Pub Date : 2025-04-25DOI: 10.1016/j.jot.2025.04.005
Wenjie Hou , Xingru Shang , Xiaoxia Hao , Chunran Pan , Zehang Zheng , Yiwen Zhang , Xiaofeng Deng , Ruimin Chi , Jiawei Liu , Fengjing Guo , Kai Sun , Tao Xu
Background
Paraptosis is a novel form of programmed cell death, generally caused by disrupted proteostasis or alterations of redox homeostasis. However, its impact and underlying mechanisms on the pathology of osteoarthritis (OA) are still unclear. This study aimed to investigate the role and regulatory mechanism of SHP2 in chondrocyte paraptosis and the effects influenced by low-intensity pulsed ultrasound (LIPUS).
Methods
SHP2, a MAPK upstream intermediary, has been identified as one of the critical targets of IL-1β-induced paraptosis in the GEO and GeneCard databases. The expression of SHP2 in chondrocytes was regulated by either siRNA knockdown or plasmid overexpression. Additionally, adeno-associated viruses were injected into the knee joints of rats to explore whether SHP2 plays a role in the development of OA. The impact of LIPUS on paraptosis and OA was examined in IL-1β-induced chondrocytes and a post-traumatic OA model, with SHP2 regulation assessed at both cellular and animal levels.
Results
An increase in cellular reactive oxygen species (ROS) caused by IL-1β halts the growth of chondrocytes and induces paraptosis in the chondrocytes. IL-1β-induced paraptosis, manifested as endoplasmic reticulum (ER)-derived vacuolization, was mediated by ROS-mediated ER stress and MAPK activation. SHP2 facilitates ROS production, thereby exacerbating the chondrocytes paraptosis. SHP2 knockdown and ROS inhibition effectively reduced this process and significantly mitigated inflammation and cartilage degeneration. Furthermore, we discovered that LIPUS delayed OA progression by inhibiting the activation of the MAPK pathway, ER stress, and ER-derived vacuoles in chondrocytes, all of which play critical roles in paraptosis, through the downregulation of SHP2 expression. Results on animals showed that LIPUS inhibited cartilage degeneration and alleviated OA progression.
Conclusion
SHP2 exacerbates IL-1β-induced oxidative stress and the subsequent paraptosis in chondrocytes, promoting OA progression. LIPUS mitigates paraptosis by modulating SHP2, which in turn slows OA progression.
The translational potential of this article
This study indicates that a novel SHP2-mediated cell death mechanism, paraptosis, plays a role in post-traumatic OA progression. LIPUS helps maintain cartilage-subchondral bone unit integrity by targeting SHP2 inhibition. SHP2 emerges as a potential therapeutic target, while LIPUS provides a promising non-invasive approach for treating trauma-related OA.
背景自噬是一种新型的程序性细胞死亡，通常由蛋白稳态紊乱或氧化还原稳态改变引起。然而，其对骨关节炎（OA）病理的影响和内在机制仍不清楚。本研究旨在探讨SHP2在软骨细胞凋亡中的作用和调控机制以及低强度脉冲超声（LIPUS）对其的影响。方法SHP2是MAPK的上游中间体，在GEO和GeneCard数据库中已被确定为IL-1β诱导凋亡的关键靶点之一。SHP2在软骨细胞中的表达受siRNA敲除或质粒过表达调控。此外，还向大鼠膝关节中注射了腺相关病毒，以探讨SHP2是否在OA的发展过程中发挥作用。结果 IL-1β引起的细胞活性氧（ROS）增加会阻止软骨细胞的生长，并诱导软骨细胞发生凋亡。IL-1β诱导的凋亡表现为内质网（ER）产生的空泡化，是由ROS介导的ER应激和MAPK活化介导的。SHP2促进了ROS的产生，从而加剧了软骨细胞的aptosis。敲除 SHP2 和抑制 ROS 可有效减少这一过程，并显著减轻炎症和软骨退化。此外，我们还发现，LIPUS通过下调SHP2的表达，抑制了软骨细胞中MAPK通路的激活、ER应激和ER衍生空泡，从而延缓了OA的进展。动物实验结果表明，LIPUS 可抑制软骨变性，缓解 OA 进展。LIPUS通过调节SHP2减轻副aptosis，进而减缓OA的进展。本文的转化潜力这项研究表明，SHP2介导的一种新型细胞死亡机制--副aptosis在创伤后OA进展中发挥了作用。LIPUS通过靶向抑制SHP2有助于维持软骨-软骨下骨单元的完整性。SHP2 成为潜在的治疗靶点，而 LIPUS 则为治疗创伤相关的 OA 提供了一种前景广阔的非侵入性方法。
{"title":"SHP2-mediated ROS activation induces chondrocyte paraptosis in osteoarthritis and is attenuated by low-intensity pulsed ultrasound","authors":"Wenjie Hou , Xingru Shang , Xiaoxia Hao , Chunran Pan , Zehang Zheng , Yiwen Zhang , Xiaofeng Deng , Ruimin Chi , Jiawei Liu , Fengjing Guo , Kai Sun , Tao Xu","doi":"10.1016/j.jot.2025.04.005","DOIUrl":"10.1016/j.jot.2025.04.005","url":null,"abstract":"<div><h3>Background</h3><div>Paraptosis is a novel form of programmed cell death, generally caused by disrupted proteostasis or alterations of redox homeostasis. However, its impact and underlying mechanisms on the pathology of osteoarthritis (OA) are still unclear. This study aimed to investigate the role and regulatory mechanism of SHP2 in chondrocyte paraptosis and the effects influenced by low-intensity pulsed ultrasound (LIPUS).</div></div><div><h3>Methods</h3><div>SHP2, a MAPK upstream intermediary, has been identified as one of the critical targets of IL-1β-induced paraptosis in the GEO and GeneCard databases. The expression of SHP2 in chondrocytes was regulated by either siRNA knockdown or plasmid overexpression. Additionally, adeno-associated viruses were injected into the knee joints of rats to explore whether SHP2 plays a role in the development of OA. The impact of LIPUS on paraptosis and OA was examined in IL-1β-induced chondrocytes and a post-traumatic OA model, with SHP2 regulation assessed at both cellular and animal levels.</div></div><div><h3>Results</h3><div>An increase in cellular reactive oxygen species (ROS) caused by IL-1β halts the growth of chondrocytes and induces paraptosis in the chondrocytes. IL-1β-induced paraptosis, manifested as endoplasmic reticulum (ER)-derived vacuolization, was mediated by ROS-mediated ER stress and MAPK activation. SHP2 facilitates ROS production, thereby exacerbating the chondrocytes paraptosis. SHP2 knockdown and ROS inhibition effectively reduced this process and significantly mitigated inflammation and cartilage degeneration. Furthermore, we discovered that LIPUS delayed OA progression by inhibiting the activation of the MAPK pathway, ER stress, and ER-derived vacuoles in chondrocytes, all of which play critical roles in paraptosis, through the downregulation of SHP2 expression. Results on animals showed that LIPUS inhibited cartilage degeneration and alleviated OA progression.</div></div><div><h3>Conclusion</h3><div>SHP2 exacerbates IL-1β-induced oxidative stress and the subsequent paraptosis in chondrocytes, promoting OA progression. LIPUS mitigates paraptosis by modulating SHP2, which in turn slows OA progression.</div></div><div><h3>The translational potential of this article</h3><div>This study indicates that a novel SHP2-mediated cell death mechanism, paraptosis, plays a role in post-traumatic OA progression. LIPUS helps maintain cartilage-subchondral bone unit integrity by targeting SHP2 inhibition. SHP2 emerges as a potential therapeutic target, while LIPUS provides a promising non-invasive approach for treating trauma-related OA.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 233-248"},"PeriodicalIF":5.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873722","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 : 2025-04-25DOI: 10.1016/j.jot.2025.04.008
Chao Jiang , Yuhang Gong , Xinyu Wu , Jiangjie Chen , Yiyu Chen , Jingyao Chen , Fang Tang , Zhiyu Fang , Yuxuan Bao , Jiajing Ye , Zhangfu Wang , Zhenghua Hong
Background
Osteoarthritis (OA), the most prevalent form of arthritis, is swiftly emerging as a chronic health condition, that poses the primary cause of disability and significant socioeconomic burden. Despite its prevalence, effective therapeutic options for OA remain elusive. This study seeks to explore the therapeutic potential of edaravone (EDA), a FDA-approved free radical scavenger, in the context of OA development and to elucidate its underlying mechanisms.
