Pub Date : 2024-07-25DOI: 10.1016/j.jot.2024.07.001
Background
Hyperbaric oxygen (HBO) therapy is widely used to treat bone defects, but the correlation of high oxygen concentration and pressure to osteogenesis is unclear.
Methods
Bilateral monocortical tibial defect surgeries were performed on 12-week-old Prrx1-Cre; Rosa26-tdTomato and Prrx1-Cre; Piezo1fl/+ mice. Daily HBO treatment was applied on post-surgery day (PSD) 1–9; and daily mechanical loading on tibia was from PSD 5 to 8. The mice were euthanized on PSD 10, and bone defect repair in their tibias was evaluated using μCT, biomechanical testing, and immunofluorescence deep-tissue imaging. The degree of angiogenesis–osteogenesis coupling was determined through spatial correlation analysis. Bone marrow stromal cells from knockout mice were cultured in vitro, and their osteogenic capacities of the cells were assessed. The activation of genes in the Piezo1–YAP pathway was evaluated using RNA sequencing and quantitative real-time polymerase chain reaction.
Results
Lineage tracing showed HBO therapy considerably altered the number of Prrx1+ cells and their progeny in a healing bone defect. Using conditional knockdown mice, we found that HBO stimulation activates the Piezo1–YAP axis in Prrx1+ cells and promotes osteogenesis–angiogenesis coupling during bone repair. The beneficial effect of HBO was similar to that of anabolic mechanical stimulation, which also acts through the Piezo1–YAP axis. Subsequent transcriptome sequencing results revealed that similar mechanosensitive pathways are activated by HBO therapy in a bone defect.
Conclusion
HBO therapy promotes bone tissue regeneration through the mechanosensitive Piezo1–YAP pathway in a population of Prrx1+ osteogenic progenitors. Our results contribute to the understanding of the mechanism by which HBO therapy treats bone defects.
The Translational Potential of this Article
Hyperbaric oxygen therapy is widely used in clinical settings. Our results show that osteogenesis was induced by the activation of the Piezo1–YAP pathway in osteoprogenitors after HBO stimulation, and the underlying mechanism was elucidated. These results may help improve current HBO methods and lead to the formulation of alternative treatments that achieve the same functional outcomes.
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Pub Date : 2024-07-25DOI: 10.1016/j.jot.2024.07.006
Background
Diabetic bone healing remains a great challenge due to its pathological features including biochemical disturbance, excessive inflammation, and reduced blood vessel formation. In previous studies, small intestine submucosa (SIS) has been demonstrated for its immunomodulatory and angiogenic properties, which are necessary to diabetic bone healing. However, the noticeable drawbacks of SIS such as fast degradation rate, slow gelling time, and weak mechanical property seriously impede the 3D printing of SIS for bone repair.
Method
In this study, we developed a novel kind of 3D-printed scaffold composed of alginate, nano-hydroxyapatite, and SIS. The morphological characterization, biocompatibility, and in vitro biological effects of the scaffolds were evaluated, and an established diabetic rat model was used for testing the in vivo biological effect of the scaffold after implantation.
Results
The in vitro and in vivo results show that the addition of SIS can tune the immunomodulatory properties and angiogenic and osteogenic performances of 3D-printed scaffold, where the macrophages polarization of M2 phenotype, migration and tube formation of HUVECs, as well as osteogenic expression of ALP, are all improved, which bode well with the functional requirements for treating diabetic bone nonunion. Furthermore, the incorporation of alginate substantially improves the printability of composites with tunable degradation properties, thereby broadening the application prospect of SIS-based materials in the field of tissue engineering.
Conclusion
The fabricated 3D-printed Alg/HA/SIS scaffold provides desirable immunomodulatory effect, as well as good osteogenic and angiogenic performances in vitro and in vivo, which properties are well-suited with the requirement for treating diabetic bone defects.
Translational potential of this article
The incorporation of SIS and alginate acid not only provides good printability of the newly fabricated 3D-printed Alg/HA/SIS scaffold, but also improves its immunoregulatory and angiogenic properties, which suits well with the requirement for treating diabetic bone disease and opens up new horizons for the development of implants associating diabetic bone healings.
