Bone Research最新文献_第2页

Bone-brain interaction: mechanisms and potential intervention strategies of biomaterials 骨脑相互作用：生物材料的机制和潜在干预策略

IF 12.7 1区医学

Bone Research Pub Date : 2025-03-17 DOI: 10.1038/s41413-025-00404-5

Jiaze Yu, Luli Ji, Yongxian Liu, Xiaogang Wang, Jing Wang, Changsheng Liu

{"title":"Bone-brain interaction: mechanisms and potential intervention strategies of biomaterials","authors":"Jiaze Yu, Luli Ji, Yongxian Liu, Xiaogang Wang, Jing Wang, Changsheng Liu","doi":"10.1038/s41413-025-00404-5","DOIUrl":"https://doi.org/10.1038/s41413-025-00404-5","url":null,"abstract":"Following the discovery of bone as an endocrine organ with systemic influence, bone-brain interaction has emerged as a research hotspot, unveiling complex bidirectional communication between bone and brain. Studies indicate that bone and brain can influence each other’s homeostasis via multiple pathways, yet there is a dearth of systematic reviews in this area. This review comprehensively examines interactions across three key areas: the influence of bone-derived factors on brain function, the effects of brain-related diseases or injuries (BRDI) on bone health, and the concept of skeletal interoception. Additionally, the review discusses innovative approaches in biomaterial design inspired by bone-brain interaction mechanisms, aiming to facilitate bone-brain interactions through materiobiological effects to aid in the treatment of neurodegenerative and bone-related diseases. Notably, the integration of artificial intelligence (AI) in biomaterial design is highlighted, showcasing AI’s role in expediting the formulation of effective and targeted treatment strategies. In conclusion, this review offers vital insights into the mechanisms of bone-brain interaction and suggests advanced approaches to harness these interactions in clinical practice. These insights offer promising avenues for preventing and treating complex diseases impacting the skeleton and brain, underscoring the potential of interdisciplinary approaches in enhancing human health.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"55 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635696","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}

引用次数: 0

Organelle-tuning condition robustly fabricates energetic mitochondria for cartilage regeneration 细胞器调谐条件为软骨再生强力制造高能线粒体

IF 12.7 1区医学

Bone Research Pub Date : 2025-03-17 DOI: 10.1038/s41413-025-00411-6

Xuri Chen, Yunting Zhou, Wenyu Yao, Chenlu Gao, Zhuomin Sha, Junzhi Yi, Jiasheng Wang, Xindi Liu, Chenjie Dai, Yi Zhang, Zhonglin Wu, Xudong Yao, Jing Zhou, Hua Liu, Yishan Chen, Hongwei Ouyang

{"title":"Organelle-tuning condition robustly fabricates energetic mitochondria for cartilage regeneration","authors":"Xuri Chen, Yunting Zhou, Wenyu Yao, Chenlu Gao, Zhuomin Sha, Junzhi Yi, Jiasheng Wang, Xindi Liu, Chenjie Dai, Yi Zhang, Zhonglin Wu, Xudong Yao, Jing Zhou, Hua Liu, Yishan Chen, Hongwei Ouyang","doi":"10.1038/s41413-025-00411-6","DOIUrl":"https://doi.org/10.1038/s41413-025-00411-6","url":null,"abstract":"Mitochondria are vital organelles whose impairment leads to numerous metabolic disorders. Mitochondrial transplantation serves as a promising clinical therapy. However, its widespread application is hindered by the limited availability of healthy mitochondria, with the dose required reaching up to 109 mitochondria per injection/patient. This necessitates sustainable and tractable approaches for producing high-quality human mitochondria. In this study, we demonstrated a highly efficient mitochondria-producing strategy by manipulating mitobiogenesis and tuning organelle balance in human mesenchymal stem cells (MSCs). Utilizing an optimized culture medium (mito-condition) developed from our established formula, we achieved an 854-fold increase in mitochondria production compared to normal MSC culture within 15 days. These mitochondria were not only significantly expanded but also exhibited superior function both before and after isolation, with ATP production levels reaching 5.71 times that of normal mitochondria. Mechanistically, we revealed activation of the AMPK pathway and the establishment of a novel cellular state ideal for mitochondrial fabrication, characterized by enhanced proliferation and mitobiogenesis while suppressing other energy-consuming activities. Furthermore, the in vivo function of these mitochondria was validated in the mitotherapy in a mouse osteoarthritis model, resulting in significant cartilage regeneration over a 12-week period. Overall, this study presented a new strategy for the off-the-shelf fabrication of human mitochondria and provided insights into the molecular mechanisms governing organelle synthesis.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"124 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635685","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}

