Journal of Orthopaedic Translation最新文献

{"title":"Humanin reduces nucleus pulposus cells ferroptosis to alleviate intervertebral disc degeneration: An in vitro and in vivo study.","authors":"Daxue Zhu, Zhaoheng Wang, Yanhu Li, Shijie Chen, Xuewen Kang","doi":"10.1016/j.jot.2024.12.002","DOIUrl":"https://doi.org/10.1016/j.jot.2024.12.002","url":null,"abstract":"<p><strong>Background: </strong>Intervertebral disc degeneration (IDD) is a prevalent etiology of low back pain in the global adult population, leading to considerable morbidity and healthcare costs. Existing therapeutic modalities for IDD remain constrained. Ferroptosis in the nucleus pulposus (NP) cells emerges as a pivotal contributor to IDD. Humanin (HN), a mitochondrial-secreted peptide, is intricately linked to age-related maladies and showcases antioxidant, anti-inflammatory, and anti-apoptotic properties. Nonetheless, its precise involvement in IDD remains enigmatic.</p><p><strong>Methods: </strong>The expression profile of HN in IDD was scrutinized utilizing human NP cell cultures and an IDD rat model (n = 5). The therapeutic efficacy of HN in rats was assessed via MRI and histological evaluation, alongside an exploration of the molecular underpinnings of HN's therapeutic actions in IDD management.</p><p><strong>Results: </strong>This pioneering study unveiled a downregulation of HN expression in IDD patients, a finding corroborated through cell and rat IDD models. Furthermore, it was ascertained that exogenous HN could trigger endogenous HN expression, impede the JAK2/STAT3 and NF-κB pathways, thereby mitigating erastin-induced ferroptosis in NP cells, contingent upon the upregulation of HSP27 expression. Moreover, the study validated the role of HN in preserving mitochondrial homeostasis, curbing mitochondrial reactive oxygen species (mtROS) generation and mtDNA leakage, consequently hindering mtDNA binding to TLR9 and subsequent activation of the NF-κB pathway. Notably, in vivo rat experiments underscored the efficacy of HN treatment in ameliorating IDD progression induced by annulus fibrosus puncture.</p><p><strong>Conclusion: </strong>By assuaging ferroptosis in NP cells, HN exhibits promise as a viable candidate for IDD treatment, capable of impeding disease advancement. <b>The translational potential of this article</b>: This study highlights the importance and effectiveness of HN in alleviating IDD by inhibiting ferroptosis in NP cells. The addition of exogenous HN may represent a potential therapeutic strategy for treating IDD.</p>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"50 ","pages":"274-294"},"PeriodicalIF":5.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current status of nano-embedded growth factors and stem cells delivery to bone for targeted repair and regeneration.","authors":"Wenqing Liang, Chao Zhou, Xiankun Liu, Qiong Xie, Linying Xia, Lu Liu, Wenwen Bao, Hongming Lin, Xiaochun Xiong, Hao Zhang, Zeping Zheng, Jiayi Zhao","doi":"10.1016/j.jot.2024.12.006","DOIUrl":"https://doi.org/10.1016/j.jot.2024.12.006","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Bone-related diseases like osteoarthritis and osteoporosis impact millions globally, affecting quality of life. Osteoporosis considerably enhances the probability of bone fractures of the wrist, hip, and spine. Enhancement and acceleration of functional bone development can be achieved through the sustained delivery of growth factors (GFs) and cells in biomaterial carriers. The delivery of bioactive compounds in a targeted, spatiotemporal way that most closely resembles the natural defect repair process can be achieved by designing the carrier system with established release kinetics. Furthermore, the carrier can serve as a substrate that mimics the extracellular matrix, facilitating osteoprogenitor cell infiltration and growth for integrative tissue healing. In this report, we explore the significance of GFs within the realm of bone and cartilage tissue engineering, encompassing their encapsulation and delivery methodologies, the kinetics of release, and their amalgamation with biomaterials and stem cells (SCs) to facilitate the mending of bone fractures. Moreover, the significance of GFs in evaluating the microenvironment of bone tissue through reciprocal signaling with cells and biomaterial scaffolds is emphasized which