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Qu F, Shen YY, Zhang XY, Wu YQ, Xu ZH, Zhai ZD, Zhong Q, Fan Z, Xu C. Ephrin-B2 acts as a positive regulator of osteogenesis-angiogenesis coupling. Int J Biol Macromol 2025; 302:140555. [PMID: 39894124 DOI: 10.1016/j.ijbiomac.2025.140555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 01/12/2025] [Accepted: 01/30/2025] [Indexed: 02/04/2025]
Abstract
AIMS The aim of this study was to explore the role and potential mechanisms of Ephrin-B2 signaling in osteogenesis-angiogenesis coupling and to provide guidance for periodontal tissue engineering. MATERIALS AND METHODS Considering the close relationship between periodontitis and periodontal bone defects, single-cell transcriptomic data from periodontal tissues in published databases (GEO number: GSE171213) were analyzed to characterize Ephrin-B2 signaling between osteoblastic lineages and endothelial cells. To observe the effects and mechanisms of Ephrin-B2 in angiogenesis and periodontal bone regeneration, osteoblasts were constructed that overexpress Ephrin-B2 and were then co-cultured with human umbilical vein cells (HUVECs). RESULTS Single-cell sequencing revealed a deficiency in Ephrin-B2 signaling from osteoblastic lineages in periodontitis, resulting in impaired transduction of Ephrin-B2 signaling between osteoblasts and endothelial cells. In an osteoblast-endothelial cell co-culture system, Ephrin-B2 signaling from osteoblasts promoted angiogenesis. The downstream pathway might be related to VEGFR2-PI3K. The cotransplantation of osteoblasts overexpressing Ephrin-B2 and HUVECs facilitated angiogenesis and new bone generation in vivo. CONCLUSIONS This study confirmed that Ephrin-B2 signaling is an indispensable positive regulatory factor in the osteogenesis-angiogenesis coupling of periodontal tissue remodeling. These findings may help to optimize transplantation strategies and provide a new solution for the targeted treatment of periodontal bone defects. LAY SUMMARY Sufficient vascularization is a prerequisite for periodontal bone regeneration. The cotransplantation of angiogenic endothelial cells and bone-forming cells is a promising tissue engineering strategy. To facilitate the effect of the transplantation, we found evidence of Ephrin-B2 signaling deficiency in osteoblastic lineages and vascular endothelial cells of periodontitis patients from single-cell sequencing data. Moreover, by constructing a cotransplantation system with overexpression of Ephrin-B2, we found its positive role in promoting periodontal vascularized bone regeneration. The present study elucidates the positive role and potential mechanisms of Ephrin-B2 signaling in osteogenesis-angiogenesis coupling, which will help to promote the effect of periodontal tissue engineering.
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Affiliation(s)
- Fang Qu
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China; Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai, China
| | - Ying-Yi Shen
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China; Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai, China
| | - Xin-Yu Zhang
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China; Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai, China
| | - Ya-Qin Wu
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China; Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai, China
| | - Zi-Hang Xu
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China; Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai, China
| | - Zi-Di Zhai
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China; Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai, China
| | - Qi Zhong
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China; Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai, China
| | - Zhen Fan
- Department of Implantology, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, 200072, China.
| | - Chun Xu
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China; Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai, China.
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Bai Y, Li X, Wu K, Heng BC, Zhang X, Deng X. Biophysical stimuli for promoting bone repair and regeneration. MEDICAL REVIEW (2021) 2025; 5:1-22. [PMID: 39974560 PMCID: PMC11834751 DOI: 10.1515/mr-2024-0023] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 06/19/2024] [Indexed: 02/21/2025]
Abstract
Bone injuries and diseases are associated with profound changes in the biophysical properties of living bone tissues, particularly their electrical and mechanical properties. The biophysical properties of healthy bone are attributed to the complex network of interactions between its various cell types (i.e., osteocytes, osteoclast, immune cells and vascular endothelial cells) with the surrounding extracellular matrix (ECM) against the backdrop of a myriad of biomechanical and bioelectrical stimuli arising from daily physical activities. Understanding the pathophysiological changes in bone biophysical properties is critical to developing new therapeutic strategies and novel scaffold biomaterials for orthopedic surgery and tissue engineering, as well as provides a basis for the application of various biophysical stimuli as therapeutic agents to restore the physiological microenvironment of injured/diseased bone tissue, to facilitate its repair and regeneration. These include mechanical, electrical, magnetic, thermal and ultrasound stimuli, which will be critically examined in this review. A significant advantage of utilizing such biophysical stimuli to facilitate bone healing is that these may be applied non-invasively with minimal damage to surrounding tissues, unlike conventional orthopedic surgical procedures. Furthermore, the effects of such biophysical stimuli can be localized specifically at the bone defect site, unlike drugs or growth factors that tend to diffuse away after delivery, which may result in detrimental side effects at ectopic sites.
