Journal of Orthopaedic Translation最新文献

{"title":"Macropinocytosis fuels osteoclast differentiation in bone-related diseases","authors":"Mengqin Gu ,&nbsp;Linyu Xue ,&nbsp;Shidian Ran ,&nbsp;Ying Yuan ,&nbsp;Qiming Zhai ,&nbsp;Hongmei Zhang ,&nbsp;Hua Zhang ,&nbsp;Ping Ji","doi":"10.1016/j.jot.2025.09.005","DOIUrl":"10.1016/j.jot.2025.09.005","url":null,"abstract":"<div><h3>Objective</h3><div>Multinucleated osteoclasts are the principal specialised cells responsible for bone resorption, but osteoclastogenesis, the formation of osteoclasts, entails substantial nutrient and bioenergetic demands. Macropinocytosis is an efficient pathway for nutrient scavenging in metabolically active cells; however, the interplay among metabolic state, osteoclast differentiation and macropinocytosis in bone-related diseases remains poorly understood.</div></div><div><h3>Methods</h3><div>In this study, osteoclast differentiation was induced using murine bone marrow-derived macrophages and RAW 264.7 cells to investigate the role of macropinocytosis in metabolic regulation. Lipopolysaccharide (LPS) was applied to mimic inflammatory conditions in vitro to assess the influence of macropinocytosis on both metabolic profiles and inflammation-associated osteoclastogenesis. Additionally, ligature-induced periodontitis and ovariectomy (OVX)-induced bone loss models in mice were employed to evaluate the in vivo impact of macropinocytosis on bone resorption.</div></div><div><h3>Results</h3><div>Enhanced macropinocytosis promoted osteoclast formation, with LPS further accelerating differentiation and increasing macropinocytic activity. This upregulation helped to meet the energy requirements of osteoclastogenesis via oxidative phosphorylation and glycolysis. Inhibition of macropinocytosis with (N-ethyl-N-isopropyl) amiloride (EIPA) reduced energy production and suppressed osteoclast differentiation. Elevated macropinocytosis was also observed in the periodontitis and OVX models, and its inhibition led to early, dose-dependent restoration of bone mass.</div></div><div><h3>Conclusion</h3><div>Macropinocytosis provides a critical energy source for osteoclast differentiation. Targeting this pathway with EIPA represents a promising therapeutic approach for bone-related diseases.</div></div><div><h3>The translational potential of this article</h3><div>As a bulk endocytic process, macropinocytosis offers a novel therapeutic target for bone-related diseases. The efficacy of EIPA in suppressing osteoclastogenesis and bone resorption suggests its potential as a clinical intervention drug.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 267-279"},"PeriodicalIF":5.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145220805","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}

{"title":"Histone modifications: Unveiling the epigenetic enigma of degenerative skeletal diseases","authors":"Yao Zhang ,&nbsp;Jiale Wang ,&nbsp;Di Hua ,&nbsp;Chunyang Fan ,&nbsp;Wei He ,&nbsp;Yongkang Deng ,&nbsp;Maoting Tang ,&nbsp;Dechun Geng ,&nbsp;Xiexing Wu ,&nbsp;Haiqing Mao","doi":"10.1016/j.jot.2025.08.013","DOIUrl":"10.1016/j.jot.2025.08.013","url":null,"abstract":"<div><div>Degenerative skeletal diseases, including osteoporosis, osteoarthritis, and intervertebral disc degeneration, are prevalent age-related conditions characterized by progressive tissue degeneration and functional decline. Histone modifications are covalent modifications of histone residues, catalyzed by specific enzymes, that modulate chromatin architecture and transcriptional activity. Accumulating evidence highlights the critical involvement of histone modifications in orchestrating disease-associated transcriptional programs. In osteoporosis, histone modifications regulate osteoblast and osteoclast differentiation, thereby disrupting bone homeostasis. In osteoarthritis, they drive the expression of matrix-degrading enzymes in chondrocytes, contributing to cartilage degradation. In intervertebral disc degeneration, they are implicated in nucleus pulposus cell senescence, apoptosis, and extracellular matrix degradation. This review summarizes the distinct mechanistic roles of histone modifications across these conditions and explores the therapeutic potential of targeting histone-modifying enzymes, underscoring epigenetic regulation as a promising strategy for precision intervention in degenerative skeletal diseases.</div><div>The translational potential of this article: This review comprehensively explores the role of histone modifications in degenerative skeletal diseases and evaluates the potential of histone-modifying enzyme inhibitors as therapeutic targets. These insights provide new strategies and directions for the treatment of degenerative skeletal diseases.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 245-266"},"PeriodicalIF":5.9,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096426","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}