will serve as the foundation for prospective advances in bone and cartilage tissue engineering as well as therapeutic equipment. Nanoparticles are being used in regenerative medicine to promote bone regeneration and repair by delivering osteoinductive growth factors like BMP-2, VEGF, TGF-β. These nanocarriers allow controlled release, minimizing adverse effects and ensuring growth factors are concentrated at the injury site. They are also mixed with mesenchymal stem cells (MSCs) to improve their engraftment, differentiation, and survival. This approach is a key step in developing multi-model systems that more efficiently facilitate bone regeneration. Researchers are exploring smart nanoparticles with immunomodulatory qualities to improve bonre regeneration and reduce inflammation in injury site. Despite promising preclinical results, challenges include cost management, regulatory approval, and long term safety. However, incorporating stem cell transport and growth factors in nanoparticles could revolutionize bone regeneration and offer more personalized therapies for complex bone disorders and accidents.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;The translational potential of this article: &lt;/strong&gt;Stem cell transport and growth factors encapsulated in nanoparticles are becoming revolutionary methods for bone regeneration and repair. By encouraging stem cells to develop into osteoblasts, osteoinductive GFs like BMP-2, VEGF, and TGF-β can be delivered under control due to nanomaterials like nanoparticles, nanofibers, and nanotubes. By ensuring sustained release, these nanocarriers lessen adverse effects and enhance therapeutic results. In order to prove their survival and development, MCSs, which are essential for bone regeneration, are mixed with na","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"50 ","pages":"257-273"},"PeriodicalIF":5.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Silence of HOTAIR promotes osteogenic differentiation and accelerates distraction osteogenesis by mediating FTO ubiquitination.","authors":"Xiao-Min Wu, Yong-Xin Mai, Yong-Fa Wen, Zhi-Peng Li, Yu-Xin Sun, Jun-Jing Chen, Fengzhen Meng, Feng-Xiang Pang, Huai-Ming Li, Yu Pan, Jin-Fang Zhang, Xiao-Hua Pan","doi":"10.1016/j.jot.2024.12.001","DOIUrl":"10.1016/j.jot.2024.12.001","url":null,"abstract":"<p><strong>Background: </strong>Distraction osteogenesis(DO) is a valuable bone regeneration technique, yet its prolonged consolidation phase often entails pain, high costs, infection risks, and lifestyle disruptions. Finding adjunctive approaches to shorten treatment duration is thus of clinical significance. Long noncoding RNAs have been demonstrated to play pivotal roles in regulating bone formation, and homeobox transcript antisense intergenic RNA(HOTAIR) was also reported to regulate osteogenesis and bone formation. However, its role in DO remains unclear.</p><p><strong>Methods: </strong>The effects of HOTAIR on osteogenesis were examined in rat bone marrow-derived mesenchymal stem cells(BMSCs) by asssessing ALP activity, calcification, and osteogenic gene expression with HOTAIR knockdown or overexpression. Using a tibial DO model, HOTAIR-stably silenced BMSCs or control cells were locally injected into the percutaneous distraction gap, and the effects were evaluated by micro-CT, dual-energy X-ray examination, mechanical testing, hematoxylin and eosin staining, and immunohistochemistry.</p><p><strong>Results: </strong>In the present study, it was found that HOTAIR silence promoted while its overexpression suppressed the osteogenic differentiation of BMSCs<i>.</i> The Mechanistic study revealed that HOTAIR physically interacted with FTO, and disrupted FTO ubiquitination and degradation, leading to FTO up-regulation and suppressing osteogenesis. Using DO animal model, HOTAIR-silenced BMSCs stimulated new bone formation and accelerated DO healing <i>in vivo</i>.</p><p><strong>Conclusion: </strong>Silence of HOTAIR enhanced osteogenesis in BMSCs and facilitated DO healing by recruiting FTO and inducing its degradation.</p><p><strong>Translational potential: </strong>The findings generated from this study suggest that inhibitor of HOTAIR may be developed as a promising strategy for DO patients.</p>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"50 ","pages":"248-256"},"PeriodicalIF":5.