引用次数: 0

SIRT3-PINK1-PKM2 axis prevents osteoarthritis via mitochondrial renewal and metabolic switch

IF 12.7 1区医学

Bone Research Pub Date : 2025-03-14 DOI: 10.1038/s41413-025-00413-4

Yaoge Deng, Mingzhuang Hou, Yubin Wu, Yang Liu, Xiaowei Xia, Chenqi Yu, Jianfeng Yu, Huilin Yang, Yijian Zhang, Xuesong Zhu

{"title":"SIRT3-PINK1-PKM2 axis prevents osteoarthritis via mitochondrial renewal and metabolic switch","authors":"Yaoge Deng, Mingzhuang Hou, Yubin Wu, Yang Liu, Xiaowei Xia, Chenqi Yu, Jianfeng Yu, Huilin Yang, Yijian Zhang, Xuesong Zhu","doi":"10.1038/s41413-025-00413-4","DOIUrl":"https://doi.org/10.1038/s41413-025-00413-4","url":null,"abstract":"Maintaining mitochondrial homeostasis is critical for preserving chondrocyte physiological conditions and increasing resistance against osteoarthritis (OA). However, the underlying mechanisms governing mitochondrial self-renewal and energy production remain elusive. In this study, we demonstrated mitochondrial damage and aberrant mitophagy in OA chondrocytes. Genetically overexpressing PTEN-induced putative kinase 1 (PINK1) protects against cartilage degeneration by removing defective mitochondria. PINK1 knockout aggravated cartilage damage due to impaired mitophagy. SIRT3 directly deacetylated PINK1 to promote mitophagy and cartilage anabolism. Specifically, PINK1 phosphorylated PKM2 at the Ser127 site, preserving its active tetrameric form. This inhibited nuclear translocation and the interaction with β-catenin, resulting in a metabolic shift and increased energy production. Finally, a double-knockout mouse model demonstrated the role of the SIRT3-PINK1-PKM2 axis in safeguarding the structural integrity of articular joints and improving motor functions. Overall, this study provides a novel insight into the regulation of mitochondrial renewal and metabolic switches in OA.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"16 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618613","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}

引用次数: 0

Characterizing a new rat model of chronic pain after spine surgery 新型脊柱手术后慢性疼痛大鼠模型的特征描述

IF 12.7 1区医学

Bone Research Pub Date : 2025-03-12 DOI: 10.1038/s41413-025-00408-1

Qichao Wu, Neil C. Ford, Shaoqiu He, Chi Zhang, Xiang Cui, Jing Liu, Xueming Chen, Xu Cao, Yun Guan, Lei Zang