{"title":"An aptamer specifically targeting mCRP ameliorates experimental arthritis","authors":"Zhuqian Wang ,&nbsp;Duoli Xie ,&nbsp;Peixi Zhu ,&nbsp;Jianmin Guo ,&nbsp;Chunhao Cao ,&nbsp;Yu Du ,&nbsp;Aiping Lu ,&nbsp;Chao Liang","doi":"10.1016/j.jot.2025.08.010","DOIUrl":"10.1016/j.jot.2025.08.010","url":null,"abstract":"<div><h3>Background</h3><div>Recent evidence highlights the important role of the liver–bone axis in the development of arthritis, particularly rheumatoid arthritis (RA) and osteoarthritis (OA). The liver secretes various factors that impact joint health, one of which is C-reactive protein (CRP), elevated in RA and OA patients. Traditionally regarded as an inflammatory marker, the causal role of CRP in arthritis development remains a topic of debate due to the existence of its two isoforms with opposing functions: native pentameric CRP (nCRP) and monomeric CRP (mCRP).</div></div><div><h3>Methods</h3><div>We generated hepatocyte-specific CRP knockout mice to investigate the causal role of CRP in RA and OA mouse models. <em>In vitro</em> experiments were conducted to assess the effects of mCRP and nCRP on phenotypic changes in effector cells common to RA and OA, including fibroblast-like synoviocytes (FLSs), monocytes/macrophages, and chondrocytes. Using systematic evolution of ligands by exponential enrichment (SELEX), we screened nucleic acid aptamers targeting mCRP rather than nCRP. We determined the neutralizing effects of the selected aptamers on mCRP <em>in vitro</em> and explored their therapeutic potential and safety in RA and OA mouse models.</div></div><div><h3>Results</h3><div>Hepatocyte-specific knockout of CRP significantly reduced disease severity in RA and OA mouse models. mCRP promoted <em>in vitro</em> pathological changes in FLSs, monocytes/macrophages, and chondrocytes, while nCRP exhibited minimal or slightly protective effects. We identified an aptamer, ApmCRP3, which effectively inhibited mCRP-induced pathological changes of RA and OA effector cells <em>in vitro</em>. In mouse models of RA and OA, ApmCRP3 displayed strong therapeutic effects and a favorable safety profile.</div></div><div><h3>Conclusion</h3><div>This study identifies hepatocyte-derived mCRP as a contributor to RA and OA pathogenesis and highlights ApmCRP3 aptamer as a promising therapeutic candidate.</div></div><div><h3>The translational potential of this article</h3><div>This study highlights the therapeutic potential of ApmCRP3 in attenuating mCRP-driven pathology and controlling arthritis progression.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 228-244"},"PeriodicalIF":5.9,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096427","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}

{"title":"Advanced bioactive materials and strategies for tendon repair and function restoration","authors":"Sidan Wang ,&nbsp;Zixuan Ou ,&nbsp;Feng Xiao ,&nbsp;Xiaobo Feng ,&nbsp;Lei Tan ,&nbsp;Shuangshuang Cheng ,&nbsp;Di Wu ,&nbsp;Cao Yang ,&nbsp;Haoqun Yao","doi":"10.1016/j.jot.2025.08.012","DOIUrl":"10.1016/j.jot.2025.08.012","url":null,"abstract":"<div><div>Tendon injury is one of the most common clinical challenges in musculoskeletal disorders. Effective tendon repair is crucial for restoring patients' motor function and improving their quality of life. Recent advances in bioactive material-mediated tendon regeneration have shown great therapeutic potential and clinical relevance. However, systematic reviews that comprehensively integrate these developments are still scarce. Firstly, this article presents the selection of bioactive components, mainly including cell-based therapeutic strategies and nanodrug delivery strategies. Secondly, bioactive materials delivery system using tissue-engineered scaffolds is discussed in detail. In this section, we discuss the efficacy of scaffolds in tendon repair through different scaffold preparation methods and synthetic raw materials. Furthermore, the application of hydrogel systems such as enhanced hydrogels, bioadhesive hydrogels and multifunctional hydrogels in tendon repair strategies is systematically and comprehensively presented. Finally, based on a detailed review of the field, current challenges in the field were proposed and potential research directions in the field were identified, including potential research directions in smart bioactive materials and personalized treatment strategies.</div></div><div><h3>The translational potential of this article</h3><div>This review synthesizes tendon regeneration strategies—from molecular mechanisms to tissue-level integration—including bioactive component selection and delivery systems using tissue-engineered scaffolds. It identifies translational barriers and proposes new strategies in tendon-specific safety validation, scalable manufacturing uniformity and cost-effectiveness versus conventional therapies. These insights will refine clinical strategies for tendon injuries and advance targeted bioactive biomaterials for localized regeneration.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 204-227"},"PeriodicalIF":5.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145060059","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}