背景：由于糖尿病的病理特征包括生化紊乱、过度炎症和血管形成减少，其骨愈合仍然是一个巨大的挑战。在以往的研究中，小肠粘膜下层（SIS）已被证实具有免疫调节和血管生成特性，而这正是糖尿病骨愈合所必需的。然而，小肠粘膜降解速度快、胶凝时间慢、机械性能弱等明显缺点严重阻碍了小肠粘膜用于骨修复的三维打印技术：本研究开发了一种由海藻酸盐、纳米羟基磷灰石和 SIS 组成的新型 3D 打印支架。方法：我们开发了一种由海藻酸盐、纳米羟基磷灰石和 SIS 组成的新型三维打印支架，评估了支架的形态特征、生物相容性和体外生物效应，并利用已建立的糖尿病大鼠模型测试了支架植入后的体内生物效应：体外和体内实验结果表明，SIS的加入可以调节三维打印支架的免疫调节性能、血管生成和成骨性能，其中巨噬细胞的M2表型极化、HUVECs的迁移和管形成以及ALP的成骨表达均得到改善，这与治疗糖尿病骨不连的功能要求相吻合。此外，海藻酸盐的加入大大提高了具有可调降解特性的复合材料的可打印性，从而拓宽了基于 SIS 的材料在组织工程领域的应用前景：本文的转化潜力：SIS和海藻酸的加入不仅为新制作的Alg/HA/SIS三维打印支架提供了良好的可打印性，还改善了其免疫调节和血管生成性能，非常适合治疗糖尿病骨病的要求，为开发与糖尿病骨愈合相关的植入物开辟了新天地。
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Pub Date : 2024-07-01DOI: 10.1016/j.jot.2024.06.010
Zhiyuan Wei , Jian Zhou , Jie Shen , Dong Sun , Tianbao Gao , Qin Liu , Hongri Wu , Xiaohua Wang , Shulin Wang , Shiyu Xiao , Chao Han , Di Yang , Hui Dong , Yuzhang Wu , Yi Zhang , Shuai Xu , Xian Wang , Jie Luo , Qijie Dai , Jun Zhu , Zhao Xie
Background
Osteomyelitis (OM) is an inflammatory condition of bone characterized by cortical bone devascularization and necrosis. Dysregulation of bone remodelling is triggered by OM. Bone remodelling is precisely coordinated by bone resorption and formation via a reversal phase. However, the cellular and molecular mechanisms underlying bone remodelling failure after osteomyelitis remain elusive.
Methods
To elucidate the cellular and molecular mechanism underlying bone healing after osteomyelitis, we employed single-cell RNA sequencing (scRNA-seq) to depict the atlas of human cortical bone in normal, infected and reconstructed states. Dimensionality reduction by t-stochastic neighbourhood embedding (t-SNE) and graph-based clustering were applied to analyse the detailed clusters of osteoclast lineages. After trajectory analysis of osteoclast lineages over pseudotime, real-time PCR and immunofluorescence (IF) staining were applied to identify marker gene expression of various osteoclast lineages in the osteoclast induction model and human bone sections, respectively. The potential function and communication of osteoclasts were analysed via gene set enrichment analysis (GSEA) and CellChat. The chemotactic ability of mesenchymal stem cells (MSCs) and osteoclast lineage cells in various differentiation states was determined by transwell assays and coculture assays. The effects of various osteoclast lineages on the osteogenic differentiation potential of MSCs were also determined by using this coculture system. A normal mouse tibia fracture model and an osteomyelitis-related tibia fracture model were generated via injection of luciferase-labelled Staphylococcus aureus to verify the relationships between a novel osteoclast lineage and MSCs. Then, the infection was detected by a bioluminescence imaging system. Finally, immunofluorescence staining was used to detect the expression of markers of MSCs and novel osteoclast lineages in different remodelling phases in normal and infected bone remodelling models.
Results
In this study, we constructed a cell atlas encompassing normal, infected, and reconstructed cortical bone. Then, we identified a novel subset at the earlier stage of the osteoclast lineage that exhibited increased expression of IDO1, CCL3, and CCL4. These IDO1highCCL3highCCL4high cells, termed osteostaticytes (OSCs), were further regarded as the reservoir of osteoclasts in the reversal phase. Notably, OSCs exhibited the highest chemotactic activity, surpassing other lineage subsets. We also discovered that cells at the earlier stage of the osteoclast lineage play a significant role in recruiting mesenchymal stem cells (MSCs). Finally, the data revealed that OSCs might be positively related to the occurrence of bone MSCs and the contribution of bone remodelling.