{"title":"Characterizing a new rat model of chronic pain after spine surgery","authors":"Qichao Wu, Neil C. Ford, Shaoqiu He, Chi Zhang, Xiang Cui, Jing Liu, Xueming Chen, Xu Cao, Yun Guan, Lei Zang","doi":"10.1038/s41413-025-00408-1","DOIUrl":"https://doi.org/10.1038/s41413-025-00408-1","url":null,"abstract":"Chronic pain after spine surgery (CPSS) is a complex disorder characterized by multifactorial pathogenesis that occurs in 8%–40% of patients undergoing lumbar spine surgery. We aimed to develop a rat model that mimics clinical CPSS conditions by taking two sequential surgical procedures. Step 1: A plastic rod was inserted into the left L5 intervertebral foramen to produce a steady compression on the dorsal root ganglion (DRG) and the spinal nerve, a common cause of low back pain (LBP). Step 2: The rod was removed after 7 days when rats exhibited mechanical and heat hypersensitivity in the ipsilateral hindpaw, followed by a full L5 laminectomy to mimic spine decompression surgery in LBP patients. The retention of the rod induced a prolonged LBP-like behavior but was quickly resolved after rod removal without laminectomy. However, rats that received laminectomy after rod removal developed heightened mechanical and heat sensitivity in the hindpaw, impaired gait, and reduced spontaneous exploration activity, indicating CPSS. Patch clamp recording revealed a significant augmentation in the intrinsic excitability of small-diameter DRG neurons in CPSS rats. Administration of Dermorphin [D-Arg2, Lys4] (1–4) amide (DALDA, 5 mg /kg, i.p.), a peripherally acting mu-opioid receptor (MOR)-preferred agonist, attenuated pain hypersensitivity, capsaicin-induced [Ca2+]i rising and the increased intrinsic excitability of DRG neurons from CPSS rats. Our findings suggest that this new model, which mirrors the nature of CPSS developed in patients, may be useful for future studies of the underlying mechanisms.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"54 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599846","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}

引用次数: 0

LATS1-modulated ZBTB20 perturbing cartilage matrix homeostasis contributes to early-stage osteoarthritis

IF 12.7 1区医学

Bone Research Pub Date : 2025-03-12 DOI: 10.1038/s41413-025-00414-3

Xue Hao, Jing Zhao, Liyuan Jia, Guangyu Ding, Xiaoju Liang, Fei Su, Shuai Yang, Yating Yang, Jing Fan, Weiping J. Zhang, Liu Yang, Qiang Jie

{"title":"LATS1-modulated ZBTB20 perturbing cartilage matrix homeostasis contributes to early-stage osteoarthritis","authors":"Xue Hao, Jing Zhao, Liyuan Jia, Guangyu Ding, Xiaoju Liang, Fei Su, Shuai Yang, Yating Yang, Jing Fan, Weiping J. Zhang, Liu Yang, Qiang Jie","doi":"10.1038/s41413-025-00414-3","DOIUrl":"https://doi.org/10.1038/s41413-025-00414-3","url":null,"abstract":"Osteoarthritis (OA) is one of the most common degenerative joint diseases in the elderly, increasing in prevalence and posing a substantial socioeconomic challenge, while no disease-modifying treatments available. Better understanding of the early molecular events will benefit the early-stage diagnosis and clinical therapy. Here, we observed the nucleus accumulation of ZBTB20, a member of ZBTB-protein family, in the chondrocytes of early-stage OA. Chondrocytes-specific depletion of Zbtb20 in adult mice attenuated DMM-induced OA progress, restored the balance of extracellular matrix anabolism and catabolism. The NF-κB signaling mediated disturbance of ECM maintenance by ZBTB20 requires its suppression of Pten and consequent PI3K-Akt signaling activation. Furthermore, the subcellular localization of ZBTB20 was modulated by the kinase LATS1. Independent approaches to modulating ZBTB20 via utilizing TRULI and DAPA can restore ECM homeostasis, improving the abnormal behavior and moderating cartilage degeneration. The compounds TRULI and DAPA modulating ZBTB20 may serve as anti-OA drugs.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"49 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599844","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}

引用次数: 0

Reprogramming to restore youthful epigenetics of senescent nucleus pulposus cells for mitigating intervertebral disc degeneration and alleviating low back pain

IF 12.7 1区医学

Bone Research Pub Date : 2025-03-12 DOI: 10.1038/s41413-025-00416-1

Wenzheng Ma, Wantao Wang, Lei Zhao, Jinghao Fan, Lei Liu, Lin Huang, Baogan Peng, Jianru Wang, Baoshan Xu, Hongmei Liu, Decheng Wu, Zhaomin Zheng