{"title":"Development and multi-center validation of a software program, Ofeye 3.0, for automated all-inclusive vertebral fracture detection with chest/abdominal CT images","authors":"Ben-Heng Xiao ,&nbsp;Zhen-Hua Gao ,&nbsp;Cai-Ying Li ,&nbsp;Xiao-Ming Leng ,&nbsp;Er-Zhu Du ,&nbsp;Jian-Bing Ma ,&nbsp;Fu-Shan Liu ,&nbsp;Jing-Shan Gong ,&nbsp;Zhi-Guo Ju ,&nbsp;Ming-Yuan Yuan ,&nbsp;Hui-Ming Zhu ,&nbsp;Michael S.Y. Zhu ,&nbsp;Timothy YC. Kwok ,&nbsp;Yì Xiáng J. Wáng","doi":"10.1016/j.jot.2025.08.011","DOIUrl":"10.1016/j.jot.2025.08.011","url":null,"abstract":"<div><h3>Background</h3><div>Missing report for fragility vertebral fracture (VF) on chest/abdominal CT is common when the indication is not spine disorders. This represents a missed opportunity to alert patients to take preventive measures to improve bone health and prevent further severe fractures. In this study, we aim to develop a software program for automated detection of VF with existing chest/abdominal CT scans and validate its detection performance.</div></div><div><h3>Methods</h3><div>An automated sagittal Central Slab reconstruction (CSR) method for CT axial images was developed. For reference VF reading<em>,</em> VFs inclusive of those of with &lt;20 % vertebral height loss and those of endplate fracture with minimal vertebral height loss were identified. VFs were also differentiated from osteoarthritic wedging and endplatitis short vertebrae. Prior knowledge of VF detection models for lateral radiograph were transferred to a new ‘Ofeye 3.0’ model optimized for VF detection on CT image. Training CT images were obtained from nine centers, totaling 3313 cases without VF and 835 cases with VF. For external validation, CT images were from five centers totaling 732 cases without VF and 224 cases with VF.</div></div><div><h3>Results</h3><div>The automated CSR method showed advantages in demonstrating structural changes of the endplate and adjacent structures. For detecting VF in chest/abdominal CT scans, counting case-by-case and compared with the reference reading, the average performance of Ofeye 3.0 was accuracy 0.967, sensitivity 0.906, and specificity 0.986. Most of false negative or false positive cases were minimal or mild VF, or with image artifacts, or with VF close to the peripheral of CSR images.</div></div><div><h3>Conclusions</h3><div>Despite the challenging requirements for the software to detect all-inclusive VF, our results compare favorably with other published automated VF detection models.</div></div><div><h3>The translational potential of this article</h3><div>We developed a software program for automated all-inclusive VF detection on chest and/or abdominal CT image data and conducted a multi-center external validation study. This software is proved to have high VF detection precision. By alerting patients of the VFs likely related to osteoporosis and in turn the patients taking measures to prevent further fracture, the integration of this software into radiological practice will improve patient outcomes and reduce healthcare costs.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 192-203"},"PeriodicalIF":5.9,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045683","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}