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Affiliation(s)
- Yunyang Bai
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing, China
| | - Xiaochan Li
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing, China
| | - Ke Wu
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing, China
| | - Boon C. Heng
- Department of Dental Materials & Dental Medical Devices Testing Center, Peking University School and Hospital of Stomatology, Beijing, China
| | - Xuehui Zhang
- Department of Dental Materials & Dental Medical Devices Testing Center, Peking University School and Hospital of Stomatology, Beijing, China
- National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, NMPA Key Laboratory for Dental Materials, Beijing Laboratory of Biomedical Materials & Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, China
| | - Xuliang Deng
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing, China
- Department of Dental Materials & Dental Medical Devices Testing Center, Peking University School and Hospital of Stomatology, Beijing, China
- National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, NMPA Key Laboratory for Dental Materials, Beijing Laboratory of Biomedical Materials & Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, China
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Borstein SR, Hammer MP, O'Meara BC, McGee MD. The macroevolutionary dynamics of pharyngognathy in fishes fail to support the key innovation hypothesis. Nat Commun 2024; 15:10325. [PMID: 39609375 PMCID: PMC11605008 DOI: 10.1038/s41467-024-53141-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 09/30/2024] [Indexed: 11/30/2024] Open
Abstract
Key innovations, traits that provide species access to novel niches, are thought to be a major generator of biodiversity. One commonly cited example of key innovation is pharyngognathy, a set of modifications to the pharyngeal jaws found in some highly species-rich fish clades such as cichlids and wrasses. Here, using comparative phylogenomics and phylogenetic comparative methods, we investigate the genomic basis of pharyngognathy and the impact of this innovation on diversification. Whole genomes resolve the relationships of fish clades with this innovation and their close relatives, but high levels of topological discordance suggest the innovation may have evolved fewer times than previously thought. Closer examination of the topology of noncoding elements accelerated in clades with the pharyngognathy innovation reveals hidden patterns of shared ancestry across putatively independent transitions to pharyngognathy. When our updated phylogenomic relationships are used alongside large-scale phylogenetic and ecological datasets, we find no evidence pharyngognathy consistently modifies the macroevolutionary landscape of trophic ecology nor does it increase diversification. Our results highlight the necessity of incorporating genomic information in studies of key innovation.
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Affiliation(s)
- Samuel R Borstein
- Department of Biology, Texas State University, San Marcos, TX, 78666, USA.
- Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, MI, 48109, USA.
- Department of Ecology and Evolutionary Biology, University of Tennessee, Knoxville, TN, 37996, USA.
| | - Michael P Hammer
- Museum and Art Gallery of the Northern Territory, Darwin, Northern Territory, Australia
| | - Brian C O'Meara
- Department of Ecology and Evolutionary Biology, University of Tennessee, Knoxville, TN, 37996, USA
| | - Matthew D McGee
- School of Biological Sciences, Monash University, Clayton, Victoria, Australia
- Museums Victoria, Melbourne, Victoria, Australia
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Roseti L, Borciani G, Grassi F, Desando G, Gambari L, Grigolo B. Nutraceuticals in osteoporosis prevention. Front Nutr 2024; 11:1445955. [PMID: 39416651 PMCID: PMC11479890 DOI: 10.3389/fnut.2024.1445955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Accepted: 09/03/2024] [Indexed: 10/19/2024] Open
Abstract
Nutraceuticals are gaining popularity as they can contribute to bone health by delaying the onset or slowing down the progression of pathological bone loss. Osteoporosis's bone loss is a concern for older adults and a crucial aspect of aging. Maintaining healthy bones is the key to living a full and active life. Our review explores the current knowledge on the role of nutraceuticals in preventing osteoporosis by focusing on three main aspects. First, we provide an overview of osteoporosis. Second, we discuss the latest findings on natural nutraceuticals and their efficacy in reducing bone loss, emphasizing clinical trials. Third, we conduct a structured analysis to evaluate nutraceuticals' pros and cons and identify translational gaps. In conclusion, we must address several challenges to consolidate our knowledge, better support clinicians in their prescriptions, and provide people with more reliable nutritional recommendations to help them lead healthier lives.