Methods
In vitro, oxidative stress models were induced by stimulating chondrocytes with t-butylhydroperoxide (TBHP); then, we investigated the influence of EDA on chondrocyte dysfunction, apoptosis, inflammatory responses and mitochondrial function in TBHP-treated chondrocytes, along with the underlying mechanisms. In vivo, destabilization of the medial meniscus (DMM) model was used to investigate the impact of EDA on OA progression. Nrf2−/− mice were applied to determine the potential role of NRF2 as a target for EDA.
Results
EDA notably alleviates chondrocyte dysfunction triggered by oxidative stress, safeguards chondrocytes from apoptosis and inflammatory responses, and preserves mitochondrial function and redox balance within chondrocytes. At the molecular level, EDA appears to halt the progression of OA by engaging and activating the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, which is crucial for maintaining mitochondrial function and redox equilibrium. Notably, the protective effects of EDA on OA are abolished in Nrf2−/− mice, underscoring the significance of the NRF2 signaling pathway in mediating EDA's therapeutic effects.
Conclusion
EDA has the potential to mitigate chondrocyte degeneration, thereby slowing the progression of OA. Thus, EDA may represent a novel therapeutic agent for the treatment of OA, potentially expanding its clinical utility.
The translational potential of this article
As a clinically licensed drug used for the treatment of neurological disorders, edaravone has shown promising therapeutic effects on OA development. Mechanistically, edaravone stabilized mitochondrial function and maintained redox homeostasis by activating NRF2 signaling pathway. The protective effects of edaravone against OA were verified in vivo and in vitro. These findings presented robust evidence for repurposing edaravone for the treatment of OA in clinic.
{"title":"Therapeutic effect of edaravone on osteoarthritis: targeting NRF2 signaling and mitochondrial function","authors":"Chao Jiang , Yuhang Gong , Xinyu Wu , Jiangjie Chen , Yiyu Chen , Jingyao Chen , Fang Tang , Zhiyu Fang , Yuxuan Bao , Jiajing Ye , Zhangfu Wang , Zhenghua Hong","doi":"10.1016/j.jot.2025.04.008","DOIUrl":"10.1016/j.jot.2025.04.008","url":null,"abstract":"<div><h3>Background</h3><div>Osteoarthritis (OA), the most prevalent form of arthritis, is swiftly emerging as a chronic health condition, that poses the primary cause of disability and significant socioeconomic burden. Despite its prevalence, effective therapeutic options for OA remain elusive. This study seeks to explore the therapeutic potential of edaravone (EDA), a FDA-approved free radical scavenger, in the context of OA development and to elucidate its underlying mechanisms.</div></div><div><h3>Methods</h3><div><em>In vitro</em>, oxidative stress models were induced by stimulating chondrocytes with t-butylhydroperoxide (TBHP); then, we investigated the influence of EDA on chondrocyte dysfunction, apoptosis, inflammatory responses and mitochondrial function in TBHP-treated chondrocytes, along with the underlying mechanisms. <em>In vivo</em>, destabilization of the medial meniscus (DMM) model was used to investigate the impact of EDA on OA progression. <em>Nrf2</em><sup>−/−</sup> mice were applied to determine the potential role of NRF2 as a target for EDA.</div></div><div><h3>Results</h3><div>EDA notably alleviates chondrocyte dysfunction triggered by oxidative stress, safeguards chondrocytes from apoptosis and inflammatory responses, and preserves mitochondrial function and redox balance within chondrocytes. At the molecular level, EDA appears to halt the progression of OA by engaging and activating the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, which is crucial for maintaining mitochondrial function and redox equilibrium. Notably, the protective effects of EDA on OA are abolished in <em>Nrf2</em><sup>−/−</sup> mice, underscoring the significance of the NRF2 signaling pathway in mediating EDA's therapeutic effects.</div></div><div><h3>Conclusion</h3><div>EDA has the potential to mitigate chondrocyte degeneration, thereby slowing the progression of OA. Thus, EDA may represent a novel therapeutic agent for the treatment of OA, potentially expanding its clinical utility.</div></div><div><h3>The translational potential of this article</h3><div>As a clinically licensed drug used for the treatment of neurological disorders, edaravone has shown promising therapeutic effects on OA development. Mechanistically, edaravone stabilized mitochondrial function and maintained redox homeostasis by activating NRF2 signaling pathway. The protective effects of edaravone against OA were verified <em>in vivo</em> and <em>in vitro</em>. These findings presented robust evidence for repurposing edaravone for the treatment of OA in clinic.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 220-232"},"PeriodicalIF":5.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869086","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 : 2025-04-24DOI: 10.1016/j.jot.2025.03.022
Zhuang Miao , Songlin Li , Yange Luo , Shihao Li , Ziyue Chu , Weibo Zheng , Xuezhou Li , Qunshan Lu , Peilai Liu
Background
High body-mass-index (BMI) has been shown to be a risk factor for knee osteoarthritis (KOA). Previous studies have examined the global or regional burden of osteoarthritis in multiple joints, including the hip, knee, and hand. However, there is no comprehensive analysis and prediction of the global burden of KOA attributed to high BMI.
