intercellular crosstalk and mechanotransduction alterations in aging from a mechanobiological perspective, providing insights into potential therapeutic targets for bone aging and osteoporosis. It also introduces the mesoscopic scale definition and trans mesoscopic transplantation therapy as novel strategies for fracture treatment, postoperative rehabilitation, and bone regeneration, offering innovative directions for future musculoskeletal research.
The translational potential of this article
This article systematically reviews the effects of aging on the musculoskeletal system from a mechanobiological viewpoint, covering from microscopic molecular signaling to macroscopic spatial structural alterations, and proposes new strategies to complement the principles of AO therapy, optimization of braking, new insights into tumor metastasis and weight-bearing, and a new strategy for trans mesoscopic transplantation therapy. These insights will contribute to optimizing the management of geriatric fragility fractures in the elderly, exploring innovative therapies for the treatment of diseases of the aging musculoskeletal system, and facilitating the development of integrative therapies and precision medicine in the field of orthopaedics.
{"title":"Mechanical effects in aging of the musculoskeletal system: Molecular signaling and spatial scale alterations","authors":"Zeyuan Zhang , Fuming Cao , Dingfa Liang , Meng Pan , William W. Lu , Houchen Lyu , Yong Xie , Licheng Zhang , Peifu Tang","doi":"10.1016/j.jot.2025.04.018","DOIUrl":"10.1016/j.jot.2025.04.018","url":null,"abstract":"<div><div>The musculoskeletal system, the primary load-bearing structure of the human body, plays a crucial role in mechanotransduction, a process comprising mechanosensation, mechanotransduction, and mechanical effect. Aging leads to loss of ability of mechanosensitive cells to sense mechanical stimuli, disruption of transduction pathways, SASP and adiposity accumulation. At the mesoscopic level, bone, cartilage, and muscle differentiation decline, while adipogenesis increases, leading to extracellular matrix and structural aging, ultimately manifesting as macroscopic musculoskeletal degeneration. This review explores intercellular crosstalk and mechanotransduction alterations in aging from a mechanobiological perspective, providing insights into potential therapeutic targets for bone aging and osteoporosis. It also introduces the mesoscopic scale definition and trans mesoscopic transplantation therapy as novel strategies for fracture treatment, postoperative rehabilitation, and bone regeneration, offering innovative directions for future musculoskeletal research.</div></div><div><h3>The translational potential of this article</h3><div>This article systematically reviews the effects of aging on the musculoskeletal system from a mechanobiological viewpoint, covering from microscopic molecular signaling to macroscopic spatial structural alterations, and proposes new strategies to complement the principles of AO therapy, optimization of braking, new insights into tumor metastasis and weight-bearing, and a new strategy for trans mesoscopic transplantation therapy. These insights will contribute to optimizing the management of geriatric fragility fractures in the elderly, exploring innovative therapies for the treatment of diseases of the aging musculoskeletal system, and facilitating the development of integrative therapies and precision medicine in the field of orthopaedics.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 464-477"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144632102","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 : 2025-05-01DOI: 10.1016/j.jot.2025.05.002
Yanchao Zhang , Qing Fang , Yue Peng , Honglin Liu , Jiancheng Tang , Ruichen Ma , Weiguo Wang
Background
Transplantation of cartilaginous organoids for repairing cartilage defects in osteoarthritis represents a novel treatment approach. However, A controversial argument remains about whether cartilaginous organoids derived from the differentiation of bone marrow mesenchymal stem cells (BMSCs) in the three-dimensional (3D) environment are strictly organoids and whether the inflammatory microenvironment would affect the success rate of organoid transplantation. This study characterized 3D BMSC-derived cartilaginous organoids and developed an inflammatory organoid model to better understand the transcriptomic changes in the organoids induced by the microenvironment when transplanted into the knee with osteoarthritis.
Methods
Spatial growth BMSCs were generated and cultured in the cartilage differentiation medium to establish cartilaginous organoids. The model was characterized in both morphology and biology aspects. Subsequently, IL-1β induced inflammatory cartilaginous organoids were established and the transcriptomic sequencing was performed to investigate gene expression changes.
