Osteostaticytes: A novel osteoclast subset couples bone resorption and bone formation

被引:2
作者
Wei, Zhiyuan [1 ]
Zhou, Jian [2 ]
Shen, Jie [1 ]
Sun, Dong [1 ]
Gao, Tianbao [2 ]
Liu, Qin [2 ]
Wu, Hongri [1 ]
Wang, Xiaohua [1 ]
Wang, Shulin [1 ]
Xiao, Shiyu [1 ]
Han, Chao [3 ]
Yang, Di [3 ]
Dong, Hui [3 ]
Wu, Yuzhang [3 ]
Zhang, Yi [4 ]
Xu, Shuai [5 ]
Wang, Xian [6 ]
Luo, Jie [7 ,8 ]
Dai, Qijie [1 ]
Zhu, Jun [9 ]
Lin, Sien [10 ]
Luo, Fei [1 ]
Tian, Yi [3 ]
Xie, Zhao [1 ]
机构
[1] Third Mil Med Univ Army Med Univ, Affiliated Hosp 1, Dept Orthoped, Chongqing, Peoples R China
[2] Third Mil Med Univ Army Med Univ, Biomed Anal Ctr, Chongqing, Peoples R China
[3] Third Mil Med Univ Army Med Univ, PLA, Inst Immunol, Chongqing, Peoples R China
[4] Chongqing Int Inst Immunol, Chongqing, Peoples R China
[5] Third Mil Med Univ Army Med Univ, Affiliated Hosp 2, Dept Stomatol, Chongqing, Peoples R China
[6] Qingdao Univ, Med Coll, Dept Immunol, Qingdao, Shandong, Peoples R China
[7] Third Mil Med Univ Army Med Univ, Affiliated Hosp 1, Inst Pathol, Chongqing, Peoples R China
[8] Third Mil Med Univ Army Med Univ, Southwest Canc Ctr, Affiliated Hosp 1, Chongqing, Peoples R China
[9] Shanghai Introncure Biotechnol Inc, Shanghai, Peoples R China
[10] Chinese Univ Hong Kong, Dept Orthopaed & Traumatol, Musculoskeletal Res Lab, Prince Wales Hosp,Shatin,Fac Med, Hong Kong, Peoples R China
基金
中国国家自然科学基金;
关键词
Bone; Bone remodelling; Osteostaticyte; Osteoclast; Reversal phase; scRNA-seq; STAPHYLOCOCCUS-AUREUS; DENDRITIC CELLS; DIFFERENTIATION; EXPRESSION; MOUSE; OSTEOPOROSIS; MACROPHAGES;
D O I
10.1016/j.jot.2024.06.010
中图分类号
R826.8 [整形外科学]; R782.2 [口腔颌面部整形外科学]; R726.2 [小儿整形外科学]; R62 [整形外科学(修复外科学)];
学科分类号
摘要
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 graphbased 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 IDO1 hi g h CCL3 hi g h CCL4 hi g h 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. Conclusion: Collectively, our findings revealed a novel stage (OSC) within the osteoclast lineage, potentially representing elusive bone reversal cells due to its increased chemotactic ability towards MSCs and potential contribution to bone remodelling. This study provides valuable insights into the intricate mechanisms of the reversal phase during bone remodelling and unveils potential therapeutic strategies for diseases associated with bone uncoupling. Translational potential of this article: This study identified a new subset, referred to as IDO1(plus symbol) CCL3 (plus symbol) CCL4(plus symbol) osteostaticytes which displayed the highest chemotactic activity among all osteoclast lineages and may serve as reversal cells in bone remodelling. These findings offer new insights and insights for understanding bone reversal -related diseases and may serve as novel therapeutic targets for conditions such as osteomyelitis and delayed bone healing.
引用
收藏
页码:144 / 160
页数:17
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