Methods
Disease burden of KOA attributable to high BMI, from 1990 to 2021, were extracted from the Global Burden of Disease (GBD) 2021. Trends were analyzed at the global, regional, and national levels, with subgroup analyses. Joinpoint regression, age-period-cohort model, decomposition analysis, cross-country inequalities were used to analyze the trend of disease burden from multiple dimensions. Autoregressive integrated moving average (ARIMA) model, a time-series based forecasting algorithms, was applied to predict the burden for the next 20 years.
Results
From 1990 to 2021, the risk factor attribution of high BMI in KOA increased from 25.44 % (95 % CI: −2.38 %–48.66 %) to 33.52 % (95 % CI: −3.38 %–61.92 %). Globally, regionally, and nationally, the burden of KOA attributed to high BMI showed a sharp increase. Except for the decline observed in high sociodemographic index (SDI) regions from 2000 to 2005, the burden exhibited an upward trend across all other time periods and regions. Age, cohort, and period had significant impacts on disease burden. Both population growth and epidemiological changes contributed positively to the increase in the burden. Economic and social development led to increasing disparities, with lower-SDI countries showing better health outcomes. ARIMA model showed that a continued rise in the burden of KOA due to high BMI globally through 2041.
Conclusions
KOA attributable to high BMI has imposed a substantial burden globally, regionally, and nationally over the past 30 years, with a marked increase. The projections indicate a further increase in the global burden over the next 20 years. Measures need to be taken for targeted preventive intervention.
The translational potential of this article
High BMI is an important risk factor for KOA. The disease burden of KOA attributable to high BMI has increased significantly over the past 30 years. This burden is concentrated in economically developed areas, although the growth rate in less developed regions surpasses that of developed regions. This study suggested that targeted interventions addressing disease patterns across socioeconomic contexts are crucial to mitigating the burden of KOA attributable to high BMI. In addition, it is necessary to pay more attention to the disease burden of female.
{"title":"Trends, inequalities and time-series based prediction of knee osteoarthritis attributed to high body-mass-index: findings from global burden of disease 2021","authors":"Zhuang Miao , Songlin Li , Yange Luo , Shihao Li , Ziyue Chu , Weibo Zheng , Xuezhou Li , Qunshan Lu , Peilai Liu","doi":"10.1016/j.jot.2025.03.022","DOIUrl":"10.1016/j.jot.2025.03.022","url":null,"abstract":"<div><h3>Background</h3><div>High body-mass-index (BMI) has been shown to be a risk factor for knee osteoarthritis (KOA). Previous studies have examined the global or regional burden of osteoarthritis in multiple joints, including the hip, knee, and hand. However, there is no comprehensive analysis and prediction of the global burden of KOA attributed to high BMI.</div></div><div><h3>Methods</h3><div>Disease burden of KOA attributable to high BMI, from 1990 to 2021, were extracted from the Global Burden of Disease (GBD) 2021. Trends were analyzed at the global, regional, and national levels, with subgroup analyses. Joinpoint regression, age-period-cohort model, decomposition analysis, cross-country inequalities were used to analyze the trend of disease burden from multiple dimensions. Autoregressive integrated moving average (ARIMA) model, a time-series based forecasting algorithms, was applied to predict the burden for the next 20 years.</div></div><div><h3>Results</h3><div>From 1990 to 2021, the risk factor attribution of high BMI in KOA increased from 25.44 % (95 % CI: −2.38 %–48.66 %) to 33.52 % (95 % CI: −3.38 %–61.92 %). Globally, regionally, and nationally, the burden of KOA attributed to high BMI showed a sharp increase. Except for the decline observed in high sociodemographic index (SDI) regions from 2000 to 2005, the burden exhibited an upward trend across all other time periods and regions. Age, cohort, and period had significant impacts on disease burden. Both population growth and epidemiological changes contributed positively to the increase in the burden. Economic and social development led to increasing disparities, with lower-SDI countries showing better health outcomes. ARIMA model showed that a continued rise in the burden of KOA due to high BMI globally through 2041.</div></div><div><h3>Conclusions</h3><div>KOA attributable to high BMI has imposed a substantial burden globally, regionally, and nationally over the past 30 years, with a marked increase. The projections indicate a further increase in the global burden over the next 20 years. Measures need to be taken for targeted preventive intervention.</div></div><div><h3>The translational potential of this article</h3><div>High BMI is an important risk factor for KOA. The disease burden of KOA attributable to high BMI has increased significantly over the past 30 years. This burden is concentrated in economically developed areas, although the growth rate in less developed regions surpasses that of developed regions. This study suggested that targeted interventions addressing disease patterns across socioeconomic contexts are crucial to mitigating the burden of KOA attributable to high BMI. In addition, it is necessary to pay more attention to the disease burden of female.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 209-219"},"PeriodicalIF":5.9,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869088","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 : 2025-04-24DOI: 10.1016/j.jot.2025.04.006
Qinghe Zeng , Yongjia Feng , Haipeng Huang , Kaiao Zou , Wenzhe Chen , Xuefeng Li , Yuliang Huang , Weidong Wang , Wenhua Yuan , Pinger Wang , Peijian Tong , Hongting Jin , Jiali Chen
Background
Joint bleeding (hemarthrosis) is a major manifestation of joint trauma, especially repeated and spontaneous in hemophilia patients. Hemarthrosis has been identified to induce the excessive reactive oxygen species (ROS) accumulation and permanent damage in articular cartilage. Dihydroartemisinin (DHA), a well-known clinical anti-malaria drug with few sides effects therapy, has been reported to possess anti-oxidative activity. This study was aimed at exploring the effect of DHA on blood-induced cartilage erosion and its underlying mechanisms.
Methods
Two distinct hemarthrosis models were constructed respectively by fresh blood joint injection in WT and joint needle puncture in F8−/− mice, and then treated with DHA (10 or 20 mg/kg/day) for 4 weeks. In vitro chondrocytes treated with frozen-thaw blood and DHA (1, 5 or 10 μM) for 24 h. Histopathological, immunofluorescence and western blotting were investigated to demonstrate the effects of DHA on blood-induced chondrocyte senescence, ROS accumulation and extracellular matrix (ECM) degradation. Additionally, Nrf2 inhibitor (MLB385, 30 mg/kg for once a four days) and Nrf2-siRNA were used to investigate the relationship between DHA and Nrf2/Keap1 signaling in vitro and in vivo, respectively.
Results
DHA remarkably ameliorated the cartilage degeneration in both two hemarthrosis models. Similarly, in vitro experiments confirmed that DHA promoted the synthesis of ECM in blood-stimulated chondrocytes with a dose-dependent manner. DHA also effectively suppressed blood-induced chondrocyte senescence and ROS accumulation. Mechanistically, DHA activated the Nrf2 signaling by accelerating Keap1 ubiquitination and degradation. Furthermore, Nrf2 siRNA and antagonist abolished the anti-senescence and anti-oxidative functions of DHA, resulting the severe cartilage degeneration in bleeding joint of F8−/− mice.