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling MiR-3085-3p as a modulator of cartilage degeneration in facet joint osteoarthritis: A novel therapeutic target.","authors":"Zhong-Ming Lai, Cheng-Long Li, Jun-Xiong Zhang, Xiang Ao, Cheng-Shuo Fei, Xin Xiang, Yan-Lin Chen, Ze-Sen Chen, Rui-Qian Tan, Liang Wang, Zhong-Min Zhang","doi":"10.1016/j.jot.2024.11.007","DOIUrl":"10.1016/j.jot.2024.11.007","url":null,"abstract":"<p><strong>Background: </strong>Low back pain (LBP) is generally caused by lumbar degeneration without effective treatment. Lumbar degeneration is influenced by aberrant axial mechanical stress (MS), with facet joint osteoarthritis (FJOA) representing one of its primary pathological manifestations. MicroRNA (miRNA), functioning as an early intermediate in the transcription process, has frequently been demonstrated to serve as a critical mediator linking mechanical stress perception with cellular processes such as growth, development, aging, and apoptosis. We hypothesized that miR-3085-3p regulates chondrocyte apoptosis under mechanical stress, influencing FJOA and serving as a key regulator.</p><p><strong>Methods: </strong>The severity of cartilage degeneration in bipedal standing models (BSM) was established and validated through micro-CT and histopathology. Cyclic tensile strain experiments (CTS) were conducted on the ATDC5 cell line to simulate MS. In situ hybridization was utilized to assess the expression levels of miR-3085-3p in degraded facet articular cartilage. The role of miR-3085-3p and its interaction with the downstream mRNA target Hspb6 were investigated through a combination of bioinformatic analysis, quantitative real-time polymerase chain reaction, western blotting, immunofluorescence, and luciferase assay. In vivo experiments on BSM, the functional impact of miR-3085-3p was further examined through transfection with adeno-associated virus (AAV).</p><p><strong>Results: </strong>It was observed that miR-3085-3p induced endoplasmic reticulum (ER) stress and apoptosis in chondrocytes and cartilage tissues under MS. The detrimental impact of miR-3085-3p was associated with the downregulation of Hspb6 expression, resulting in disruption of endoplasmic reticulum folding function. Additionally, intra-articular transfection of AAV miR-3085-3p mimics in mice facet joints led to spontaneous cartilage loss, while AAV miRNA-3085-3p sponge administration mitigated FJOA in the murine BSM model.</p><p><strong>Conclusion: </strong>Mechanical stress-regulated miR-3085-3p up regulation induced the ER stress and aggravates FJOA development through targeting HSPB6, suggesting miR-3085-3p may be a novel therapeutic target for FJOA.Translational potential of this article: Our study confirmed the elevated expression of miR-3085-3p in lumbar facet joints following mechanical stress loading, suggesting that miR-3085-3p may serve as a biomarker for the clinical management of FJOA. Additionally, we demonstrated that the knockdown of miR-3085-3p in animal facet joints mitigated facet joint degeneration, thereby identifying a potential therapeutic target for FJOA.</p>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"50 ","pages":"235-247"},"PeriodicalIF":5.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Moldable self-setting and bioactive bone wax for bone hemostasis and defect repair.","authors":"Ziyang Liu, Chuang Liu, Huan Zhou, Chunyong Liang, Wei Chen, Yanjie Bai, Xinlong Ma, Yingze Zhang, Lei Yang","doi":"10.1016/j.jot.2024.11.009","DOIUrl":"10.1016/j.jot.2024.11.009","url":null,"abstract":"<p><strong>Objective: </strong>Bone injury complicated with bleeding and irregular shaped defect are challenging in orthopedic surgery and practices due to the lack of reliable hemostasis and simultaneous defect repair strategy. Bone wax is a century-old biomaterial for bleeding management in orthopedic surgery, characterized with ready-to-use advantage but the risk of failed bone reunion due to the biological inertness and non-degradability. In current work, integration of bioceramic cement and premixed concept was motivated to prepare a in situ self-setting bioactive calcium phosphate based bone wax (CaPBW) for bone hemostasis and defect repair.