{"title":"Reprogramming to restore youthful epigenetics of senescent nucleus pulposus cells for mitigating intervertebral disc degeneration and alleviating low back pain","authors":"Wenzheng Ma, Wantao Wang, Lei Zhao, Jinghao Fan, Lei Liu, Lin Huang, Baogan Peng, Jianru Wang, Baoshan Xu, Hongmei Liu, Decheng Wu, Zhaomin Zheng","doi":"10.1038/s41413-025-00416-1","DOIUrl":"https://doi.org/10.1038/s41413-025-00416-1","url":null,"abstract":"Aging is a pivotal risk factor for intervertebral disc degeneration (IVDD) and chronic low back pain (LBP). The restoration of aging nucleus pulposus cells (NPCs) to a youthful epigenetic state is crucial for IVDD treatment, but remains a formidable challenge. Here, we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes (Oct4, Klf4 and Sox2) in Cavin2-modified exosomes (OKS@M-Exo) for treatment of IVDD and alleviating LBP. The functional OKS@M-Exo efficaciously alleviated senescence markers (p16INK4a, p21CIP1 and p53), reduced DNA damage and H4K20me3 expression, as well as restored proliferation ability and metabolic balance in senescent NPCs, as validated through in vitro experiments. In a rat model of IVDD, OKS@M-Exo maintained intervertebral disc height, nucleus pulposus hydration and tissue structure, effectively ameliorated IVDD via decreasing the senescence markers. Additionally, OKS@M-Exo reduced nociceptive behavior and downregulated nociception markers, indicating its efficiency in alleviating LBP. The transcriptome sequencing analysis also demonstrated that OKS@M-Exo could decrease the expression of age-related pathways and restore cell proliferation. Collectively, reprogramming by the OKS@M-Exo to restore youthful epigenetics of senescent NPCs may hold promise as a therapeutic platform to treat IVDD.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599845","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}

引用次数: 0

Enhanced SIRT3 expression restores mitochondrial quality control mechanism to reverse osteogenic impairment in type 2 diabetes mellitus 增强 SIRT3 的表达可恢复线粒体质量控制机制，从而逆转 2 型糖尿病患者的成骨障碍

IF 12.7 1区医学

Bone Research Pub Date : 2025-03-03 DOI: 10.1038/s41413-024-00399-5

Yansi Xian, Bin Liu, Tao Shen, Lin Yang, Rui Peng, Hongdou Shen, Xueying An, Yutian Wang, Yu Ben, Qing Jiang, Baosheng Guo

{"title":"Enhanced SIRT3 expression restores mitochondrial quality control mechanism to reverse osteogenic impairment in type 2 diabetes mellitus","authors":"Yansi Xian, Bin Liu, Tao Shen, Lin Yang, Rui Peng, Hongdou Shen, Xueying An, Yutian Wang, Yu Ben, Qing Jiang, Baosheng Guo","doi":"10.1038/s41413-024-00399-5","DOIUrl":"https://doi.org/10.1038/s41413-024-00399-5","url":null,"abstract":"Osteoporosis represents a prevalent and debilitating comorbidity in patients diagnosed with type 2 diabetes mellitus (T2DM), which is characterized by suppressed osteoblast function and disrupted bone microarchitecture. In this study, we utilized male C57BL/6 J mice to investigate the role of SIRT3 in T2DM. Decreased SIRT3 expression and impaired mitochondrial quality control mechanism are observed in both in vitro and in vivo models of T2DM. Mechanistically, SIRT3 suppression results in hyperacetylation of FOXO3, hindering the activation of the PINK1/PRKN mediated mitophagy pathway and resulting in accumulation of dysfunctional mitochondria. Genetical overexpression or pharmacological activation of SIRT3 restores deacetylation status of FOXO3, thus facilitating mitophagy and ameliorating osteogenic impairment in T2DM. Collectively, our findings highlight the fundamental regulatory function of SIRT3 in mitochondrial quality control, crucial for maintaining bone homeostasis in T2DM. These insights not only enhance our understanding of the molecular mechanisms underlying diabetic osteoporosis but also identify SIRT3 as a promising therapeutic target for diabetic osteoporosis.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"36 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532561","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}