Results
BMSC-derived cartilaginous organoids were characterized by histology and immunofluorescence. Both Alcian blue and Safranin O staining revealed abundant articular cartilage extracellular matrix (ECM) in the organoids. The expression of cartilage specific ACAN and Col2A1 was confirmed by immunofluorescence. The organoids had the biological ability to repair cartilage defects. IL-1β induced inflammatory cartilaginous organoids were established and mRNA sequencing revealed downregulation of pathways related to cell adhesion and extracellular matrix organization. Upregulation of IL-6, TNF-α, CCL2 and CXCL1 was confirmed.
Conclusion
We thoroughly validated and characterized BMSC-derived cartilaginous organoids and established the inflammatory cartilaginous organoid models. This study revealed that the attenuation in cell adhesion and ECM formation of organoids induced by inflammatory chemokines may decrease the success rate and effectiveness of organoids auto-transplantation for fixing cartilage defects in the inflammatory microenvironment of the OA joint.
The translational potential of this article
By establishing and validating an in vitro inflammatory cartilaginous organoid model, this study provides a robust platform to examine how inflammatory mediators influence cartilage-like constructs. These findings enable the identification of targeted interventions to enhance the organoids’ resilience against the inflammatory environment commonly found in osteoarthritic joints. Ultimately, this strategy offers a novel avenue for improving transplant success and promoting cartilage defect repair in patients with OA, thereby contributing valuable insights and potential clinical applications in regenerative medicine.
{"title":"Establishment and characterization of an inflammatory cartilaginous organoids model for organoid transplantation study","authors":"Yanchao Zhang , Qing Fang , Yue Peng , Honglin Liu , Jiancheng Tang , Ruichen Ma , Weiguo Wang","doi":"10.1016/j.jot.2025.05.002","DOIUrl":"10.1016/j.jot.2025.05.002","url":null,"abstract":"<div><h3>Background</h3><div>Transplantation of cartilaginous organoids for repairing cartilage defects in osteoarthritis represents a novel treatment approach. However, A controversial argument remains about whether cartilaginous organoids derived from the differentiation of bone marrow mesenchymal stem cells (BMSCs) in the three-dimensional (3D) environment are strictly organoids and whether the inflammatory microenvironment would affect the success rate of organoid transplantation. This study characterized 3D BMSC-derived cartilaginous organoids and developed an inflammatory organoid model to better understand the transcriptomic changes in the organoids induced by the microenvironment when transplanted into the knee with osteoarthritis.</div></div><div><h3>Methods</h3><div>Spatial growth BMSCs were generated and cultured in the cartilage differentiation medium to establish cartilaginous organoids. The model was characterized in both morphology and biology aspects. Subsequently, IL-1β induced inflammatory cartilaginous organoids were established and the transcriptomic sequencing was performed to investigate gene expression changes.</div></div><div><h3>Results</h3><div>BMSC-derived cartilaginous organoids were characterized by histology and immunofluorescence. Both Alcian blue and Safranin O staining revealed abundant articular cartilage extracellular matrix (ECM) in the organoids. The expression of cartilage specific ACAN and Col2A1 was confirmed by immunofluorescence. The organoids had the biological ability to repair cartilage defects. IL-1β induced inflammatory cartilaginous organoids were established and mRNA sequencing revealed downregulation of pathways related to cell adhesion and extracellular matrix organization. Upregulation of IL-6, TNF-α, CCL2 and CXCL1 was confirmed.</div></div><div><h3>Conclusion</h3><div>We thoroughly validated and characterized BMSC-derived cartilaginous organoids and established the inflammatory cartilaginous organoid models. This study revealed that the attenuation in cell adhesion and ECM formation of organoids induced by inflammatory chemokines may decrease the success rate and effectiveness of organoids auto-transplantation for fixing cartilage defects in the inflammatory microenvironment of the OA joint.</div></div><div><h3>The translational potential of this article</h3><div>By establishing and validating an in vitro inflammatory cartilaginous organoid model, this study provides a robust platform to examine how inflammatory mediators influence cartilage-like constructs. These findings enable the identification of targeted interventions to enhance the organoids’ resilience against the inflammatory environment commonly found in osteoarthritic joints. Ultimately, this strategy offers a novel avenue for improving transplant success and promoting cartilage defect repair in patients with OA, thereby contributing valuable insights and potential clinical applications in regenerative medicine.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 376-386"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143929198","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}
Spinal cord injury (SCI) remains an unresolved and complex medical challenge. In SCI, mitochondrial dysfunction leads to calcium overload and an increase in reactive oxygen species (ROS). Intercellular mitochondrial transfer has the potential to rescue surviving neurons, while exogenous mitochondrial transplantation can be performed through direct injection or cell-assisted methods. This review explored the current state of research on mitochondrial transplantation and transfer as potential treatments for SCI. It also analyzed the therapeutic implications, influencing factors, and advanced delivery methods for both endogenous mitochondrial transfer and exogenous mitochondrial transplantation. Furthermore, future research directions, including optimizing mitochondrial delivery methods, determining optimal dosages for different delivery approaches, were discussed based on larger animal models and clinical trials. The goal of this review was to introduce novel concepts and prospects for SCI therapy and to contribute to the advancement of medical research in this field.