Conclusion
Our findings indicate that DHA effectively reduces chondrocyte senescence and mitigates cartilage destruction following hemarthrosis via activation of Nrf2/Keap1 signaling pathway.
The Translational potential of this article
On the one hand, this study highlights the important role of chondrocyte senescence in hemarthrosis-induced cartilage degradation, implying that inhibiting chondrocyte senescence may be a viable therapeutic strategy for blood-induced arthropathy. On the other hand, our findings demonstrate the remarkable chondroprotective effect of DHA in bleeding joint by modulating the Nrf2/Keap1 anti-oxidative signaling pathway, suggesting DHA may serve as a potential candidate drug for the therapy of blood-induced arthropathy.
{"title":"Dihydroartemisinin ameliorates hemarthrosis-induced cartilage degeneration by suppressing chondrocyte senescence via activation of Keap1-Nrf2 signaling pathway","authors":"Qinghe Zeng , Yongjia Feng , Haipeng Huang , Kaiao Zou , Wenzhe Chen , Xuefeng Li , Yuliang Huang , Weidong Wang , Wenhua Yuan , Pinger Wang , Peijian Tong , Hongting Jin , Jiali Chen","doi":"10.1016/j.jot.2025.04.006","DOIUrl":"10.1016/j.jot.2025.04.006","url":null,"abstract":"<div><h3>Background</h3><div>Joint bleeding (hemarthrosis) is a major manifestation of joint trauma, especially repeated and spontaneous in hemophilia patients. Hemarthrosis has been identified to induce the excessive reactive oxygen species (ROS) accumulation and permanent damage in articular cartilage. Dihydroartemisinin (DHA), a well-known clinical anti-malaria drug with few sides effects therapy, has been reported to possess anti-oxidative activity. This study was aimed at exploring the effect of DHA on blood-induced cartilage erosion and its underlying mechanisms.</div></div><div><h3>Methods</h3><div>Two distinct hemarthrosis models were constructed respectively by fresh blood joint injection in WT and joint needle puncture in <em>F8</em><sup><em>−/−</em></sup> mice, and then treated with DHA (10 or 20 mg/kg/day) for 4 weeks. <em>In vitro</em> chondrocytes treated with frozen-thaw blood and DHA (1, 5 or 10 μM) for 24 h. Histopathological, immunofluorescence and western blotting were investigated to demonstrate the effects of DHA on blood-induced chondrocyte senescence, ROS accumulation and extracellular matrix (ECM) degradation. Additionally, Nrf2 inhibitor (MLB385, 30 mg/kg for once a four days) and Nrf2-siRNA were used to investigate the relationship between DHA and Nrf2/Keap1 signaling <em>in vitro</em> and <em>in vivo</em>, respectively.</div></div><div><h3>Results</h3><div>DHA remarkably ameliorated the cartilage degeneration in both two hemarthrosis models. Similarly, <em>in vitro</em> experiments confirmed that DHA promoted the synthesis of ECM in blood-stimulated chondrocytes with a dose-dependent manner. DHA also effectively suppressed blood-induced chondrocyte senescence and ROS accumulation. Mechanistically, DHA activated the Nrf2 signaling by accelerating Keap1 ubiquitination and degradation. Furthermore, Nrf2 siRNA and antagonist abolished the anti-senescence and anti-oxidative functions of DHA, resulting the severe cartilage degeneration in bleeding joint of <em>F8</em><sup><em>−/−</em></sup> mice.</div></div><div><h3>Conclusion</h3><div>Our findings indicate that DHA effectively reduces chondrocyte senescence and mitigates cartilage destruction following hemarthrosis via activation of Nrf2/Keap1 signaling pathway.</div></div><div><h3>The Translational potential of this article</h3><div>On the one hand, this study highlights the important role of chondrocyte senescence in hemarthrosis-induced cartilage degradation, implying that inhibiting chondrocyte senescence may be a viable therapeutic strategy for blood-induced arthropathy. On the other hand, our findings demonstrate the remarkable chondroprotective effect of DHA in bleeding joint by modulating the Nrf2/Keap1 anti-oxidative signaling pathway, suggesting DHA may serve as a potential candidate drug for the therapy of blood-induced arthropathy.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 192-208"},"PeriodicalIF":5.9,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869087","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 : 2025-04-23DOI: 10.1016/j.jot.2025.04.007
Jing Zhang , Wenhui Hu , Yuheng Li , Fei Kang , Xuan Yao , Jianmei Li , Shiwu Dong
<div><h3>Background</h3><div>Osteoarthritis (OA) is a chronic joint disorder that predominantly affects middle-aged or elderly individuals. Subchondral bone remodeling due to osteoclast hyperactivation is regarded as a major feature of early OA. During osteoclast fusion and multinucleation, the cytoskeleton reorganization leads to the formation of actin belts and ultimately bone resorption. Membrane-associated guanylate kinase with an inverted repeat member 1 (MAGI1) is a scaffolding protein that is crucial for linking the extracellular environment to intracellular signaling pathways and cytoskeleton. However, the role of MAGI1 in subchondral bone osteoclast fusion remains unclear.</div></div><div><h3>Methods</h3><div>In this study, we collected knee joint samples from OA patients and established the OA mouse model to examine the expression of MAGI1. Furthermore, we established the OA rat model and locally injected rAAV9-mediated shMagi1 into the subchondral bone to knock down MAGI1 expression. Micro-CT, histological staining, and immunofluorescence were employed to assess the effects of MAGI1 knockdown on subchondral bone homeostasis and OA process. We isolated and cultured osteoclasts from femoral and tibial bone marrow. Receptor activator of nuclear factor-κB ligand (RANKL)-stimulated osteoclasts served as an <em>in vitro</em> model for OA and underwent RNA sequencing. We employed gain- and loss-of-function experiments using MAGI1-overexpression plasmids and small interfering RNA to explore the role of MAGI1 in osteoclast differentiation. Further molecular experiments, including RT-qPCR, western blotting, immunofluorescence staining, and LC-MS/MS were performed to investigate underlying mechanisms.</div></div><div><h3>Results</h3><div>MAGI1 expression was significantly downregulated during RANKL-induced osteoclastogenesis <em>in vitro</em>. Additionally, a progressive decrease in MAGI1 expression was consistently observed in both knee joint samples from OA patients and mouse OA models, correlating with OA progression. Knockdown of MAGI1 in subchondral bone increased osteoclast numbers and worsened subchondral bone microarchitecture and cartilage degeneration; MAGI1 knockdown rats exhibited elevated PDGF-BB, Netrin-1, and CGRP<sup>+</sup> sensory innervation. Overexpression and knockdown of MAGI1 suppressed and promoted osteoclast differentiation, respectively. Mechanistically, MAGI1 overexpression decreased the levels of RhoA, ROCK1, and p-p65 in RANKL-treated osteoclasts, which was rescued by the addition of RhoA activator narciclasine.</div></div><div><h3>Conclusion</h3><div>Our results demonstrate that MAGI1 suppresses osteoclast fusion through the RhoA/ROCK1 signaling pathway, targeting MAGI1 in subchondral bone osteoclasts may be a promising therapeutic strategy mitigate the advancement of OA.</div></div><div><h3>The translational potential of this article</h3><div>This study reveals that the scaffold protein MAGI1 participates in osteoar