</p><p><strong>Methods: </strong>A moldable, in situ self-setting bioactive CaPBW with a novel formulation of calcium phosphate cement (CPC), monetite (DPCA) granules, modified starch and polyethylene glycol (PEG) was developed for bone hemostasis and defect repair. The CaPBW material was evaluated by characterization, physical and chemical properties, biocompatibility, osteogenic ability and hemostatic ability.</p><p><strong>Results: </strong>CaPBW adopted the ready-to-use feature of traditional bone wax, showing feasibility in shape molding and defect sealing. When interacted with physiological fluid like blood, CaPBW could transformed from putty to solid state within tens of minutes due to the gradual PEG-water exchange and CPC hydration, providing mechanical stability for bleeding clotting and bone defect filling. <i>In vitro</i> studies revealed the superiority of CaPBW over bone wax in blood coagulation and osteoblast differentiation, along with hemocompatibility and osteogenesis confirmation. <i>In vivo</i> studies demonstrated the reliability of CaPBW in hemostasis and bone regeneration compared to traditional bone wax, promoting the efficacy of bone bleeding and new bone formation.</p><p><strong>Conclusion: </strong>As compared to traditional bone hemostatic agent bone wax, CaPBW not only preserved its advantages in handling and defect sealing, but also provided platform for temporary physical support and bone regeneration acceleration.</p><p><strong>The translational potential of this article: </strong>The integrated design of osteogenesis and hemostasis makes CaPBW have the dual functions as bone hemostasis material and artificial bone substitute. CaPBW therefore demonstrates a strategy of next-generation bone wax with high translational potential for orthopedic surgery.</p>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"50 ","pages":"223-234"},"PeriodicalIF":5.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of biological performance of 3D printed trabecular porous tantalum spine fusion cage in large animal models.","authors":"Yiming Zhang, Jingzhou Yang, Wentao Wan, Qingqian Zhao, Mingyuan Di, Dachen Zhang, Gang Liu, Chao Chen, Xun Sun, Wei Zhang, Hanming Bian, Yang Liu, Ye Tian, Lu Xue, Yiming Dou, Zheng Wang, Qiulin Li, Qiang Yang","doi":"10.1016/j.jot.2024.10.010","DOIUrl":"10.1016/j.jot.2024.10.010","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The materials for artificial bone scaffolds have long been a focal point in biomaterials research. Tantalum, with its excellent bioactivity and tissue compatibility, has gradually become a promising alternative material. 3D printing technology shows unique advantages in designing complex structures, reducing costs, and providing personalized customization in the manufacture of porous tantalum fusion cages. Here we report the pre-clinical large animal (sheep) study on the newly developed 3D printed biomimetic trabecular porous tantalum fusion cage for assessing the long-term intervertebral fusion efficacy and safety.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Porous tantalum fusion cages were fabricated using laser powder bed fusion (LPBF) and chemical vapor deposition (CVD) methods. The fusion cages were characterized using scanning electron microscopy (SEM) and mechanical compression tests. Small-Tailed Han sheep served as the animal model, and the two types of fusion cages were implanted in the C3/4 cervical segments and followed for up to 12 months. Imaging techniques, including X-ray, CT scans, and Micro CT, were used to observe the bone integration of the fusion cages. Hard tissue sections were used to assess osteogenic effects and bone integration. The range of motion (ROM) of the motion segments was evaluated using a biomechanical testing machine. Serum biochemical indicators and pathological analysis of major organs were conducted to assess biocompatibility.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;X-ray imaging showed that both the 3D-printed and chemical vapor deposition porous tantalum fusion cages maintained comparable average intervertebral disc heights. Due to the presence of metal artifacts, CT and Micro CT imaging could not effectively analyze bone integration. Histomorphology data indicated that both the 3D-printed and chemical vapor deposition porous tantalum fusion cages exhibited similar levels of bone contact and integration at 3, 6, and 12 months, with bone bridging observed at 12 months. Both groups of fusion cages demonstrated consistent mechanical stability across all time points. Serum biochemistry showed no abnormalities, and no significant pathological changes were observed in the heart, liver, spleen, lungs, and kidneys.