{"title":"Osteostaticytes: A novel osteoclast subset couples bone resorption and bone formation","authors":"Zhiyuan Wei , Jian Zhou , Jie Shen , Dong Sun , Tianbao Gao , Qin Liu , Hongri Wu , Xiaohua Wang , Shulin Wang , Shiyu Xiao , Chao Han , Di Yang , Hui Dong , Yuzhang Wu , Yi Zhang , Shuai Xu , Xian Wang , Jie Luo , Qijie Dai , Jun Zhu , Zhao Xie","doi":"10.1016/j.jot.2024.06.010","DOIUrl":"https://doi.org/10.1016/j.jot.2024.06.010","url":null,"abstract":"<div><h3>Background</h3><p>Osteomyelitis (OM) is an inflammatory condition of bone characterized by cortical bone devascularization and necrosis. Dysregulation of bone remodelling is triggered by OM. Bone remodelling is precisely coordinated by bone resorption and formation via a reversal phase. However, the cellular and molecular mechanisms underlying bone remodelling failure after osteomyelitis remain elusive.</p></div><div><h3>Methods</h3><p>To elucidate the cellular and molecular mechanism underlying bone healing after osteomyelitis, we employed single-cell RNA sequencing (scRNA-seq) to depict the atlas of human cortical bone in normal, infected and reconstructed states. Dimensionality reduction by t-stochastic neighbourhood embedding (t-SNE) and graph-based clustering were applied to analyse the detailed clusters of osteoclast lineages. After trajectory analysis of osteoclast lineages over pseudotime, real-time PCR and immunofluorescence (IF) staining were applied to identify marker gene expression of various osteoclast lineages in the osteoclast induction model and human bone sections, respectively. The potential function and communication of osteoclasts were analysed via gene set enrichment analysis (GSEA) and CellChat. The chemotactic ability of mesenchymal stem cells (MSCs) and osteoclast lineage cells in various differentiation states was determined by transwell assays and coculture assays. The effects of various osteoclast lineages on the osteogenic differentiation potential of MSCs were also determined by using this coculture system. A normal mouse tibia fracture model and an osteomyelitis-related tibia fracture model were generated via injection of luciferase-labelled <em>Staphylococcus aureus</em> to verify the relationships between a novel osteoclast lineage and MSCs. Then, the infection was detected by a bioluminescence imaging system. Finally, immunofluorescence staining was used to detect the expression of markers of MSCs and novel osteoclast lineages in different remodelling phases in normal and infected bone remodelling models.</p></div><div><h3>Results</h3><p>In this study, we constructed a cell atlas encompassing normal, infected, and reconstructed cortical bone. Then, we identified a novel subset at the earlier stage of the osteoclast lineage that exhibited increased expression of IDO1, CCL3, and CCL4. These IDO1<sup>high</sup>CCL3<sup>high</sup>CCL4<sup>high</sup> cells, termed osteostaticytes (OSCs), were further regarded as the reservoir of osteoclasts in the reversal phase. Notably, OSCs exhibited the highest chemotactic activity, surpassing other lineage subsets. We also discovered that cells at the earlier stage of the osteoclast lineage play a significant role in recruiting mesenchymal stem cells (MSCs). Finally, the data revealed that OSCs might be positively related to the occurrence of bone MSCs and the contribution of bone remodelling.</p></div><div><h3>Conclusion</h3><p>Collectively, our findings revealed a nove","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000639/pdfft?md5=bdb204ccae657e06dcbcdb9506fa69ff&pid=1-s2.0-S2214031X24000639-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141479177","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}
Zinc finger-containing transcription factor Osterix/Specificity protein-7 (Sp7) is an essential transcription factor for osteoblast differentiation. However, its functions in differentiated osteoblasts remain unclear and the effects of osteoblast-specific Sp7 deletion on osteocytes have not been sufficiently studied.
Methods
Sp7floxneo/floxneo mice, in which Sp7 expression was 30 % of that in wild-type mice because of disturbed splicing by neo gene insertion, and osteoblast-specific knockout (Sp7fl/fl;Col1a1−Cre) mice using 2.3-kb Col1a1 enhanced green fluorescent protein (EGFP)-Cre were examined by micro-computed tomography (micro-CT), bone histomorphometry, serum markers, and histological analyses. The expression of osteoblast and osteocyte marker genes was examined by real-time reverse transcription (RT)-PCR analysis. Osteoblastogenesis, osteoclastogenesis, and regulation of the expression of collagen type I alpha 1 chain (Col1a1) were examined in primary osteoblasts.
Results
Femoral trabecular bone volume was higher in female Sp7floxneo/floxneo and Sp7fl/fl;Col1a1−Cre mice than in the respective controls, but not in males. Bromodeoxyuridine (BrdU)-positive osteoblastic cells were increased in male Sp7fl/fl;Col1a1−Cre mice, and osteoblast number and the bone formation rate were increased in tibial trabecular bone in female Sp7fl/fl;Col1a1−Cre mice, although osteoblast maturation was inhibited in female Sp7fl/fl;Col1a1−Cre mice as shown by the increased expression of an immature osteoblast marker gene, secreted phosphoprotein 1 (Spp1), and reduced expression of a mature osteoblast marker gene, bone gamma-carboxyglutamate protein/bone gamma-carboxyglutamate protein 2 (Bglap/Bglap2). Furthermore, alkaline phosphatase activity was increased but mineralization was reduced in the culture of primary osteoblasts from Sp7fl/fl;Col1a1−Cre mice. Therefore, the accumulated immature osteoblasts in Sp7fl/fl;Col1a1−Cre mice was likely compensated for the inhibition of osteoblast maturation at different levels in males and females. Vertebral trabecular bone volume was lower in both male and female Sp7fl/fl;Col1a1−Cre mice than in the controls and the osteoblast parameters and bone formation rate in females were lower in Sp7fl/fl;Col1a1−Cre mice than in Sp7fl/fl mice, suggesting differential regulatory mechanisms in long bones and vertebrae. The femoral cortical bone was thin and porous in Sp7floxneo/floxneo and Sp7fl/fl;Col1a1−Cre mice of both sexes, the number of can