引用次数: 0

Beclin 1 of megakaryocytic lineage cells is locally dispensable for platelet hemostasis but functions distally in bone homeostasis 巨核细胞系细胞的 Beclin 1 在局部对血小板止血不起作用，但在远端对骨稳态起作用

IF 12.7 1区医学

Bone Research Pub Date : 2025-03-03 DOI: 10.1038/s41413-025-00410-7

Lei Li, Chen Zhao, Ruizhi Zhang, Wen Wei, Bowen Liu, Jin Dong, Xueqin Gao, Di Zhang, Xueqing Wang, Meilin Lu, Yumu Zhang, Yao Yu, Na Yuan, Youjia Xu, Jianrong Wang, Yixuan Fang

{"title":"Beclin 1 of megakaryocytic lineage cells is locally dispensable for platelet hemostasis but functions distally in bone homeostasis","authors":"Lei Li, Chen Zhao, Ruizhi Zhang, Wen Wei, Bowen Liu, Jin Dong, Xueqin Gao, Di Zhang, Xueqing Wang, Meilin Lu, Yumu Zhang, Yao Yu, Na Yuan, Youjia Xu, Jianrong Wang, Yixuan Fang","doi":"10.1038/s41413-025-00410-7","DOIUrl":"https://doi.org/10.1038/s41413-025-00410-7","url":null,"abstract":"The crosstalk between megakaryocytic lineage cells and the skeletal system has just begun to be explored but remains largely elusive. Using conditional gene knockout mouse models, we demonstrated that loss of Beclin 1 (Becn1), a major regulator of mammalian autophagy, exclusively in the megakaryocytic lineage disrupted autophagy in platelets but did not compromise megakaryopoiesis or the formation and function of platelets. Unexpectedly, conditional Becn1 deletion in male mice led to a remarkable increase in bone mass with improved bone quality, in association with a decrease in sex hormone binding globulin (SHBG) and an increase in free testosterone (FT). In vivo Becn1 overexpression in megakaryocytic lineage-specific cells reduced bone mass and quality, along with an increase in SHBG and a decrease in FT. Transplantation of wild-type bone marrow cells into megakaryocytic lineage Becn1-deficient male mice restored bone mass and normalized SHBG and FT. Furthermore, bilateral orchiectomy of Becn1f/f;Pf4-iCre mice, which are crippled with the production of testosterone, resulted in a reduction in bone mass and quality, whereas in vivo overexpression of SHBG, specifically in the liver of Becn1f/f;Pf4-iCre mice, decreased FT and reduced bone mass and quality. In addition, metformin treatment, which induces SHBG expression, reduced FT and normalized bone mass in Becn1f/f;Pf4-iCre mice. We thus concluded that Becn1 of the megakaryocytic lineage is dispensable locally for platelet hemostasis but limits bone mass by increasing SHBG, which in turn reduces the FT of male mice. Our findings highlight a mechanism by which Becn1 from megakaryocytic lineage cells distally balances bone growth.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"84 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532559","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}

引用次数: 0

CD47 is required for mesenchymal progenitor proliferation and fracture repair

IF 12.7 1区医学

Bone Research Pub Date : 2025-03-03 DOI: 10.1038/s41413-025-00409-0

Robert L. Zondervan, Christina A. Capobianco, Daniel C. Jenkins, John D. Reicha, Livia Fredrick, Charles Lam, Jeanna T. Schmanski, Jeffery S. Isenberg, Jaimo Ahn, Ralph S. Marcucio, Kurt D. Hankenson