The Translational Potential of This Article
At present, SCI lacks effective therapies, with mitochondrial dysfunction playing a central role in neuronal damage. Mitochondrial transplantation holds promise for restoring bioenergetic function. However, key challenges remain, including optimizing delivery methods, determining appropriate dosages, scalability, donor mitochondrial sourcing, regulatory hurdles and ensuring successful integration. Addressing these issues requires non-invasive platforms, validation in large-animal models, and clinical trials. This approach may bridge mitochondrial biology with translational engineering, thereby advancing the development of regenerative therapies for SCI.
{"title":"Mitochondrial Transplantation/Transfer: Promising Therapeutic Strategies for Spinal Cord Injury","authors":"Xiaochun Xiong , Chao Zhou , Yijun Yu , Qiong Xie , Linying Xia , Qingping Li , Hongming Lin , Songou Zhang , Wenqing Liang","doi":"10.1016/j.jot.2025.04.017","DOIUrl":"10.1016/j.jot.2025.04.017","url":null,"abstract":"<div><div>Spinal cord injury (SCI) remains an unresolved and complex medical challenge. In SCI, mitochondrial dysfunction leads to calcium overload and an increase in reactive oxygen species (ROS). Intercellular mitochondrial transfer has the potential to rescue surviving neurons, while exogenous mitochondrial transplantation can be performed through direct injection or cell-assisted methods. This review explored the current state of research on mitochondrial transplantation and transfer as potential treatments for SCI. It also analyzed the therapeutic implications, influencing factors, and advanced delivery methods for both endogenous mitochondrial transfer and exogenous mitochondrial transplantation. Furthermore, future research directions, including optimizing mitochondrial delivery methods, determining optimal dosages for different delivery approaches, were discussed based on larger animal models and clinical trials. The goal of this review was to introduce novel concepts and prospects for SCI therapy and to contribute to the advancement of medical research in this field.</div></div><div><h3>The Translational Potential of This Article</h3><div>At present, SCI lacks effective therapies, with mitochondrial dysfunction playing a central role in neuronal damage. Mitochondrial transplantation holds promise for restoring bioenergetic function. However, key challenges remain, including optimizing delivery methods, determining appropriate dosages, scalability, donor mitochondrial sourcing, regulatory hurdles and ensuring successful integration. Addressing these issues requires non-invasive platforms, validation in large-animal models, and clinical trials. This approach may bridge mitochondrial biology with translational engineering, thereby advancing the development of regenerative therapies for SCI.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 441-450"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144071506","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 : 2025-05-01DOI: 10.1016/j.jot.2025.04.013
Jiawei Li , Huiming Jiang , Guihua Tan , Zhongyang Lv , Zizheng Liu , Hu Guo , Ziying Sun , Xingquan Xu , Dongquan Shi
Articular fibrocartilage is commonly observed on the joint surface in osteoarthritis (OA) or cartilage injury, often seen as a result of cartilage degeneration. Compared to hyaline cartilage, fibrocartilage exhibits inferior mechanical properties and biological functions, which contribute to further cartilage degeneration and the progression of OA. Despite this, research on cartilage regeneration has not sufficiently addressed the specific challenges and strategies related to fibrocartilage. Although fibrocartilage formation is an unavoidable outcome during cartilage repair, it offers several benefits in the regeneration process, such as providing a natural cell source and establishing a strong integration with surrounding tissues. Recently, a therapeutic approach focused on the in-situ modification of fibrocartilage to promote hyaline cartilage regeneration, referred to as “fibrocartilage hyalinization”, has been proposed. Our recent work has demonstrated the feasibility of converting existing fibrocartilage into hyaline cartilage in vivo within the injured area. Key elements of this strategy include modifying the extracellular matrix (ECM), targeting fibrotic chondrocytes, and altering the local microenvironment. This review summarizes the current understanding of articular fibrocartilage's characteristics and mechanisms, while also discussing potential approaches and the feasibility of fibrocartilage hyalinization for cartilage regeneration.