{"title":"MAGI1 attenuates osteoarthritis by regulating osteoclast fusion in subchondral bone through the RhoA-ROCK1 signaling pathway","authors":"Jing Zhang , Wenhui Hu , Yuheng Li , Fei Kang , Xuan Yao , Jianmei Li , Shiwu Dong","doi":"10.1016/j.jot.2025.04.007","DOIUrl":"10.1016/j.jot.2025.04.007","url":null,"abstract":"<div><h3>Background</h3><div>Osteoarthritis (OA) is a chronic joint disorder that predominantly affects middle-aged or elderly individuals. Subchondral bone remodeling due to osteoclast hyperactivation is regarded as a major feature of early OA. During osteoclast fusion and multinucleation, the cytoskeleton reorganization leads to the formation of actin belts and ultimately bone resorption. Membrane-associated guanylate kinase with an inverted repeat member 1 (MAGI1) is a scaffolding protein that is crucial for linking the extracellular environment to intracellular signaling pathways and cytoskeleton. However, the role of MAGI1 in subchondral bone osteoclast fusion remains unclear.</div></div><div><h3>Methods</h3><div>In this study, we collected knee joint samples from OA patients and established the OA mouse model to examine the expression of MAGI1. Furthermore, we established the OA rat model and locally injected rAAV9-mediated shMagi1 into the subchondral bone to knock down MAGI1 expression. Micro-CT, histological staining, and immunofluorescence were employed to assess the effects of MAGI1 knockdown on subchondral bone homeostasis and OA process. We isolated and cultured osteoclasts from femoral and tibial bone marrow. Receptor activator of nuclear factor-κB ligand (RANKL)-stimulated osteoclasts served as an <em>in vitro</em> model for OA and underwent RNA sequencing. We employed gain- and loss-of-function experiments using MAGI1-overexpression plasmids and small interfering RNA to explore the role of MAGI1 in osteoclast differentiation. Further molecular experiments, including RT-qPCR, western blotting, immunofluorescence staining, and LC-MS/MS were performed to investigate underlying mechanisms.</div></div><div><h3>Results</h3><div>MAGI1 expression was significantly downregulated during RANKL-induced osteoclastogenesis <em>in vitro</em>. Additionally, a progressive decrease in MAGI1 expression was consistently observed in both knee joint samples from OA patients and mouse OA models, correlating with OA progression. Knockdown of MAGI1 in subchondral bone increased osteoclast numbers and worsened subchondral bone microarchitecture and cartilage degeneration; MAGI1 knockdown rats exhibited elevated PDGF-BB, Netrin-1, and CGRP<sup>+</sup> sensory innervation. Overexpression and knockdown of MAGI1 suppressed and promoted osteoclast differentiation, respectively. Mechanistically, MAGI1 overexpression decreased the levels of RhoA, ROCK1, and p-p65 in RANKL-treated osteoclasts, which was rescued by the addition of RhoA activator narciclasine.</div></div><div><h3>Conclusion</h3><div>Our results demonstrate that MAGI1 suppresses osteoclast fusion through the RhoA/ROCK1 signaling pathway, targeting MAGI1 in subchondral bone osteoclasts may be a promising therapeutic strategy mitigate the advancement of OA.</div></div><div><h3>The translational potential of this article</h3><div>This study reveals that the scaffold protein MAGI1 participates in osteoar","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 167-181"},"PeriodicalIF":5.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858925","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 : 2025-04-23DOI: 10.1016/j.jot.2025.04.004
Simon von Kroge , Constantin Schmidt , Sebastian Butscheidt , Malte Ohlmeier , Michael Amling , Frank Timo Beil , Thorsten Gehrke , Klaus Püschel , Michael Hahn , Tim Rolvien
Background
Periprosthetic bone loss is a common clinical problem in hip arthroplasty that must be addressed during revision surgery to achieve adequate implant stability. Although bone allografts represent the clinical standard among substitute materials used, evidence of their regenerative potential at the microstructural, cellular, and compositional level is lacking.
Methods
A multiscale imaging approach comprising contact radiography, undecalcified histology, scanning electron microscopy, and nanoindentation was employed on human femoral explants obtained postmortem many years after allograft use during revision surgery.
Results
The degree of skeletal regeneration through allograft incorporation between host bone and allograft bone was highly dependent on the defect depth (R2 = 0.94, p < 0.001), while no association between the allograft time in situ and incorporation (R2 = 0.06, p = 0.61) was apparent. The host bone-allograft interface showed a high overlap of 4.0 ± 2.9 mm and was characterized by active bone remodelling, as indicated by osteoid accumulation, high abundance of bone cells and vasculature. While bone cement generally limited the incorporation process, the osteocytic canalicular system of the host bone reached the allograft interface to guide bone remodelling.
Conclusion
This is the first multiscale, histomorphometry-based evaluation of bone allografts used in revision hip arthroplasty for femoral bone loss in humans, demonstrating that they adequately facilitate skeletal regeneration through osteoconduction and subsequent remodelling.
The translational potential of this article
This study identified the mechanisms and determinants of femoral defect regeneration through allografts on the basis of a unique sample collection. While our results support their favourable clinical outcomes, the scientific basis for incomplete incorporation is also demonstrated.