{"title":"Roles of Sp7 in osteoblasts for the proliferation, differentiation, and osteocyte process formation","authors":"Qing Jiang , Kenichi Nagano , Takeshi Moriishi , Hisato Komori , Chiharu Sakane , Yuki Matsuo , Zhiguo Zhang , Riko Nishimura , Kosei Ito , Xin Qin , Toshihisa Komori","doi":"10.1016/j.jot.2024.06.005","DOIUrl":"https://doi.org/10.1016/j.jot.2024.06.005","url":null,"abstract":"<div><h3>Background</h3><p>Zinc finger-containing transcription factor Osterix/Specificity protein-7 (Sp7) is an essential transcription factor for osteoblast differentiation. However, its functions in differentiated osteoblasts remain unclear and the effects of osteoblast-specific <em>Sp7</em> deletion on osteocytes have not been sufficiently studied.</p></div><div><h3>Methods</h3><p><em>Sp7</em><sup>floxneo/floxneo</sup> mice, in which <em>Sp7</em> expression was 30 % of that in wild-type mice because of disturbed splicing by neo gene insertion, and osteoblast-specific knockout (<em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup>) mice using 2.3-kb <em>Col1a1</em> enhanced green fluorescent protein (EGFP)-Cre were examined by micro-computed tomography (micro-CT), bone histomorphometry, serum markers, and histological analyses. The expression of osteoblast and osteocyte marker genes was examined by real-time reverse transcription (RT)-PCR analysis. Osteoblastogenesis, osteoclastogenesis, and regulation of the expression of collagen type I alpha 1 chain (<em>Col1a1</em>) were examined in primary osteoblasts.</p></div><div><h3>Results</h3><p>Femoral trabecular bone volume was higher in female <em>Sp7</em><sup>floxneo/floxneo</sup> and <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice than in the respective controls, but not in males. Bromodeoxyuridine (BrdU)-positive osteoblastic cells were increased in male <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice, and osteoblast number and the bone formation rate were increased in tibial trabecular bone in female <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice, although osteoblast maturation was inhibited in female <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice as shown by the increased expression of an immature osteoblast marker gene, secreted phosphoprotein 1 (<em>Spp1</em>), and reduced expression of a mature osteoblast marker gene, bone gamma-carboxyglutamate protein/bone gamma-carboxyglutamate protein 2 (<em>Bglap/Bglap2</em>). Furthermore, alkaline phosphatase activity was increased but mineralization was reduced in the culture of primary osteoblasts from <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice. Therefore, the accumulated immature osteoblasts in <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice was likely compensated for the inhibition of osteoblast maturation at different levels in males and females. Vertebral trabecular bone volume was lower in both male and female <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice than in the controls and the osteoblast parameters and bone formation rate in females were lower in <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice than in <em>Sp7</em><sup>fl/fl</sup> mice, suggesting differential regulatory mechanisms in long bones and vertebrae. The femoral cortical bone was thin and porous in <em>Sp7</em><sup>floxneo/floxneo</sup> and <em>Sp7</em><sup>fl/fl;<em>Col1a1</em>−Cre</sup> mice of both sexes, the number of can","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000536/pdfft?md5=fcf3b3db8cc860edc417dcaa8f83f032&pid=1-s2.0-S2214031X24000536-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141479178","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}
Pub Date : 2024-07-01DOI: 10.1016/j.jot.2024.06.013
Hetong Li , Beini Mao , Jintao Zhong, Xiuwang Li, Hongxun Sang
Background
Diabetic bone defects present significant challenges for individuals with diabetes. While metformin has been explored for bone regeneration via local delivery, its application in treating diabetic bone defects remains under-explored. In this study, we aim to leverage 3D printing technology to fabricate a GelMA-Nanoclay hydrogel scaffold loaded with metformin specifically for this purpose. The objective is to assess whether the in situ release of metformin can effectively enhance osteogenesis, angiogenesis, and immunomodulation in the context of diabetic bone defects.
Materials and methods
Utilizing 3D printing technology, we constructed a GelMA-Nanoclay-Metformin hydrogel scaffold with optimal physical properties and biocompatibility. The osteogenic, angiogenic, and immunomodulatory characteristics of the hydrogel scaffold were thoroughly investigated through both in vitro and in vivo experiments.
Results
GelMA10%-Nanoclay8%-Metformin5mg/mL was selected as the bioink for 3D printing due to its favorable swelling rate, degradation rate, mechanical strength, and drug release rate. Through in vitro investigations, the hydrogel scaffold extract, enriched with metformin, demonstrated a substantial enhancement in the proliferation and migration of BMSCs within a high-glucose microenvironment. It effectively enhances osteogenesis, angiogenesis, and immunomodulation. In vivo experimental outcomes further underscored the efficacy of the metformin-loaded GelMA-Nanoclay hydrogel scaffold in promoting superior bone regeneration within diabetic bone defects.
Conclusions
In conclusion, while previous studies have explored local delivery of metformin for bone regeneration, our research is pioneering in its application to diabetic bone defects using a 3D printed GelMA-Nanoclay hydrogel scaffold. This localized delivery approach demonstrates significant potential for enhancing bone regeneration in diabetic patients, offering a novel approach for treating diabetic bone defects.