{"title":"Fibrocartilage hyalinization: A potential therapeutic strategy for articular fibrocartilage","authors":"Jiawei Li , Huiming Jiang , Guihua Tan , Zhongyang Lv , Zizheng Liu , Hu Guo , Ziying Sun , Xingquan Xu , Dongquan Shi","doi":"10.1016/j.jot.2025.04.013","DOIUrl":"10.1016/j.jot.2025.04.013","url":null,"abstract":"<div><div>Articular fibrocartilage is commonly observed on the joint surface in osteoarthritis (OA) or cartilage injury, often seen as a result of cartilage degeneration. Compared to hyaline cartilage, fibrocartilage exhibits inferior mechanical properties and biological functions, which contribute to further cartilage degeneration and the progression of OA. Despite this, research on cartilage regeneration has not sufficiently addressed the specific challenges and strategies related to fibrocartilage. Although fibrocartilage formation is an unavoidable outcome during cartilage repair, it offers several benefits in the regeneration process, such as providing a natural cell source and establishing a strong integration with surrounding tissues. Recently, a therapeutic approach focused on the <em>in-situ</em> modification of fibrocartilage to promote hyaline cartilage regeneration, referred to as “fibrocartilage hyalinization”, has been proposed. Our recent work has demonstrated the feasibility of converting existing fibrocartilage into hyaline cartilage <em>in vivo</em> within the injured area. Key elements of this strategy include modifying the extracellular matrix (ECM), targeting fibrotic chondrocytes, and altering the local microenvironment. This review summarizes the current understanding of articular fibrocartilage's characteristics and mechanisms, while also discussing potential approaches and the feasibility of fibrocartilage hyalinization for cartilage regeneration.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 313-324"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143902348","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 : 2025-05-01DOI: 10.1016/j.jot.2025.03.013
Xinjie Liu , Yilin Pang , Baoyou Fan , Jiawei Zhang , Shen Liu , Xiaobing Deng , Yun Li , Ying Liu , Xu Zhang , Chenxi Zhao , Xiaoyu Wang , Xudong Wu , Luhua Lai , Shiqing Feng , Wenpeng Liu , Guangzhi Ning , Xue Yao
Background
Spinal cord injury (SCI) exerts severe physical, social, and economic effects on individuals and the healthcare system. While much progress has been made in understanding the pathophysiology of SCI, the regulation of the ferroptosis master regulator, GPX4 (Glutathione Peroxidase 4), remains poorly understood.
Methods
In a rat T10 contusion SCI model, GPX4 expression was tracked with western blot and immunofluorescence. Ferroptosis was induced in primary neurons using the GPX4 inhibitor RSL3, and inflammatory cytokine release was measured. Conditioned media from these neurons was applied to microglia to assess activation. The GPX4 activator PKUMDL-LC-102 was administered to SCI rats, with functional recovery evaluated through behavioral tests, MRI, and motor-evoked potentials.
Results
We first reveal a temporal and spatial decrease of GPX4 levels in neurons after SCI. We then demonstrate that GPX4 inhibition leads to primary neuronal ferroptosis, triggering the secretion of pro-inflammatory cytokines that activate microglia. This study represents the initial in vivo investigation of GPX4-specific targeted activation, demonstrating its potential to promote functional recovery in contusive SCI by improving neuronal survival and reducing microgliosis.
Conclusion
These findings highlight the significance of GPX4 as a key factor for neuroprotection in the spinal cord. We identified the pivotal role of GPX4 in SCI and realize the neuroprotection via specific GPX4 activation to improve functional recovery in vivo.