背景：假体周围骨丢失是髋关节置换术中常见的临床问题，必须在翻修手术中加以解决，以获得足够的假体稳定性。尽管同种异体骨移植物代表了临床使用的替代材料的标准，但在微观结构，细胞和成分水平上缺乏其再生潜力的证据。方法采用多尺度成像方法，包括接触x线摄影、未钙化组织学、扫描电镜和纳米压痕，对翻修手术中使用同种异体移植多年后获得的人股骨外植体进行扫描。结果同种异体骨与宿主骨结合的骨再生程度与骨缺损深度高度相关(R2 = 0.94, p <；0.001)，而同种异体移植物原位时间与植入无明显相关性（R2 = 0.06, p = 0.61）。宿主骨-同种异体移植物界面高度重叠（4.0±2.9 mm），具有骨重构活跃的特征，表现为类骨积累、骨细胞和血管的高丰度。骨水泥通常限制了骨融合过程，宿主骨的骨细胞小管系统到达同种异体移植物界面，引导骨重建。这是第一个基于组织形态学的多尺度评估异体骨移植物用于人类股骨骨丢失的翻修髋关节置换术，证明它们通过骨传导和随后的重塑充分促进骨骼再生。本研究通过独特的样本收集确定了同种异体移植股骨缺损再生的机制和决定因素。虽然我们的结果支持其良好的临床结果，但也证明了不完全结合的科学依据。
{"title":"Allografts promote skeletal regeneration of periprosthetic femoral bone loss","authors":"Simon von Kroge , Constantin Schmidt , Sebastian Butscheidt , Malte Ohlmeier , Michael Amling , Frank Timo Beil , Thorsten Gehrke , Klaus Püschel , Michael Hahn , Tim Rolvien","doi":"10.1016/j.jot.2025.04.004","DOIUrl":"10.1016/j.jot.2025.04.004","url":null,"abstract":"<div><h3>Background</h3><div>Periprosthetic bone loss is a common clinical problem in hip arthroplasty that must be addressed during revision surgery to achieve adequate implant stability. Although bone allografts represent the clinical standard among substitute materials used, evidence of their regenerative potential at the microstructural, cellular, and compositional level is lacking.</div></div><div><h3>Methods</h3><div>A multiscale imaging approach comprising contact radiography, undecalcified histology, scanning electron microscopy, and nanoindentation was employed on human femoral explants obtained postmortem many years after allograft use during revision surgery.</div></div><div><h3>Results</h3><div>The degree of skeletal regeneration through allograft incorporation between host bone and allograft bone was highly dependent on the defect depth (R<sup>2</sup> = 0.94, <em>p <</em> 0.001), while no association between the allograft time <em>in situ</em> and incorporation (R<sup>2</sup> = 0.06, <em>p</em> = 0.61) was apparent. The host bone-allograft interface showed a high overlap of 4.0 ± 2.9 mm and was characterized by active bone remodelling, as indicated by osteoid accumulation, high abundance of bone cells and vasculature. While bone cement generally limited the incorporation process, the osteocytic canalicular system of the host bone reached the allograft interface to guide bone remodelling.</div></div><div><h3>Conclusion</h3><div>This is the first multiscale, histomorphometry-based evaluation of bone allografts used in revision hip arthroplasty for femoral bone loss in humans, demonstrating that they adequately facilitate skeletal regeneration through osteoconduction and subsequent remodelling.</div></div><div><h3>The translational potential of this article</h3><div>This study identified the mechanisms and determinants of femoral defect regeneration through allografts on the basis of a unique sample collection. While our results support their favourable clinical outcomes, the scientific basis for incomplete incorporation is also demonstrated.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 182-191"},"PeriodicalIF":5.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858926","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 : 2025-04-22DOI: 10.1016/j.jot.2025.03.020
Wenjie Liu , Qing Wang , Hao Liu , Suqin He , Hongxiang Wang , Chengwei Xu , Chaofan Jin , Na Li , Lianxin Li
Background
Titanium-based implants have demonstrated good mechanical properties and biocompatibility in clinical applications, however, their inherent low bioactivity and complex biological behaviors during the process of osseointegration have resulted in a high rate of long-term implant failure. Although the immobilization of highly bioactive peptides on the implant surface is an effective strategy to improve osseointegration, the existing mono- and bifunctional peptide-modified implant surfaces can hardly meet the needs of cell behavior regulation and tissue regeneration during the process of osseointegration, and there is an urgent need for the development of more efficient surface modification technologies.
Methods
In the present study, a multifunctional peptide-modified implant material, MPN@K6, was successfully prepared by linking one end of a tripeptide system (cell adhesion peptide RGD, osteogenic growth peptide OGP, and pro-angiogenic peptide ang), which possesses a specific biological function, to hexameric lysine, and constructing the tripeptide system on the surface of metal-polyphenol coatings (MPNs) by means of non-covalent interactions between the lysine and the polyphenol, and then the MPN@K6 - RGD/OGP/ang was used as a peptide modification. RGD/OGP/ang.
Results
The MPN@K6-RGD/OGP/Ang coating not only supported the early adhesion and migration, late osteogenesis and mineralization of BMSCs, but also promoted the adhesion, migration and vascularization of HUVECs. RT-qPCR results showed that the hybrid peptide up-regulated the expression of key factors in angiogenesis and osteogenesis. In vivo testing further confirmed these findings, with the functional peptide coating being 1.5 to 2 times more effective at inducing new bone formation at an early stage than the other two-peptide combinations, confirming the effectiveness and superiority of the tripeptide synergistic modification strategy.
Conclusions
The results showed that the MPN@K6 - RGD/OGP/ang-modified implant exhibited significant advantages at the cellular level compared to different combinations of bifunctional peptide-coated forms. It was able to promote early cell migration and adhesion more efficiently, significantly induced osteoblast differentiation and mineralization, and enhanced the level of local vascularization. In a rat bone defect animal model, the material demonstrated more excellent bone repair effects and achieved better bone healing results, confirming the effectiveness and superiority of the tripeptide synergistic modification strategy.
The translational potential of this article
The trifunctional peptide coating (MPN@K6 - RGD/OGP/Ang) constructed in this paper has a mild preparation process, is biologically safe, facilitates large-scale production, has a positive effect on bone tissue repair, and has a great potential for cl
{"title":"Endowing implants surface with enhanced vascularization and osseointegration via presenting triple-functional peptides","authors":"Wenjie Liu , Qing Wang , Hao Liu , Suqin He , Hongxiang Wang , Chengwei Xu , Chaofan Jin , Na Li , Lianxin Li","doi":"10.1016/j.jot.2025.03.020","DOIUrl":"10.1016/j.jot.2025.03.020","url":null,"abstract":"<div><h3>Background</h3><div>Titanium-based implants have demonstrated good mechanical properties and biocompatibility in clinical applications, however, their inherent low bioactivity and complex biological behaviors during the process of osseointegration have resulted in a high rate of long-term implant failure. Although the immobilization of highly bioactive peptides on the implant surface is an effective strategy to improve osseointegration, the existing mono- and bifunctional peptide-modified implant surfaces can hardly meet the needs of cell behavior regulation and tissue regeneration during the process of osseointegration, and there is an urgent need for the development of more efficient surface modification technologies.</div></div><div><h3>Methods</h3><div>In the present study, a multifunctional peptide-modified implant material, MPN@K6, was successfully prepared by linking one end of a tripeptide system (cell adhesion peptide RGD, osteogenic growth peptide OGP, and pro-angiogenic peptide ang), which possesses a specific biological function, to hexameric lysine, and constructing the tripeptide system on the surface of metal-polyphenol coatings (MPNs) by means of non-covalent interactions between the lysine and the polyphenol, and then the MPN@K6 - RGD/OGP/ang was used as a peptide modification. RGD/OGP/ang.</div></div><div><h3>Results</h3><div>The MPN@K6-RGD/OGP/Ang coating not only supported the early adhesion and migration, late osteogenesis and mineralization of BMSCs, but also promoted the adhesion, migration and vascularization of HUVECs. RT-qPCR results showed that the hybrid peptide up-regulated the expression of key factors in angiogenesis and osteogenesis. In vivo testing further confirmed these findings, with the functional peptide coating being 1.5 to 2 times more effective at inducing new bone formation at an early stage than the other two-peptide combinations, confirming the effectiveness and superiority of the tripeptide synergistic modification strategy.</div></div><div><h3>Conclusions</h3><div>The results showed that the MPN@K6 - RGD/OGP/ang-modified implant exhibited significant advantages at the cellular level compared to different combinations of bifunctional peptide-coated forms. It was able to promote early cell migration and adhesion more efficiently, significantly induced osteoblast differentiation and mineralization, and enhanced the level of local vascularization. In a rat bone defect animal model, the material demonstrated more excellent bone repair effects and achieved better bone healing results, confirming the effectiveness and superiority of the tripeptide synergistic modification strategy.</div></div><div><h3>The translational potential of this article</h3><div>The trifunctional peptide coating (MPN@K6 - RGD/OGP/Ang) constructed in this paper has a mild preparation process, is biologically safe, facilitates large-scale production, has a positive effect on bone tissue repair, and has a great potential for cl","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 150-166"},"PeriodicalIF":5.9,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143854859","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 : 2025-04-21DOI: 10.1016/j.jot.2025.03.014
Meng-Xuan Yao , Jing-Chuan Zheng , Hai-Cheng Wang , Hong-Zhi Lv , Yi-Fan Zhang , Yu-Qin Zhang , Tai-Long Shi , Yan-Ze Zhu , Ying-Ze Zhang , Xiu-Mei Wang , Wei Chen
Objective
This study aims to evaluate the efficacy of biphasic mineralized collagen/polycaprolactone (bMC/PCL) scaffolds in repairing large load-bearing bone defects, particularly femoral defects, using a sheep model.