The translational potential of this article
Our study demonstrates, for the first time, the successful loading of the systemic antidiabetic drug metformin onto a hydrogel scaffold for localized delivery. This approach exhibits significant efficacy in mending diabetic bone defects, presenting a promising new avenue for the treatment of such conditions.
{"title":"Localized delivery of metformin via 3D printed GelMA-Nanoclay hydrogel scaffold for enhanced treatment of diabetic bone defects","authors":"Hetong Li , Beini Mao , Jintao Zhong, Xiuwang Li, Hongxun Sang","doi":"10.1016/j.jot.2024.06.013","DOIUrl":"https://doi.org/10.1016/j.jot.2024.06.013","url":null,"abstract":"<div><h3>Background</h3><p>Diabetic bone defects present significant challenges for individuals with diabetes. While metformin has been explored for bone regeneration via local delivery, its application in treating diabetic bone defects remains under-explored. In this study, we aim to leverage 3D printing technology to fabricate a GelMA-Nanoclay hydrogel scaffold loaded with metformin specifically for this purpose. The objective is to assess whether the in situ release of metformin can effectively enhance osteogenesis, angiogenesis, and immunomodulation in the context of diabetic bone defects.</p></div><div><h3>Materials and methods</h3><p>Utilizing 3D printing technology, we constructed a GelMA-Nanoclay-Metformin hydrogel scaffold with optimal physical properties and biocompatibility. The osteogenic, angiogenic, and immunomodulatory characteristics of the hydrogel scaffold were thoroughly investigated through both in vitro and in vivo experiments.</p></div><div><h3>Results</h3><p>GelMA10%-Nanoclay8%-Metformin5mg/mL was selected as the bioink for 3D printing due to its favorable swelling rate, degradation rate, mechanical strength, and drug release rate. Through in vitro investigations, the hydrogel scaffold extract, enriched with metformin, demonstrated a substantial enhancement in the proliferation and migration of BMSCs within a high-glucose microenvironment. It effectively enhances osteogenesis, angiogenesis, and immunomodulation. In vivo experimental outcomes further underscored the efficacy of the metformin-loaded GelMA-Nanoclay hydrogel scaffold in promoting superior bone regeneration within diabetic bone defects.</p></div><div><h3>Conclusions</h3><p>In conclusion, while previous studies have explored local delivery of metformin for bone regeneration, our research is pioneering in its application to diabetic bone defects using a 3D printed GelMA-Nanoclay hydrogel scaffold. This localized delivery approach demonstrates significant potential for enhancing bone regeneration in diabetic patients, offering a novel approach for treating diabetic bone defects.</p></div><div><h3>The translational potential of this article</h3><p>Our study demonstrates, for the first time, the successful loading of the systemic antidiabetic drug metformin onto a hydrogel scaffold for localized delivery. This approach exhibits significant efficacy in mending diabetic bone defects, presenting a promising new avenue for the treatment of such conditions.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000664/pdfft?md5=49e870b4d7434a75f558a1352e15d3ca&pid=1-s2.0-S2214031X24000664-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141542541","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}
Pub Date : 2024-07-01DOI: 10.1016/j.jot.2024.07.003
{"title":"Understanding pathophysiology and injury mechanisms is the foundation for invention/innovation and clinical translation in orthopaedics","authors":"","doi":"10.1016/j.jot.2024.07.003","DOIUrl":"10.1016/j.jot.2024.07.003","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000718/pdfft?md5=c0520133f484f6ac36c367d5f097c670&pid=1-s2.0-S2214031X24000718-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141692130","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}
Pub Date : 2024-07-01DOI: 10.1016/j.jot.2024.06.015
Yanzhi Liu , Rui Lin , Haiping Fang , Lixian Li, Min Zhang, Lujiao Lu, Xiang Gao, Jintong Song, Jinsong Wei, Qixian Xiao, Fucheng Zhang, Kefeng Wu, Liao Cui
Background
Osteoarthritis (OA) presents a formidable challenge, characterized by as-yet-unclear mechanical intricacies within cartilage and the dysregulation of bone homeostasis. Our preliminary data revealed the encouraging potential of a Sargassum polysaccharide (SP), in promoting chondrogenesis. The aim of our study is to comprehensively assess the therapeutic effects of SP on OA models and further elucidate its potential mechanism.
Methods
The protective effects of SP were initially evaluated in an inflammation-induced human chondrocyte (C28) cell model. CCK-8 assays, Alcian blue staining, RT-qPCR and Western blotting were used to verify the chondrogenesis of SP in vitro. To assess the efficacy of SP in vivo, surgically induced medial meniscus destabilization (DMM) OA rats underwent an 8-week SP treatment. The therapeutic effects of SP in OA rats were comprehensively evaluated using X-ray imaging, micro-computed tomography (μ-CT), histopathological analysis, as well as immunohistochemical and immunofluorescent staining. Following these assessments, we delved into the potential signaling pathways of SP in inflammatory chondrocytes utilizing RNA-seq analysis. Validation of these findings was conducted through RT-qPCR and western blotting techniques.