The translational potential of this article
These findings provide a novel avenue for therapeutic intervention to enhance functional recovery after SCI through GPX4 targeted activation.
{"title":"GPX4 activator enhances neuroprotection and functional recovery in spinal cord injury","authors":"Xinjie Liu , Yilin Pang , Baoyou Fan , Jiawei Zhang , Shen Liu , Xiaobing Deng , Yun Li , Ying Liu , Xu Zhang , Chenxi Zhao , Xiaoyu Wang , Xudong Wu , Luhua Lai , Shiqing Feng , Wenpeng Liu , Guangzhi Ning , Xue Yao","doi":"10.1016/j.jot.2025.03.013","DOIUrl":"10.1016/j.jot.2025.03.013","url":null,"abstract":"<div><h3>Background</h3><div>Spinal cord injury (SCI) exerts severe physical, social, and economic effects on individuals and the healthcare system. While much progress has been made in understanding the pathophysiology of SCI, the regulation of the ferroptosis master regulator, GPX4 (Glutathione Peroxidase 4), remains poorly understood.</div></div><div><h3>Methods</h3><div>In a rat T10 contusion SCI model, GPX4 expression was tracked with western blot and immunofluorescence. Ferroptosis was induced in primary neurons using the GPX4 inhibitor RSL3, and inflammatory cytokine release was measured. Conditioned media from these neurons was applied to microglia to assess activation. The GPX4 activator PKUMDL-LC-102 was administered to SCI rats, with functional recovery evaluated through behavioral tests, MRI, and motor-evoked potentials.</div></div><div><h3>Results</h3><div>We first reveal a temporal and spatial decrease of GPX4 levels in neurons after SCI. We then demonstrate that GPX4 inhibition leads to primary neuronal ferroptosis, triggering the secretion of pro-inflammatory cytokines that activate microglia. This study represents the initial <em>in vivo</em> investigation of GPX4-specific targeted activation, demonstrating its potential to promote functional recovery in contusive SCI by improving neuronal survival and reducing microgliosis.</div></div><div><h3>Conclusion</h3><div>These findings highlight the significance of GPX4 as a key factor for neuroprotection in the spinal cord. We identified the pivotal role of GPX4 in SCI and realize the neuroprotection via specific GPX4 activation to improve functional recovery <em>in vivo</em>.</div></div><div><h3>The translational potential of this article</h3><div>These findings provide a novel avenue for therapeutic intervention to enhance functional recovery after SCI through GPX4 targeted activation.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 344-359"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143913044","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 : 2025-05-01DOI: 10.1016/j.jot.2025.04.011
Song Chen , Jhanvee Patel , Torey Katzmeyer , Ming Pei
While known sex differences in bone health exist, scientific studies on bone degeneration and regeneration frequently disregard sex impact as a variable in outcomes. Evidence has established a higher risk of osteoporosis and increased bone degradation rates in women when compared to men. Accumulating research suggests that this disparity is also present in bone regeneration and repair. However, no comprehensive review highlighting the influence of sex currently exists in this field. This paper aims to review the information presently available on the cellular mechanisms behind skeletal sexual dimorphism specific to hormones and bone's degenerative and regenerative sex differences. This review will discuss the optimization of personalized regenerative therapies accounting for sex. The review emphasizes that sex impact must further be investigated to advance the field of bone regeneration and improve patient outcomes and quality of life.
As translational medicine is JOT's focus, authors must highlight the translational potential or clinical significance of their work in both the abstract and the discussion. To this effect, it is required to include a statement following the abstract (included in the abstract word count) under the following heading: "The Translational Potential of this Article". 2. Please re-edit the reference list according to the following guidelines: 1) The last names and initials of all the authors up to 6 should be included, but when authors number 7 or more, list the first 6 authors only followed by 'et al'; 2) The "[eng]" in the reference list should be removed (if any); 3) Reference to a standard journal article (Please pay particular attention to the formatting, word capitalization, spacing and style): “Niemansburg SL, van Delden JJ, Dhert WJ, Bredenoord AL. Regenerative medicine interventions for orthopedic disorders: ethical issues in the translation into patients. Regen Med 2013;8:65–73.