Methods
The bMC/PCL scaffolds were prepared by combining porous mineralized collagen/polycaprolactone (pMC/PCL) with compact mineralized collagen/polycaprolactone (cMC/PCL). The scaffolds were characterized using scanning electron microscopy to observe the microstructure and compression testing to assess mechanical properties. Twenty female sheep were selected to create a 20 mm femoral defect model, divided into a blank group (no material implanted) and an experimental group (bMC/PCL scaffolds implanted), with 10 sheep in each group. Bone healing and lower limb functional recovery were assessed at 1 month, 3 months, and 6 months postoperatively using Lane-Sandhu scores and visual analog scale scores for lameness. Additionally, bone repair progress was analyzed through X-ray, Micro-CT, and histological analyses.
Results
Compared with the blank group, the bMC/PCL scaffold group showed significant improvement in bone defect repair. At 3 and 6 months postoperatively, X-ray, Micro-CT scans, and histological staining indicated stable scaffold integration and gradual new bone formation. The Lane-Sandhu scores in the experimental group were 3.60 ± 0.548 and 4.00 ± 0.707 at 3 and 6 months, respectively, whereas the blank group experienced plate/screw breakage leading to fixation failure, with scores of 1, indicating better bone healing in the experimental group. The lameness scores in the experimental group were 2.71 ± 0.97 and 1.48 ± 0.86 at 3 and 6 months, respectively, significantly lower than those in the blank group (p < 0.0001 and p = 0.0002). Micro-CT analysis showed that bone volume to tissue volume ratio increased from 28.07 ± 9.22 % to 62.02 ± 11.82 %, bone mineral density increased from 0.392 ± 0.032 g/cm3 to 0.583 ± 0.125 g/cm3, trabecular thickness increased from 0.690 ± 0.224 mm to 1.049 ± 0.089 mm, and trabecular separation decreased from 2.766 ± 1.183 mm to 0.501 ± 0.268 mm at 3 and 6 months postoperatively.
Conclusion
This study evaluated the efficacy of bMC/PCL scaffolds in repairing large load-bearing bone defects. The bMC/PCL scaffolds demonstrated good bioactivity and mechanical properties, indicating promising clinical application prospects. Future studies should further verify the safety and efficacy of these scaffolds in a wider range of animal models to support their clinical application.
Significance statement
The bMC/PCL scaffolds offer a promising solution for large femoral bone defects, with potential for clinical use in orthopedic and trauma surgeries.
{"title":"Application of biphasic mineralized collagen/polycaprolactone scaffolds in the repair of large load-bearing bone defects: A study in a sheep model","authors":"Meng-Xuan Yao , Jing-Chuan Zheng , Hai-Cheng Wang , Hong-Zhi Lv , Yi-Fan Zhang , Yu-Qin Zhang , Tai-Long Shi , Yan-Ze Zhu , Ying-Ze Zhang , Xiu-Mei Wang , Wei Chen","doi":"10.1016/j.jot.2025.03.014","DOIUrl":"10.1016/j.jot.2025.03.014","url":null,"abstract":"<div><h3>Objective</h3><div>This study aims to evaluate the efficacy of biphasic mineralized collagen/polycaprolactone (bMC/PCL) scaffolds in repairing large load-bearing bone defects, particularly femoral defects, using a sheep model.</div></div><div><h3>Methods</h3><div>The bMC/PCL scaffolds were prepared by combining porous mineralized collagen/polycaprolactone (pMC/PCL) with compact mineralized collagen/polycaprolactone (cMC/PCL). The scaffolds were characterized using scanning electron microscopy to observe the microstructure and compression testing to assess mechanical properties. Twenty female sheep were selected to create a 20 mm femoral defect model, divided into a blank group (no material implanted) and an experimental group (bMC/PCL scaffolds implanted), with 10 sheep in each group. Bone healing and lower limb functional recovery were assessed at 1 month, 3 months, and 6 months postoperatively using Lane-Sandhu scores and visual analog scale scores for lameness. Additionally, bone repair progress was analyzed through X-ray, Micro-CT, and histological analyses.</div></div><div><h3>Results</h3><div>Compared with the blank group, the bMC/PCL scaffold group showed significant improvement in bone defect repair. At 3 and 6 months postoperatively, X-ray, Micro-CT scans, and histological staining indicated stable scaffold integration and gradual new bone formation. The Lane-Sandhu scores in the experimental group were 3.60 ± 0.548 and 4.00 ± 0.707 at 3 and 6 months, respectively, whereas the blank group experienced plate/screw breakage leading to fixation failure, with scores of 1, indicating better bone healing in the experimental group. The lameness scores in the experimental group were 2.71 ± 0.97 and 1.48 ± 0.86 at 3 and 6 months, respectively, significantly lower than those in the blank group (<em>p</em> < 0.0001 and <em>p</em> = 0.0002). Micro-CT analysis showed that bone volume to tissue volume ratio increased from 28.07 ± 9.22 % to 62.02 ± 11.82 %, bone mineral density increased from 0.392 ± 0.032 g/cm<sup>3</sup> to 0.583 ± 0.125 g/cm<sup>3</sup>, trabecular thickness increased from 0.690 ± 0.224 mm to 1.049 ± 0.089 mm, and trabecular separation decreased from 2.766 ± 1.183 mm to 0.501 ± 0.268 mm at 3 and 6 months postoperatively.</div></div><div><h3>Conclusion</h3><div>This study evaluated the efficacy of bMC/PCL scaffolds in repairing large load-bearing bone defects. The bMC/PCL scaffolds demonstrated good bioactivity and mechanical properties, indicating promising clinical application prospects. Future studies should further verify the safety and efficacy of these scaffolds in a wider range of animal models to support their clinical application.</div></div><div><h3>Significance statement</h3><div>The bMC/PCL scaffolds offer a promising solution for large femoral bone defects, with potential for clinical use in orthopedic and trauma surgeries.</div></div><div><h3>The translational potential of this article</h3><div>The applicatio","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 138-149"},"PeriodicalIF":5.9,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143854842","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 : 2025-04-15DOI: 10.1016/j.jot.2025.03.023
Chao Wang , Hao Li , Fakai Li , Yongkang Yang , Ziheng Xu , Tianze Gao , Runmeng Li , Ruiyang Zhang , Yuhao Mu , Zheng Guo , Quanyi Guo , Shuyun Liu
Background
The process of allogeneic chondrocyte implantation entails obtaining donor chondrocytes, culturing them in a medium enriched with growth factors, and then introducing them-either individually or in conjunction with biocompatible scaffolds-into areas of cartilage damage. While promising, this approach is hindered by mitochondrial dysfunction in the implanted chondrocytes.