Results
SP significantly enhance the viability of C28 chondrocytes, and increased the secretion of acidic glycoproteins. Moreover, SP stimulated the expression of chondrogenic genes (Aggrecan, Sox9, Col2a1) and facilitated the synthesis of Collagen II protein in C28 inflammatory chondrocytes. In vivo experiments revealed that SP markedly ameliorated knee joint stenosis, alleviated bone and cartilage injuries, and reduced the histopathological scores in the OA rats. μ-CT analysis confirmed that SP lessened bone impairments in the medial femoral condyle and the subchondral bone of the tibial plateau, significantly improving the microarchitectural parameters of the subchondral bone. Histopathological analyses indicated that SP notably enhanced cartilage quality on the surface of the tibial plateau, leading to increased cartilage thickness and area. Immunohistochemistry staining and immunofluorescence staining corroborated these findings by showing a significant promotion of Collagen II expression in OA joints treated with SP. RNA-seq analysis suggest that SP's effects were mediated through the regulation of the ITGβ1-PI3K-AKT signaling axis, thereby stimulating chondrogenesis. Verification through RT-qPCR and Western blot analyses confirmed that SP significantly upregulated the expression of ITGβ1, p110δ, AKT1, ACAN, and Col2a1. Notably, knock-down of ITGβ1 using siRNA in C28 chondrocytes inhibited the expression of ITGβ1, p110δ, AKT1, and ACAN. However, these inhibitory effects were not completely reversed by supplemental SP intervention.
Conclusions
In summa
背景骨关节炎（OA）是一项艰巨的挑战，其特点是软骨内错综复杂的机械结构和骨平衡失调。我们的初步数据显示，马尾藻多糖（SP）在促进软骨生成方面具有令人鼓舞的潜力。我们研究的目的是全面评估马尾藻多糖对 OA 模型的治疗效果，并进一步阐明其潜在机制。方法首先在炎症诱导的人软骨细胞（C28）模型中评估马尾藻多糖的保护作用。方法首先在炎症诱导的人软骨细胞（C28）模型中评估了SP的保护作用，并使用CCK-8测定、阿尔西恩蓝染色、RT-qPCR和Western印迹法验证了SP在体外的软骨生成作用。为了评估SP在体内的疗效，对手术诱导的内侧半月板失稳（DMM）OA大鼠进行了为期8周的SP治疗。我们使用 X 射线成像、微型计算机断层扫描（μ-CT）、组织病理学分析以及免疫组织化学和免疫荧光染色对 SP 对 OA 大鼠的治疗效果进行了全面评估。在这些评估之后，我们利用 RNA-seq 分析深入研究了 SP 在炎性软骨细胞中的潜在信号通路。结果 SP 显著提高了 C28 软骨细胞的活力，并增加了酸性糖蛋白的分泌。此外，SP 还能刺激 C28 炎性软骨细胞中软骨生成基因（Aggrecan、Sox9、Col2a1）的表达，促进胶原蛋白 II 的合成。μ-CT分析证实，SP减轻了股骨内侧髁和胫骨平台软骨下骨的骨损伤，显著改善了软骨下骨的微结构参数。组织病理学分析表明，SP 显著提高了胫骨平台表面软骨的质量，增加了软骨的厚度和面积。免疫组化染色和免疫荧光染色也证实了这些发现，显示在使用 SP 治疗的 OA 关节中，胶原蛋白 II 的表达明显增加。RNA-seq分析表明，SP的作用是通过调节ITGβ1-PI3K-AKT信号轴介导的，从而刺激软骨生成。RT-qPCR 和 Western 印迹分析证实，SP 能显著上调 ITGβ1、p110δ、AKT1、ACAN 和 Col2a1 的表达。值得注意的是，在 C28 软骨细胞中使用 siRNA 敲除 ITGβ1，可抑制 ITGβ1、p110δ、AKT1 和 ACAN 的表达。总之，我们的研究结果表明，SP 能显著增强体外和体内的软骨生成，缓解骨和软骨中的 OA 进展。我们的研究首次揭示了 SP 在治疗 OA 中的优势作用和潜在机制。SP的临床前景为下一代多糖类药物治疗OA提供了令人信服的新证据。
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Pub Date : 2024-07-01DOI: 10.1016/j.jot.2024.03.006
Jianjing Lin , Kejia Li , Zhen Yang , Fuyang Cao , Liang Gao , Tong Ning , Dan Xing , Hui Zeng , Qiang Liu , Zigang Ge , Jianhao Lin
Background
Numerous approaches have been utilized to optimize mesenchymal stem cells (MSCs) performance in treating osteoarthritis (OA), however, the constrained diminished activity and chondrogenic differentiation capacity impede their therapeutic efficacy. Previous investigations have successfully shown that pretreatment with nanosecond pulsed electric fields (nsPEFs) significantly enhances the chondrogenic differentiation of MSCs. Therefore, this study aims to explore nsPEFs as a strategy to improve OA therapy by enhancing MSCs' activity and chondrogenic differentiation and also investigate its potential mechanism.