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Affiliation(s)
| | - Giorgia Borciani
- RAMSES Laboratory, Rizzoli RIT-Research, Innovation & Technology Department, Istituto di Ricerca Codivilla Putti, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
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Rodríguez-Sosa MR, Del Castillo LM, Belarra A, Zapata AG, Alfaro D. The lack of EphB3 receptor prevents bone loss in mouse models of osteoporosis. J Bone Miner Res 2024; 39:1008-1024. [PMID: 38739682 DOI: 10.1093/jbmr/zjae075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 03/21/2024] [Accepted: 05/10/2024] [Indexed: 05/16/2024]
Abstract
Bone homeostasis is a complex process in which some Eph kinase receptors and their ephrin ligands appear to be involved. In the present study, we address this issue by examining, both in vitro and in vivo, the role of EphB2 and EphB3 in mesenchymal stromal/stem cell (MSC) differentiation into bone tissue. This was first evaluated by quantitative reverse transcription PCR (RT-qPCR) and histological staining in MSCs cultured in specific mediums revealing that although EphB2-/- MSCs mainly expressed pro-adipogenic transcription factors, EphB3-/- MSCs showed abundant osteogenic transcripts, such as Runx2, Msx2, and Sp7. To clarify the underlying molecular mechanisms, we found that the lack of EphB3 signaling alters the genetic profile of differentiating MSCs, reducing the expression of many inhibitory molecules and antagonists of the BMP signaling pathway, and increasing Bmp7 expression, a robust bone inductor. Then, to confirm the osteogenic role of EphB3 in vivo, we studied the condition of 2 mouse models of induced bone loss (ovariectomy or long-term glucocorticoid treatment). Interestingly, in both models, both WT and EphB2-/- mice equally developed the disease but EphB3-/- mice did not exhibit the typical bone loss, nor an increase in urine Ca2+ or blood serum CTX-1. This phenotype in EphB3-KO mice could be due to their significantly higher proportions of osteoprogenitor cells and preosteoblasts, and their lower number of osteoclasts, as compared with WT and EphB2-KO mice. Thus, we conclude that EphB3 acts as a negative regulator of the osteogenic differentiation, and its absence prevents bone loss in mice subjected to ovariectomy or dexamethasone treatment.
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Affiliation(s)
- Mariano R Rodríguez-Sosa
- Department of Cell Biology, Faculty of Biological Sciences, Complutense University of Madrid, C.P. 28040, Madrid, Spain
- Research Institute Hospital "12 de Octubre" (imas12), C.P. 28041, Madrid, Spain
| | - Luis M Del Castillo
- Reproductive Medicine Research Group, IVI Foundation, Health Research Institute Hospital La Fe (IIS La Fe), C.P. 46026, Valencia, Spain
| | - Adrián Belarra
- Micro-CT Laboratory, Central Radioactive Facility, Department of Radiology, Rehabilitation and Physiotherapy, Faculty of Medicine, Complutense University of Madrid, C.P. 28040, Madrid, Spain
| | - Agustín G Zapata
- Department of Cell Biology, Faculty of Biological Sciences, Complutense University of Madrid, C.P. 28040, Madrid, Spain
| | - David Alfaro
- Department of Cell Biology, Faculty of Biological Sciences, Complutense University of Madrid, C.P. 28040, Madrid, Spain
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Chen S, Liang B, Xu J. Unveiling heterogeneity in MSCs: exploring marker-based strategies for defining MSC subpopulations. J Transl Med 2024; 22:459. [PMID: 38750573 PMCID: PMC11094970 DOI: 10.1186/s12967-024-05294-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 05/11/2024] [Indexed: 05/19/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) represent a heterogeneous cell population distributed throughout various tissues, demonstrating remarkable adaptability to microenvironmental cues and holding immense promise for disease treatment. However, the inherent diversity within MSCs often leads to variability in therapeutic outcomes, posing challenges for clinical applications. To address this heterogeneity, purification of MSC subpopulations through marker-based isolation has emerged as a promising approach to ensure consistent therapeutic efficacy. In this review, we discussed the reported markers of MSCs, encompassing those developed through candidate marker strategies and high-throughput approaches, with the aim of explore viable strategies for addressing the heterogeneity of MSCs and illuminate prospective research directions in this field.