Methods
This research introduced an innovative approach by creating a new type of scaffold derived from Decellularized Umbilical Cord Wharton's Jelly (DUCWJ) extracted from human umbilical cords. The scaffold was manufactured using procedures involving decellularization and lyophilization. The resulting scaffold demonstrated superior characteristics, including high porosity, hydrophilic properties, and excellent biocompatibility. To enhance its function, SS31 peptides, known for their mitochondrial-protective properties, were chemically bonded to the scaffold surface, creating an SS31@DUCWJ system. This system aims to protect chondrocytes and regulate the mitochondrial respiratory chain (MRC), thereby improving cartilage repair mediated by allogeneic chondrocyte implantation.
Results
In vitro studies have shown that SS31 effectively attenuates metabolic dysfunction, extracellular matrix degradation, oxidative stress, inflammation, and mitochondrial damage induced by serial cell passages. Complementary in vivo experiments showed that the SS31@DUCWJ scaffold promoted regeneration of healthy articular cartilage in femoral condylar defects in rabbits.
Conclusions
This SS31-modified porous decellularized scaffold represents an innovative biomaterial with anti-inflammatory properties and targeted mitochondrial regulation. It offers a promising new approach for treating articular cartilage injuries.
The translational potential of this article
Our study was the first to successfully load the mitochondrial protectant SS31 onto a DUCWJ hydrogel scaffold for localized drug delivery. This method is highly efficacious in repairing cartilage defects and offers a promising new avenue for the treatment of such conditions.
{"title":"The mitochondrial protectant SS31 optimized decellularized Wharton's jelly scaffold improves allogeneic chondrocyte implantation-mediated articular cartilage repair","authors":"Chao Wang , Hao Li , Fakai Li , Yongkang Yang , Ziheng Xu , Tianze Gao , Runmeng Li , Ruiyang Zhang , Yuhao Mu , Zheng Guo , Quanyi Guo , Shuyun Liu","doi":"10.1016/j.jot.2025.03.023","DOIUrl":"10.1016/j.jot.2025.03.023","url":null,"abstract":"<div><h3>Background</h3><div>The process of allogeneic chondrocyte implantation entails obtaining donor chondrocytes, culturing them in a medium enriched with growth factors, and then introducing them-either individually or in conjunction with biocompatible scaffolds-into areas of cartilage damage. While promising, this approach is hindered by mitochondrial dysfunction in the implanted chondrocytes.</div></div><div><h3>Methods</h3><div>This research introduced an innovative approach by creating a new type of scaffold derived from Decellularized Umbilical Cord Wharton's Jelly (DUCWJ) extracted from human umbilical cords. The scaffold was manufactured using procedures involving decellularization and lyophilization. The resulting scaffold demonstrated superior characteristics, including high porosity, hydrophilic properties, and excellent biocompatibility. To enhance its function, SS31 peptides, known for their mitochondrial-protective properties, were chemically bonded to the scaffold surface, creating an SS31@DUCWJ system. This system aims to protect chondrocytes and regulate the mitochondrial respiratory chain (MRC), thereby improving cartilage repair mediated by allogeneic chondrocyte implantation.</div></div><div><h3>Results</h3><div>In vitro studies have shown that SS31 effectively attenuates metabolic dysfunction, extracellular matrix degradation, oxidative stress, inflammation, and mitochondrial damage induced by serial cell passages. Complementary in vivo experiments showed that the SS31@DUCWJ scaffold promoted regeneration of healthy articular cartilage in femoral condylar defects in rabbits.</div></div><div><h3>Conclusions</h3><div>This SS31-modified porous decellularized scaffold represents an innovative biomaterial with anti-inflammatory properties and targeted mitochondrial regulation. It offers a promising new approach for treating articular cartilage injuries.</div></div><div><h3>The translational potential of this article</h3><div>Our study was the first to successfully load the mitochondrial protectant SS31 onto a DUCWJ hydrogel scaffold for localized drug delivery. This method is highly efficacious in repairing cartilage defects and offers a promising new avenue for the treatment of such conditions.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"52 ","pages":"Pages 126-137"},"PeriodicalIF":5.9,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828966","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 : 2025-04-12DOI: 10.1016/j.jot.2025.03.011
Wang Xiao , Wang Yike , Liu Gongwen , Xu Youjia
Osteoporosis is a common systemic metabolic disease, characterized by decreased bone mass and susceptibility to fragility fractures, often associated with aging, menopause, genetics, and immunity. Ferroptosis plays an underestimated yet crucial role in the further impact of immune function changes on osteoporosis. Cell ferroptosis can induce alterations in immune function, subsequently influencing bone metabolism. In this context, this review summarizes several mechanisms of ferroptosis and introduces the latest insights on how ferroptosis regulates immune responses, exploring the interactions between ferroptosis and other mechanisms such as oxidative stress, inflammation, etc. This review elucidates potential treatment strategies for osteoporosis, emphasizing the promising potential of ferroptosis as an emerging target in the treatment of osteoporosis. In conclusion, preparations related to ferroptosis exhibit substantial clinical promise for enhancing bone mass restoration.
The translational potential of this article: This review elucidates a nuanced conversation between the immune system and osteoporosis, with ferroptosis serving as the connecting link. These findings underscore the potential of ferroptosis inhibition as a therapeutic strategy for osteoporosis.
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