Methods
In this study, a million MSCs were carefully suspended within a 0.4-cm gap cuvette and subjected to five pulses of nsPEFs (100 ns at 10 kV/cm, 1 Hz), with a 1-s interval between each pulse. A control group of MSCs was maintained without nsPEFs treatment for comparative analysis. nsPEFs were applied to regulate the MSCs performance and hinder OA progresses. In order to further explore the corresponding mechanism, we examined the changes of MSCs transcriptome after nsPEF pretreatment. Finally, we studied the properties of extracellular vesicles (EVs) secreted by MSCs affected by nsPEF and the therapeutic effect on OA.
Results
We found that nsPEFs pretreatment promoted MSCs migration and viability, particularly enhancing their viability temporarily in vivo, which is also confirmed by mRNA sequencing analysis. It also significantly inhibited the development of OA-like chondrocytes in vitro and prevented OA progression in rat models. Additionally, we discovered that nsPEFs pretreatment reprogrammed MSC performance by enhancing EVs production (5.77 ± 0.92 folds), and consequently optimizing their therapeutic potential.
Conclusions
In conclusion, nsPEFs pretreatment provides a simple and effective strategy for improving the MSCs performance and the therapeutic effects of MSCs for OA. EVs-nsPEFs may serve as a potent therapeutic material for OA and hold promise for future clinical applications.
The translational potential of this article
This study indicates that MSCs pretreated by nsPEFs greatly inhibited the development of OA. nsPEFs pretreatment will be a promising and effective method to optimize the therapeutic effect of MSCs in the future.
背景人们已经采用了许多方法来优化间充质干细胞（MSCs）在治疗骨关节炎（OA）中的表现，然而，间充质干细胞活性和软骨源分化能力的降低阻碍了它们的疗效。先前的研究成功表明，纳秒脉冲电场（nsPEFs）的预处理能显著提高间充质干细胞的软骨分化能力。本研究将一百万个间充质干细胞小心地悬浮在一个0.4厘米间隙的比色皿中，并对其施加5次纳秒脉冲电场（100纳秒，10千伏/厘米，1赫兹），每次脉冲间隔1秒。nsPEFs 的作用是调节间充质干细胞的性能，阻碍 OA 的发展。为了进一步探究其相应的机制，我们研究了nsPEF预处理后间叶干细胞转录组的变化。结果我们发现，nsPEFs预处理促进了间充质干细胞的迁移和活力，尤其是暂时增强了它们在体内的活力，这也得到了mRNA测序分析的证实。nsPEFs还能明显抑制体外OA样软骨细胞的发育，并阻止大鼠模型中OA的进展。结论总之，nsPEFs 预处理为改善间充质干细胞性能和间充质干细胞对 OA 的治疗效果提供了一种简单有效的策略。本研究表明，经nsPEFs预处理的间充质干细胞极大地抑制了OA的发生。
{"title":"Functionally improved mesenchymal stem cells via nanosecond pulsed electric fields for better treatment of osteoarthritis","authors":"Jianjing Lin , Kejia Li , Zhen Yang , Fuyang Cao , Liang Gao , Tong Ning , Dan Xing , Hui Zeng , Qiang Liu , Zigang Ge , Jianhao Lin","doi":"10.1016/j.jot.2024.03.006","DOIUrl":"https://doi.org/10.1016/j.jot.2024.03.006","url":null,"abstract":"<div><h3>Background</h3><p>Numerous approaches have been utilized to optimize mesenchymal stem cells (MSCs) performance in treating osteoarthritis (OA), however, the constrained diminished activity and chondrogenic differentiation capacity impede their therapeutic efficacy. Previous investigations have successfully shown that pretreatment with nanosecond pulsed electric fields (nsPEFs) significantly enhances the chondrogenic differentiation of MSCs. Therefore, this study aims to explore nsPEFs as a strategy to improve OA therapy by enhancing MSCs' activity and chondrogenic differentiation and also investigate its potential mechanism.</p></div><div><h3>Methods</h3><p>In this study, a million MSCs were carefully suspended within a 0.4-cm gap cuvette and subjected to five pulses of nsPEFs (100 ns at 10 kV/cm, 1 Hz), with a 1-s interval between each pulse. A control group of MSCs was maintained without nsPEFs treatment for comparative analysis. nsPEFs were applied to regulate the MSCs performance and hinder OA progresses. In order to further explore the corresponding mechanism, we examined the changes of MSCs transcriptome after nsPEF pretreatment. Finally, we studied the properties of extracellular vesicles (EVs) secreted by MSCs affected by nsPEF and the therapeutic effect on OA.</p></div><div><h3>Results</h3><p>We found that nsPEFs pretreatment promoted MSCs migration and viability, particularly enhancing their viability temporarily <em>in vivo</em>, which is also confirmed by mRNA sequencing analysis. It also significantly inhibited the development of OA-like chondrocytes <em>in vitro</em> and prevented OA progression in rat models. Additionally, we discovered that nsPEFs pretreatment reprogrammed MSC performance by enhancing EVs production (5.77 ± 0.92 folds), and consequently optimizing their therapeutic potential.