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Affiliation(s)
- Si Chen
- Shenzhen University Medical School, Shenzhen University, Shenzhen, 518000, People's Republic of China
| | - Bowei Liang
- Shenzhen University Medical School, Shenzhen University, Shenzhen, 518000, People's Republic of China
| | - Jianyong Xu
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-Implantation, Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-Implantation, Shenzhen Zhongshan Obstetrics & Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital), Fuqiang Avenue 1001, Shenzhen, 518060, Guangdong, People's Republic of China.
- Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-Implantation, Shenzhen, 518000, People's Republic of China.
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Chatzikalil E, Stergiou IE, Papadakos SP, Konstantinidis I, Theocharis S. The Clinical Relevance of the EPH/Ephrin Signaling Pathway in Pediatric Solid and Hematologic Malignancies. Int J Mol Sci 2024; 25:3834. [PMID: 38612645 PMCID: PMC11011407 DOI: 10.3390/ijms25073834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/26/2024] [Accepted: 03/26/2024] [Indexed: 04/14/2024] Open
Abstract
Pediatric neoplasms represent a complex group of malignancies that pose unique challenges in terms of diagnosis, treatment, and understanding of the underlying molecular pathogenetic mechanisms. Erythropoietin-producing hepatocellular receptors (EPHs), the largest family of receptor tyrosine kinases and their membrane-tethered ligands, ephrins, orchestrate short-distance cell-cell signaling and are intricately involved in cell-pattern morphogenesis and various developmental processes. Unraveling the role of the EPH/ephrin signaling pathway in the pathophysiology of pediatric neoplasms and its clinical implications can contribute to deciphering the intricate landscape of these malignancies. The bidirectional nature of the EPH/ephrin axis is underscored by emerging evidence revealing its capacity to drive tumorigenesis, fostering cell-cell communication within the tumor microenvironment. In the context of carcinogenesis, the EPH/ephrin signaling pathway prompts a reevaluation of treatment strategies, particularly in pediatric oncology, where the modest progress in survival rates and enduring treatment toxicity necessitate novel approaches. Molecularly targeted agents have emerged as promising alternatives, prompting a shift in focus. Through a nuanced understanding of the pathway's intricacies, we aim to lay the groundwork for personalized diagnostic and therapeutic strategies, ultimately contributing to improved outcomes for young patients grappling with neoplastic challenges.
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Affiliation(s)
- Elena Chatzikalil
- Division of Pediatric Hematology-Oncology, First Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Ioanna E. Stergiou
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Stavros P. Papadakos
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | | | - Stamatios Theocharis
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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Zheng H, Liu Y, Deng Y, Li Y, Liu S, Yang Y, Qiu Y, Li B, Sheng W, Liu J, Peng C, Wang W, Yu H. Recent advances of NFATc1 in rheumatoid arthritis-related bone destruction: mechanisms and potential therapeutic targets. Mol Med 2024; 30:20. [PMID: 38310228 PMCID: PMC10838448 DOI: 10.1186/s10020-024-00788-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 01/22/2024] [Indexed: 02/05/2024] Open
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by inflammation of the synovial tissue and joint bone destruction, often leading to significant disability. The main pathological manifestation of joint deformity in RA patients is bone destruction, which occurs due to the differentiation and proliferation of osteoclasts. The transcription factor nuclear factor-activated T cell 1 (NFATc1) plays a crucial role in this process. The regulation of NFATc1 in osteoclast differentiation is influenced by three main factors. Firstly, NFATc1 is activated through the upstream nuclear factor kappa-B ligand (RANKL)/RANK signaling pathway. Secondly, the Ca2+-related co-stimulatory signaling pathway amplifies NFATc1 activity. Finally, negative regulation of NFATc1 occurs through the action of cytokines such as B-cell Lymphoma 6 (Bcl-6), interferon regulatory factor 8 (IRF8), MAF basic leucine zipper transcription factor B (MafB), and LIM homeobox 2 (Lhx2). These three phases collectively govern NFATc1 transcription and subsequently affect the expression of downstream target genes including TRAF6 and NF-κB. Ultimately, this intricate regulatory network mediates osteoclast differentiation, fusion, and the degradation of both organic and inorganic components of the bone matrix. This review provides a comprehensive summary of recent advances in understanding the mechanism of NFATc1 in the context of RA-related bone destruction and discusses potential therapeutic agents that target NFATc1, with the aim of offering valuable insights for future research in the field of RA. To assess their potential as therapeutic agents for RA, we conducted a drug-like analysis of potential drugs with precise structures.