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;This study confirms that 3D-printed and chemical vapor deposition porous tantalum fusion cages exhibit comparable, excellent osteogenic effects and long-term biocompatibility. Additionally, 3D-printed porous tantalum fusion cages offer unique advantages in achieving complex structural designs, low-cost manufacturing, and personalized customization, providing robust scientific support for future clinical applications.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;The translational potential of this article: &lt;/strong&gt;The translational potential of this paper is to use 3D printed biomimetic trabecular porous tantalum spine fusion cage with bone trabecular structure and validating its feasi","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"50 ","pages":"185-195"},"PeriodicalIF":5.9,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Vitamin D-Sirt1/PGC1α Axis Regulates Bone Metabolism and Counteracts Osteoporosis.","authors":"Cuicui Yang, Lulu Chen, Xiaoli Guo, Haijian Sun, Dengshun Miao","doi":"10.1016/j.jot.2024.10.011","DOIUrl":"10.1016/j.jot.2024.10.011","url":null,"abstract":"<p><strong>Background: </strong>Objective: Vitamin D insufficiency is a major contributor to osteoporosis. This study aimed to elucidate the mechanisms by which the vitamin D-Sirt1/PGC1α axis regulates bone metabolism and counteracts osteoporosis induced by active vitamin D insufficiency.</p><p><strong>Methods: </strong>Mouse models including Sirt1 transgenic (Sirt1^Tg), Cyp27b1^+/- (active vitamin D deficient), and compound Sirt1^TgCyp27b1^+/- mice were utilized. Bone parameters were assessed by radiography, micro-CT, histology, and immunohistochemistry. In vitro studies used bone marrow-derived mesenchymal stem cells (BM-MSCs). Gene and protein expression were analyzed by RT-PCR and Western blotting. Chromatin immunoprecipitation and luciferase assays investigated transcriptional regulation. Effects of resveratrol supplementation were examined.</p><p><strong>Results: </strong>1,25-dihydroxyvitamin D (1,25(OH)₂D) insufficiency caused downregulation of Sirt1 expression, leading to accelerated bone loss. Overexpression of Sirt1 in mesenchymal stem cells corrected bone loss by inhibiting oxidative stress, DNA damage, osteocyte senescence and senescence-associated secretory phenotype, promoting osteoblastic bone formation, and reducing osteoclastic bone resorption. 1,25(OH)₂D₃ transcriptionally upregulated Sirt1 expression in BM-MSCs through vitamin D receptor binding to the Sirt1 gene promoter. Resveratrol, a Sirt1 agonist, attenuated osteoporosis induced by 1,25(OH)₂D insufficiency by modulating the Sirt1/PGC1α axis. Sirt1 interacted with and deacetylated PGC1α, a transcriptional coactivator involved in mitochondrial biogenesis and energy metabolism. Deacetylated PGC1α mediated the effects of Sirt1 on osteogenesis, oxidative stress, and cellular senescence in BM-MSCs.</p><p><strong>Conclusion: </strong>This study elucidated the critical role of the vitamin D-Sirt1/PGC1α axis in regulating bone metabolism and counteracting osteoporosis induced by active vitamin D insufficiency. The findings highlight the potential of this axis as a therapeutic target for the prevention and treatment of osteoporosis.</p>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"50 ","pages":"211-222"},"PeriodicalIF":5.9,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11787469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LRP1 mitigates intervertebral disc degeneration by inhibiting endoplasmic reticulum stress through stabilizing the PPARγ.","authors":"Dengbo Yao, Ming Li, Weike Zeng, Kun Wang, Zhuangyao Liao, Enming Chen, Tong Xing, Yuwei Liang, Jun Tang, Guoming Wen, Qing Ning, Yuxi Li, Lin Huang","doi":"10.1016/j.jot.2024.12.009","DOIUrl":"10.1016/j.jot.2024.12.009","url":null,"abstract":"<p><strong>Background: </strong>Intervertebral disc degeneration (IDD) is a significant cause of lower back pain, characterized by inflammation-mediated extracellular matrix (ECM) degradation, apoptosis, and aging of nucleus pulposus (NP) cells. Identifying key regulatory targets for these processes is crucial for IDD treatment. Previous research has highlighted the role of low-density lipoprotein receptor-related protein 1 (LRP1) in regulating ECM levels and cell fate, but its role in IDD remains under-explored. This study aims to elucidate the function and mechanism of LRP1 in the progression of IDD.