</p></div><div><h3>Conclusions</h3><p>In conclusion, nsPEFs pretreatment provides a simple and effective strategy for improving the MSCs performance and the therapeutic effects of MSCs for OA. EVs-nsPEFs may serve as a potent therapeutic material for OA and hold promise for future clinical applications.</p></div><div><h3>The translational potential of this article</h3><p>This study indicates that MSCs pretreated by nsPEFs greatly inhibited the development of OA. nsPEFs pretreatment will be a promising and effective method to optimize the therapeutic effect of MSCs in the future.</p></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000317/pdfft?md5=6ac37a15ef597a795635e5119c89e763&pid=1-s2.0-S2214031X24000317-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141542540","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}
Pub Date : 2024-07-01DOI: 10.1016/j.jot.2024.06.014
Shida Kuang , Wen Sheng , Jiahao Meng , Weijie Liu , Yifan Xiao , Hang Tang , Xinying Fu , Min Kuang , Qinghu He , Shuguang Gao
The pathogenesis of osteoarthritis (OA) involves a multifaceted interplay of inflammatory processes. The initiation of pyroptosis involves the secretion of pro-inflammatory cytokines and has been identified as a critical factor in regulating the development of OA. Upon initiation of pyroptosis, a multitude of inflammatory mediators are released and can be disseminated throughout the synovial fluid within the joint cavity, thereby facilitating intercellular communication across the entire joint. The main cellular components of joints include chondrocytes (CC), fibroblast-like synoviocytes (FLS) and macrophages (MC). Investigating their interplay can enhance our understanding of OA pathogenesis. Therefore, we comprehensively examine the mechanisms underlying pyroptosis and specifically investigate the intercellular interactions associated with pyroptosis among these three cell types, thereby elucidating their collective contribution to the progression of OA. We propose the concept of ' CC-FLS-MC pyroptosis-related crosstalk', describe the various pathways of pyroptotic interactions among these three cell types, and focus on recent advances in intervening pyroptosis in these three cell types for treating OA. We hope this will provide a possible direction for diversification of treatment for OA.
The Translational potential of this article. The present study introduces the concept of ‘MC-FLS-CC pyroptosis-related crosstalk' and provides an overview of the mechanisms underlying pyroptosis, as well as the pathways through which it affects MC, FLS, and CC. In addition, the role of regulation of these three types of cellular pyroptosis in OA has also been concerned. This review offers novel insights into the interplay between these cell types, with the aim of providing a promising avenue for diversified management of OA.
骨关节炎（OA）的发病机制涉及炎症过程的多方面相互作用。脓毒血症的启动涉及促炎细胞因子的分泌，已被确定为调节 OA 发展的关键因素。热渗透开始后，多种炎症介质会释放出来，并扩散到关节腔内的滑液中，从而促进整个关节的细胞间交流。关节的主要细胞成分包括软骨细胞（CC）、纤维母细胞样滑膜细胞（FLS）和巨噬细胞（MC）。研究它们之间的相互作用可以加深我们对 OA 发病机制的了解。因此，我们全面研究了热凋亡的内在机制，并特别研究了这三种细胞类型之间与热凋亡相关的细胞间相互作用，从而阐明它们对 OA 进展的共同贡献。我们提出了 "CC-FLS-MC 热昏迷相关串扰 "的概念，描述了这三种细胞间热昏迷相互作用的各种途径，并重点介绍了干预这三种细胞的热昏迷以治疗 OA 的最新进展。我们希望这将为OA的多样化治疗提供一个可能的方向。本研究提出了 "MC-FLS-CC热蛋白沉积相关串扰 "的概念，并概述了热蛋白沉积的机制及其影响MC、FLS和CC的途径。此外，还关注了这三种细胞热凋亡在 OA 中的调控作用。这篇综述对这些细胞类型之间的相互作用提出了新的见解，旨在为 OA 的多样化治疗提供一条前景广阔的途径。
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Pub Date : 2024-07-01DOI: 10.1016/j.jot.2024.06.011
Zihan Zhang, Huixue Tang, Tingting Du, Di Yang
Copper is an essential trace element for the human body. Abnormalities in copper metabolism can lead to bone defects, mainly by directly affecting the viability of osteoblasts and osteoclasts and their bone remodeling function, or indirectly regulating bone metabolism by influencing enzyme activities as cofactors. Copper ions released from biological materials can affect osteoblasts and osteoclasts, either directly or indirectly by modulating the inflammatory response, oxidative stress, and rapamycin signaling. This review presents an overview of recent progress in the impact of copper on bone metabolism.
Translational potential of this article: The impact of copper on bone metabolism can provide insights into clinical application of copper-containing supplements and biomaterials.
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