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Affiliation(s)
- Hao Zheng
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Yuexuan Liu
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Yasi Deng
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Yunzhe Li
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Shiqi Liu
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Yong Yang
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Yun Qiu
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Bin Li
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Wenbing Sheng
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Jinzhi Liu
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Caiyun Peng
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Wei Wang
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China.
| | - Huanghe Yu
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Innovative Materia Medica Research Institute, Hunan University of Chinese Medicine, Changsha, 410208, China.
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Vincenzi M, Mercurio FA, Leone M. EPHA2 Receptor as a Possible Therapeutic Target in Viral Infections. Curr Med Chem 2024; 31:5670-5701. [PMID: 37828671 DOI: 10.2174/0109298673256638231003111234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 08/02/2023] [Accepted: 08/24/2023] [Indexed: 10/14/2023]
Abstract
BACKGROUND The receptor tyrosine kinase EphA2 plays a role in many diseases, like cancer, cataracts, and osteoporosis. Interestingly, it has also been linked to viral infections. OBJECTIVE Herein, current literature has been reviewed to clarify EphA2 functions in viral infections and explore its potential role as a target in antiviral drug discovery strategies. METHODS Research and review articles along with preprints connecting EphA2 to different viruses have been searched through PubMed and the web. Structures of complexes between EphA2 domains and viral proteins have been retrieved from the PDB database. RESULTS EphA2 assumes a key role in Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein Barr virus (EBV) infections by directly binding, through its ligand binding domain, viral glycoproteins. For human cytomegalovirus (HCMV), the role of EphA2 in maintaining virus latency state, through cooperation with specific viral proteins, has also been speculated. In certain cells, with high EphA2 expression levels, following ligand stimulation, receptor activation might contribute to severe symptoms accompanying a few viral infections, including lung injuries often related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). CONCLUSION Since EphA2 works as a host receptor for certain viruses, it might be worth more deeply investigating known compounds targeting its extracellular ligand binding domain as antiviral therapeutics. Due to EphA2's function in inflammation, its possible correlation with SARS-CoV-2 cannot be excluded, but more experimental studies are needed in this case to undoubtedly attribute the role of this receptor in viral infections.