{"title":"Multi-scale biomimetic fusion construction of cerium ion hydrogel-scaffold for promoting osteoporotic bone defect repair","authors":"Yesheng Jin ,&nbsp;Shuqing Lv ,&nbsp;Nanning Lv ,&nbsp;Yixue Huang ,&nbsp;Jia Wang ,&nbsp;Yun Xiao ,&nbsp;Xinfeng Zhou ,&nbsp;Yanxia Ma ,&nbsp;Gang Zhao ,&nbsp;Fan He ,&nbsp;Yong Xu","doi":"10.1016/j.jot.2025.08.015","DOIUrl":"10.1016/j.jot.2025.08.015","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;The treatment of bone defects in the context of osteoporosis encounters numerous challenges. In the osteoporotic microenvironment, bone resorption outweighs bone formation, impeding the self-repair of bone defect areas. Furthermore, the deterioration of osteogenesis-angiogenesis coupling function at the defect sites and excessive inflammatory responses further complicate the treatment of bone defects. Hence, an improved approach is urgently needed to enhance the treatment of osteoporotic bone defects.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Our efficient strategy has developed a multi-scale biomimetic fusion alendronate sodium cerium ion hydrogel scaffold, integrating 3D-printed tricalcium phosphate (TCP) scaffolds, collagen-methacrylate (COMA) hydrogel, and nanoparticles of alendronate sodium cerium ions. &lt;em&gt;In vitro&lt;/em&gt;, we intervened osteoporosis rat derived bone marrow stromal cells (BMSCs) with the extract of TCP-H-Alendronate sodium cerium ion nanoparticles (ACNP) scaffold and detected the osteogenesis-related indicators through alkaline phosphatase (ALP) enzymatic activity staining, alizarin red staining, Western Blot, RT-qPCR and immunofluorescence staining to evaluate the osteogenic differentiation effect of TCP-H-ACNP scaffold. Through transcriptome sequencing, we explored the mechanism of TCP-H-ACNP scaffold affecting osteogenic differentiation of osteoporotic BMSCs. We intervened human umbilical vein endothelial cells (HUVECs) with the extract of TCP-H-ACNP scaffold and evaluated the angiogenic effect of TCP-H-ACNP scaffold through tube formation assay and cell scratch assay. &lt;em&gt;In vivo&lt;/em&gt;, we established a distal femoral bone defect model in osteoporotic rats and evaluated the therapeutic effect &lt;em&gt;in vivo&lt;/em&gt; through Mirco CT, Hematoxylin and Eosin (H&amp;E) stainin, Masson staining and immunohistochemical staining.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;The results demonstrated that &lt;em&gt;in&lt;/em&gt; &lt;em&gt;vitro&lt;/em&gt;, TCP-H-ACNP scaffolds could promote osteogenic differentiation of osteoporotic BMSCs from rats and angiogenesis of HUVECs. &lt;em&gt;In vivo&lt;/em&gt;, TCP-H-ACNP scaffolds could promote bone regeneration and repair of distal femoral bone defects in osteoporotic rats and improve local angiogenesis. Mechanistically, TCP-H-ACNP scaffolds could directly promote osteogenic differentiation of osteoporotic BMSCs from rats through the Wnt signaling pathway, and indirectly promote osteogenic differentiation by influencing Ca ion transport and improving mitochondrial function.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;We create a hydrogel scaffold that not only offers adequate mechanical support but also possesses a favorable microenvironment for cell growth and contains biological factors promoting osteogenic and angiogenic differentiation.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;The translational potential of this paper&lt;/h3&gt;&lt;div&gt;This application represents a pioneering aspect of multi-scale biomimetic hydrogel scaffolds in addressing o","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 172-191"},"PeriodicalIF":5.9,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045684","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}

{"title":"LOXL2 alleviates post-traumatic knee osteoarthritis and pain","authors":"Faiza Ali ,&nbsp;Rajnikant Dilip Raut ,&nbsp;Chumki Choudhury ,&nbsp;Amit Kumar Chakraborty ,&nbsp;Cheyleann Del Valle-Ponce De Leon ,&nbsp;Pushkar Mehra ,&nbsp;Manish V. Bais","doi":"10.1016/j.jot.2025.08.016","DOIUrl":"10.1016/j.jot.2025.08.016","url":null,"abstract":"<div><h3>Background</h3><div>Cartilage has limited potential for self-regeneration, and damage results in structural, molecular, and functional aberrations, leading to osteoarthritis (OA). Traumatic knee injuries can also lead to cartilage degeneration and post-traumatic OA (PTOA). This study aimed to explore whether lysyl oxidase-like 2 (LOXL2) deletion aggravate PTOA and overexpression alleviate inflammation and pain at mechanical as well as molecular levels.</div></div><div><h3>Methods</h3><div>Modified medial meniscectomy was performed on C57BL/6J mice knee followed by aggrecan promotes specific deletion of <em>Loxl2</em> in cartilage. Transcriptomic aberrations were studied using RNA-seq and qPCR, and biomechanics and allodynia was evaluated using treadmill exhaustion and von Frey nociception test after adenovirus-delivered LOXL2 intra-articular treatment.</div></div><div><h3>Results</h3><div>LOXL2 was found to be downregulated in mouse knee PTOA. <em>Loxl2</em> deletion in knee cartilage, shows OA-like molecular changes, and aggravates PTOA. Transcriptomics analysis revealed the upregulation of cartilage degeneration factors, signatures of inflammatory M1 macrophages, and pain. These <em>Loxl2</em> deleted PTOA mice have a molecular resemblance to the human knee OA pathogenic gene signature. Interestingly, LOXL2 treatment alleviates knee joint function, reduces M1 macrophage infiltration, restores biomechanic capabilities, and reduces mechanical allodynia by relieving knee joint disability and pain.</div></div><div><h3>Conclusion</h3><div>LOXL2 deletion enhances the severity of PTOA, similar to human OA, whereas overexpression mitigates these effects by reducing inflammation and pain, offering LOXL2 as a therapeutic option in OA.</div></div><div><h3>The translational potential of this article</h3><div>LOXL2 modulates inflammation, pain, and degeneration, showing strong translational potential as a disease-modifying therapy for human PTOA.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"55 ","pages":"Pages 159-171"},"PeriodicalIF":5.9,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045685","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}