{"title":"Sex-dependent variation in bone adaptation: from degeneration to regeneration","authors":"Song Chen , Jhanvee Patel , Torey Katzmeyer , Ming Pei","doi":"10.1016/j.jot.2025.04.011","DOIUrl":"10.1016/j.jot.2025.04.011","url":null,"abstract":"<div><div>While known sex differences in bone health exist, scientific studies on bone degeneration and regeneration frequently disregard sex impact as a variable in outcomes. Evidence has established a higher risk of osteoporosis and increased bone degradation rates in women when compared to men. Accumulating research suggests that this disparity is also present in bone regeneration and repair. However, no comprehensive review highlighting the influence of sex currently exists in this field. This paper aims to review the information presently available on the cellular mechanisms behind skeletal sexual dimorphism specific to hormones and bone's degenerative and regenerative sex differences. This review will discuss the optimization of personalized regenerative therapies accounting for sex. The review emphasizes that sex impact must further be investigated to advance the field of bone regeneration and improve patient outcomes and quality of life.</div><div>As translational medicine is JOT's focus, authors must highlight the translational potential or clinical significance of their work in both the abstract and the discussion. To this effect, it is required to include a statement following the abstract (included in the abstract word count) under the following heading: \"The Translational Potential of this Article\". 2. Please re-edit the reference list according to the following guidelines: 1) The last names and initials of all the authors up to 6 should be included, but when authors number 7 or more, list the first 6 authors only followed by 'et al'; 2) The \"[eng]\" in the reference list should be removed (if any); 3) Reference to a standard journal article (Please pay particular attention to the formatting, word capitalization, spacing and style): “Niemansburg SL, van Delden JJ, Dhert WJ, Bredenoord AL. Regenerative medicine interventions for orthopedic disorders: ethical issues in the translation into patients. Regen Med 2013;8:65–73.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 325-343"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143907873","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 : 2025-05-01DOI: 10.1016/j.jot.2025.04.014
Yining Liu , Xiaolei Ji , Jinge Zhang , Jinhong Lu , Boyang Liu , Haijian Sun , Dengshun Miao
<div><h3>Background/objective</h3><div>Bone homeostasis, maintained by a balance between osteoblastic bone formation and osteoclastic bone resorption, is disrupted in osteoporosis, leading to reduced bone mass and increased fracture risk. Bmi1, a polycomb group protein, is crucial for stem cell self-renewal and senescence regulation. Bmi1 deficiency has been linked to oxidative stress, DNA damage, and premature osteoporosis. Checkpoint kinase 2 (Chk2) is a key mediator of the DNA damage response (DDR) pathway, which can exacerbate bone aging through oxidative stress and senescence. This study investigated the role of Chk2 deletion in mitigating bone loss and cellular senescence caused by Bmi1 deficiency and explored the underlying molecular mechanisms, focusing on the regulation of oxidative stress via Cyp1a1.</div></div><div><h3>Methods</h3><div>We utilized Bmi1-deficient (Bmi1<sup>−/−</sup>), Chk2-deficient (Chk2<sup>−/−</sup>), and double knockout (Bmi1<sup>−/−</sup>Chk2<sup>−/−</sup>) mice to assess bone homeostasis. Bone mineral density (BMD), trabecular architecture, and bone turnover markers were evaluated using X-ray imaging, micro-CT, histological staining, and bone histomorphometry. Oxidative stress markers, DDR pathway activation, and senescence-associated secretory phenotype (SASP) were analyzed using Western blotting, immunohistochemistry, and real-time PCR. Transcriptome sequencing identified differentially expressed genes, including Cyp1a1, which was further validated through chromatin immunoprecipitation (ChIP), luciferase assays, and knockdown experiments in bone marrow mesenchymal stem cells (BMSCs).