</p><p><strong>Methods: </strong>LRP1 expression was assessed in clinical tissue samples from patients diagnosed with IDD and in a rat IDD model established using needle puncture injuries. The effects of LRP1 knockdown and treatment with the LRP1 activator SP16 on apoptosis and ECM metabolism in NP cells were analyzed, with a focus on their relationship with endoplasmic reticulum (ER) stress. The interaction and regulatory mechanism between LRP1 and peroxisome proliferator-activated receptor gamma (PPARγ) were further explored to clarify how LRP1 regulates ER stress. Finally, the in vivo therapeutic effect of SP16 was investigated using a rat tail IDD model.</p><p><strong>Results: </strong>We found that LRP1 expression was significantly downregulated in IDD. In NP cells with LRP1 knockdown, there was a marked increase in apoptosis and detrimental ECM remodeling, which were associated with the activation of ER stress. Our research further revealed that LRP1 interacts with PPARγ, stabilizing the PPARγ protein and preventing its lysosomal degradation, thereby mitigating ER stress. Activation of LRP1 in our models significantly reduced ER stress, matrix degradation, and apoptosis, thereby attenuating IDD both in vitro and in vivo.</p><p><strong>Conclusion: </strong>This study systematically investigated the role and mechanisms of the LRP1/PPARγ/ER stress signaling axis in IDD. Our findings suggest that targeting LRP1 to modulate this signaling pathway could provide a promising therapeutic approach for the treatment of IDD.</p><p><strong>The translational potential of this article: </strong>Our study demonstrated that LRP1 can reduce apoptosis and ECM degradation by inhibiting ER stress through stabilizing PPARγ, indicating that targeting LRP1 may be a novel therapeutic strategy for IDD.</p>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"50 ","pages":"196-210"},"PeriodicalIF":5.9,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk-stratified lifetime risk and incidence of hip fracture and falls in middle-aged and elderly Chinese population: The China health and retirement longitudinal study.","authors":"Guangyuan Du, Zijuan Fan, Kenan Fan, Haifeng Liu, Jing Zhang, Dijun Li, Lei Yan, Jingwei Jiu, Ruoqi Li, Xiaoke Li, Songyan Li, Ligan Jia, Huachen Liu, Yijia Ren, Xuanbo Liu, Jiao Jiao Li, Bin Wang","doi":"10.1016/j.jot.2024.10.013","DOIUrl":"10.1016/j.jot.2024.10.013","url":null,"abstract":"<p><strong>Background: </strong>Hip fracture (HF) is one of the most prevalent orthopedic conditions among the elderly, with falls being the primary risk factor for HF. With the surge of aged population, China is facing great challenges from HF and falls. However, a comprehensive long-term observation of risk factors affecting HF and falls and their association are little reported at a national level.</p><p><strong>Methods: </strong>The longitudinal cohort was established using the China Health and Retirement Longitudinal Study (CHARLS) data from 2011 to 2018. The incidence density and multi-risk-stratified lifetime risk (up to 90 years of age) of falls and HF were studied at index ages of 50, 60, and 70, as well as the lifetime risk stratified by six regions in China, based on the modified Kaplan-Meier method with Statistical Analysis System (SAS).</p><p><strong>Results: </strong>This study identified 17 705 subjects aged 50-89. The incidence density of falls was 65.07 and 47.53 per 1000 person-years in women and men, respectively. The incidence density of HF was also higher in women at 5.58 per 1000 person-years than in men at 4.88. By age 50, the lifetime risk of experiencing a HF was 18.58 % for women and 13.72 % for men. Vision and hearing abilities were significantly related to the lifetime risk of both falls and HF. Obesity-related factors presented age-relevant relationships with lifelong risks. Lack of naps, poor lower limb strength, and physical capabilities were indicative of HF risk. The north-western region of China had the lowest lifetime risk of falls but highest risk of HF, while other regions showed a consistent trend between falls and HF.