{"title":"CD47 is required for mesenchymal progenitor proliferation and fracture repair","authors":"Robert L. Zondervan, Christina A. Capobianco, Daniel C. Jenkins, John D. Reicha, Livia Fredrick, Charles Lam, Jeanna T. Schmanski, Jeffery S. Isenberg, Jaimo Ahn, Ralph S. Marcucio, Kurt D. Hankenson","doi":"10.1038/s41413-025-00409-0","DOIUrl":"https://doi.org/10.1038/s41413-025-00409-0","url":null,"abstract":"CD47 is a ubiquitous and pleiotropic cell-surface receptor. Disrupting CD47 enhances injury repair in various tissues but the role of CD47 has not been studied in bone injuries. In a murine closed-fracture model, CD47-null mice showed decreased callus bone formation as assessed by microcomputed tomography 10 days post-fracture and increased fibrous volume as determined by histology. To understand the cellular basis for this phenotype, mesenchymal progenitors (MSC) were harvested from bone marrow. CD47-null MSC showed decreased large fibroblast colony formation (CFU-F), significantly less proliferation, and fewer cells in S-phase, although osteoblast differentiation was unaffected. However, consistent with prior research, CD47-null endothelial cells showed increased proliferation relative to WT cells. Similarly, in a murine ischemic fracture model, CD47-null mice showed reduced fracture callus size due to a reduction in bone relative to WT 15 days-post fracture. Consistent with our in vitro results, in vivo EdU labeling showed decreased cell proliferation in the callus of CD47-null mice, while staining for CD31 and endomucin demonstrated increased endothelial cell density. Finally, WT mice with ischemic fracture that were administered a CD47 morpholino, which blocks CD47 protein production, showed a callus phenotype similar to that of ischemic fractures in CD47-null mice, suggesting the phenotype was not due to developmental changes in the knockout mice. Thus, inhibition of CD47 during bone healing reduces both non-ischemic and ischemic fracture healing, in part, by decreasing MSC proliferation. Furthermore, the increase in endothelial cell proliferation and early blood vessel density caused by CD47 disruption is not sufficient to overcome MSC dysfunction.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"130 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532558","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}

引用次数: 0

Apolipoprotein E is a marker of all chondrocytes in the growth plate resting zone

IF 12.7 1区医学

Bone Research Pub Date : 2025-03-03 DOI: 10.1038/s41413-025-00407-2

Joe Kodama, Takeshi Oichi, Kevin J. Wilkinson, Joshua M. Abzug, Takashi Kaito, Motomi Enomoto-Iwamoto, Masahiro Iwamoto, Satoru Otsuru

{"title":"Apolipoprotein E is a marker of all chondrocytes in the growth plate resting zone","authors":"Joe Kodama, Takeshi Oichi, Kevin J. Wilkinson, Joshua M. Abzug, Takashi Kaito, Motomi Enomoto-Iwamoto, Masahiro Iwamoto, Satoru Otsuru","doi":"10.1038/s41413-025-00407-2","DOIUrl":"https://doi.org/10.1038/s41413-025-00407-2","url":null,"abstract":"The resting zone (RZ) in mammalian growth plates is critical for maintaining and regulating chondrocyte turnover during longitudinal bone growth as a control tower and stem cell reservoir. Although recent lineage tracing studies have identified several markers for stem cells in the RZ, these markers only partially label chondrocytes in the RZ, suggesting that the resting chondrocytes (RCs) are a heterogeneous population with different types of stem cells. Since a comprehensive marker for RCs is still lacking, the RZ is generally determined based on ambiguous histological criteria, such as small and round chondrocytes without columnar formation, which may lead to inconsistencies among researchers. Therefore, in this study, we used single-cell RNA sequencing (scRNAseq) of growth plate chondrocytes followed by validation by fluorescence in situ hybridization (FISH) to precisely annotate cell clusters in scRNAseq and search for a marker of RCs. The scRNAseq analysis revealed that apolipoprotein E (Apoe) was the top-hit gene, which was ubiquitously expressed in the RC cluster. FISH confirmed that Apoe was exclusively localized to the histologically defined RZ. In newly generated ApoemCherry knock-in mice, we further confirmed that mCherry expression mirrored the distribution of Apoe-expressing chondrocytes in the RZ particularly after the formation of the secondary ossification center. These mCherry+ RCs were slow cycling in vivo and exhibited stem cell properties in vitro. Moreover, APOE was detected in human growth plate RCs. These findings suggest that apolipoprotein E is a novel pan-RC marker in both mouse and human growth plates.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"5 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532498","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}

引用次数: 0