</div></div><div><h3>Results</h3><div>Bmi1 deficiency activated the ATM-Chk2-p53 DDR pathway, increased oxidative stress, and induced osteocyte senescence and senescence-associated secretory phenotype (SASP), leading to reduced osteoblastic bone formation, increased osteoclastic bone resorption, and significant bone loss. Chk2 knockout rescued these defects by reducing oxidative stress and senescence. In Bmi1<sup>−/−</sup>Chk2<sup>−/−</sup> mice, BMD, trabecular bone volume, collagen deposition, and osteoblast markers (Runx2 and OPN) were significantly improved, while osteoclast markers (TRAP and RANKL/OPG ratio) were reduced compared to Bmi1<sup>−/−</sup> mice. Oxidative stress markers, including SOD1 and SOD2, were restored, and senescence markers such as p16, p21, and β-gal activity were significantly decreased. Transcriptome analysis identified Cyp1a1 as a key regulator of oxidative stress downstream of Bmi1 and Chk2. Bmi1 deficiency upregulated Cyp1a1, increasing ROS levels, while Chk2 knockout downregulated Cyp1a1 and mitigated oxidative stress. Mechanistically, p53 was shown to directly bind the Cyp1a1 promoter and activate its transcription, with Chk2 knockout reducing p53-mediated Cyp1a1 expression. These findings highlight the critical role of the Bmi1-Chk2-p53-Cyp1a1 axis in regulating bone homeostasis.</div></div><div><h3
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Pub Date : 2025-05-01DOI: 10.1016/j.jot.2025.04.002
Jia-run Bai , Chao Zhang , Gen Li , Yu-gang Wang , Yu-qi Dong , Roland M. Klar , Tao He
<div><h3>Background</h3><div>Segmental bone defect is a challenging clinical problem that often requires autologous bone grafting, which has limitations such as donor site morbidity and insufficient supply. Bone tissue engineering aims to create functional bone substitutes that can mimic the properties and processes of native bone. However, the discrepancy between <em>in vitro</em> and <em>in vivo</em> conditions hinders the successful translation of bone tissue engineering from animal models to human applications. Organoids, such as muscle pouch-based models, are emerging as promising tools that can closely resemble the osteogenic niche and overcome some of the limitations of conventional <em>in vitro</em> models.</div></div><div><h3>Methods</h3><div>In this study, we explored two distinct muscle-biomaterial based bone induction models: an <em>in vivo</em> heterotopic implantation model and a novel <em>ex vivo</em> muscle pouch-based coral-derived macroporous construct organoid model. They both utilized the coral-derived constructs, specifically 13 % hydroxyapatite/calcium carbonate (13 % HA/CC) as the biomaterial. We implanted 72 coral-derived devices into rats' <em>rectus abdominis</em> muscle, divided equally between <em>in vivo</em> and <em>ex vivo</em> groups. Samples were harvested at 15, 30, and 60 days for molecular and histological analyses. We assessed the relative gene expression of angiogenesis markers (<em>Vegfa</em> and <em>Col4a1</em>) and osteogenesis signaling and structural markers (<em>Runx2</em>, <em>Bmp2</em>, <em>Ocn</em> and <em>Alp</em>) using qRT-PCR. We analyzed tissue morphogenesis, angiogenesis and induction of bone formation by H&E and modified Goldner's Trichrome staining. Immunostaining was further used to detect the expression and localization of OCN, VEGFA and CD31 in both <em>in vivo</em> and <em>ex vivo</em> models.</div></div><div><h3>Results</h3><div>We demonstrated that <em>ex vivo</em> muscle pouch-based coral-derived macroporous construct organoid model supported tissue survival up to 60 days with compromised tissue ingrowth compared to the <em>in vivo</em> model. Primary vascular structures formed at the tissue–scaffold interface in the organoid system with persistent up-regulation of <em>Vegfa</em> and <em>Col4a1,</em> while comprehensive angiogenesis took place with early up-regulation of <em>Vegfa</em> and <em>Col4a1 in vivo</em>. Proper bone formation was absent in both the <em>ex vivo</em> and <em>in vivo</em> models, but the <em>in vivo</em> models showed an up-regulation of <em>Bmp2</em> and <em>Alp</em> in early phase and a delayed <em>Ocn</em> expression on day 30. The <em>ex vivo</em> model showed connective tissue formation, comprehensive OCN deposition, and gene expression patterns mimicking <em>in vivo</em> trends but with some distinctions.</div></div><div><h3>Conclusions</h3><div>The <em>ex vivo</em> muscle pouch-based coral-derived macroporous construct organoid model in this study can
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