</p><p><strong>Conclusion: </strong>The aging population worldwide faces a considerable risk of falls and HF. Several risk factors were identified in this study using a Chinese population, relating to disease history, lifestyle habits, health status and physical function, and the risks differed among six regions in China. Future precautionary management programs, as well as patient self-awareness are necessary for improving the prevention of falls and HF to reduce their incidence in the aging population.</p><p><strong>The translational potential of this article: </strong>With the greatest aged population worldwide, China faces the unparalleled challenge on public health. The study poses the lifetime risk of hip fracture and falls stratified by multiple risk factors in people from 45 to 90 in a national scale, which would shed a light on the early and continuous prevention of such injury.</p>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"50 ","pages":"174-184"},"PeriodicalIF":5.9,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel application perspective of the clinical-used drug verapamil on osteoporosis via targeting <i>Txnip</i>.","authors":"Xiankun Cao, Kewei Rong, Yinghua Li, Pu Zhang, Kexin Liu, Lei Cui, Shaotian Fu, Qi Hua, Xiao Yang, Hang Zhang, Xiaofei Cheng, Peixiang Ma, Jie Zhao, An Qin","doi":"10.1016/j.jot.2024.10.006","DOIUrl":"10.1016/j.jot.2024.10.006","url":null,"abstract":"<p><strong>Background: </strong>RANKL and SCLEROSTIN antibodies have provided a strong effective choice for treating osteoporosis in the past years, which suggested novel molecular target identification and therapeutic strategies development are important for the treatment of osteoporosis. The therapeutic effect of verapamil, a drug previously used for cardiovascular diseases, on diabetes was due to the inhibition of TXNIP expression, which has also been reported as a target in mice osteoporosis. Whether verapamil-inhibited TXNIP expression is related to osteoporosis and how it works on the molecular level is worthy to be explored.</p><p><strong>Methods: </strong>The polymorphism genotyping analysis was performed on patients with different degrees of osteoporosis. The responsiveness of bone marrow-derived macrophage cells (bone marrow-derived mesenchymal stem cells) to verapamil was evaluated by CCK-8, TRAP staining assay (ALP and AR staining assay), Bone Resorption Assay, and RNA-Sequencing. The expression and cytoplasmic efflux of ChREBP were determined by western blotting and immunofluorescence. Bilateral ovariectomy models were created, rescued by verapamil injection and the effectiveness was evaluated by Micro-CT and Histological analysis.</p><p><strong>Results: </strong>Here we discovered that rs7211 single nucleotide polymorphism (SNP) of <i>TXNIP</i> is closely associated with increased femur neck bone mineral density (BMD) and decreased osteoporosis rate, suggesting the importance of TXNIP in the development of osteoporosis. Verapamil suppresses <i>Txnip</i> expression, reduces bone turnover rate and thus rescues ovariectomy-induced mice bone loss. Mechanistically, verapamil promoted ChREBP cytoplasmic efflux, regulated Pparγ expression both mediating Txnip-MAPK, NF- <math><mrow><mi>κ</mi></mrow> </math> B axis in osteoclasts, and suppressed the ChREBP-Txnip-Bmp2 axis in osteoblasts.</p><p><strong>Conclusions: </strong>The results of our study show the correlation of rs7211 <i>TXNIP-T</i> allele with Chinese increased femur neck BMD and decreased osteoporosis rate. In addition, verapamil can rescue mice from osteoporosis by regulateing ChREBP, Pparγ-Txnip-MAPK, NF- <math><mrow><mi>κ</mi></mrow> </math> B axis in osteoclasts and ChREBP-Txnip-Bmp2 axis in osteoblasts.</p><p><strong>The translational potential of this article: </strong>The inhibition of Txnip by verapamil in osteoclasts and osteoblasts leads to low bone turnover and reduced bilateral ovariectomy-induced mice bone loss, which points out its great clinical translation potential on postmenopausal osteoporosis treatment.</p>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"50 ","pages":"158-173"},"PeriodicalIF":5.9,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}