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Affiliation(s)
- Marian Vincenzi
- Institute of Biostructures and Bioimaging, National Research Council of Italy (CNR-IBB), Naples, Italy
| | - Flavia Anna Mercurio
- Institute of Biostructures and Bioimaging, National Research Council of Italy (CNR-IBB), Naples, Italy
| | - Marilisa Leone
- Institute of Biostructures and Bioimaging, National Research Council of Italy (CNR-IBB), Naples, Italy
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Ren L, Zhu X, Tan J, Lv X, Wang J, Hua F. MiR-210 promotes bone formation in ovariectomized rats by regulating osteogenic/adipogenic differentiation of bone marrow mesenchymal stem cells through downregulation of EPHA2. J Orthop Surg Res 2023; 18:811. [PMID: 37904187 PMCID: PMC10617172 DOI: 10.1186/s13018-023-04213-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 09/16/2023] [Indexed: 11/01/2023] Open
Abstract
PURPOSE In osteoporosis, the balance between osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs) is disrupted. The osteogenic differentiation of bone marrow MSCs (BMSCs) is important for improving osteoporosis. The aim of this study was to explore the role and molecular mechanism of miR-210 in the balance of osteogenic/adipogenic differentiation of BMSCs in postmenopausal osteoporosis. METHODS Postmenopausal osteoporosis rat models were constructed by ovariectomy (OVX). BMSCs were isolated from the femur in rats of Sham and OVX groups. MiR-210 was overexpressed and suppressed by miR-210 mimics and inhibitor, respectively. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the relative mRNA expression of miR-210, ephrin type-A receptor 2 (EPHA2), alkaline phosphatase (ALP), osterix (OSX), osteocalcin (Bglap), Runt-related transcription factor 2 (Runx2), peroxisome proliferator activated receptor gamma, and fatty acid binding protein 4 (FABP4) in each group of rat femoral tissues or BMSCs. Western blot was applied to detect the protein expression level of EPHA2 in rat femoral tissues and cells. Alizarin red S staining and oil red O staining were performed to assess the osteogenic and adipogenic differentiation of BMSCs, respectively. In addition, the targeting relationship between miR-210 and EPHA2 was verified by a dual luciferase gene reporter assay. RESULTS The expression of miR-210 was significantly reduced in femoral tissues and BMSCs of OVX rats, and its low expression was associated with reduced bone formation. The osteogenic differentiation was enhanced in OVX rats treated with miR-210 mimic. Overexpression of miR-210 in transfected BMSCs was also found to significantly promote osteogenic differentiation and even inhibit adipogenic differentiation in BMSCs, while knockdown of miR-210 did the opposite. Further mechanistic studies showed that miR-210 could target and inhibit the expression of EPHA2 in BMSCs, thus promoting osteogenic differentiation and inhibiting adipogenic differentiation of BMSCs. CONCLUSION MiR-210 promotes osteogenic differentiation and inhibits adipogenic differentiation of BMSCs by down-regulating EPHA2 expression. As it plays an important role in the osteogenic/adipogenic differentiation of osteoporosis, miR-210 can serve as a potential miRNA biomarker for osteoporosis.
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Affiliation(s)
- Lijue Ren
- Department of Endocrinology, The Third Affiliated Hospital of Soochow University, Changzhou, 213100, Jiangsu, China
- Department of Endocrinology, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, 014010, Inner Mongolia, China
| | - Xiaohui Zhu
- Department of Endocrinology, The Third Affiliated Hospital of Soochow University, Changzhou, 213100, Jiangsu, China
| | - Jiuting Tan
- Department of Endocrinology, The Third Affiliated Hospital of Soochow University, Changzhou, 213100, Jiangsu, China
| | - Xiangyu Lv
- Department of Endocrinology, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, 014010, Inner Mongolia, China
| | - Jiahui Wang
- Department of Endocrinology, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, 014010, Inner Mongolia, China
| | - Fei Hua
- Department of Endocrinology, The Third Affiliated Hospital of Soochow University, Changzhou, 213100, Jiangsu, China.
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11
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Papadakos SP, Stergiou IE, Gkolemi N, Arvanitakis K, Theocharis S. Unraveling the Significance of EPH/Ephrin Signaling in Liver Cancer: Insights into Tumor Progression and Therapeutic Implications. Cancers (Basel) 2023; 15:3434. [PMID: 37444544 PMCID: PMC10340246 DOI: 10.3390/cancers15133434] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 06/27/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
Liver cancer is a complex and challenging disease with limited treatment options and dismal prognosis. Understanding the underlying molecular mechanisms driving liver cancer progression and metastasis is crucial for developing effective therapeutic strategies. The EPH/ephrin system, which comprises a family of cell surface receptors and their corresponding ligands, has been implicated in the pathogenesis of HCC. This review paper aims to provide an overview of the current understanding of the role of the EPH/ephrin system in HCC. Specifically, we discuss the dysregulation of EPH/ephrin signaling in HCC and its impact on various cellular processes, including cell proliferation, migration, and invasion. Overall, the EPH/ephrin signaling system emerges as a compelling and multifaceted player in liver cancer biology. Elucidating its precise mechanisms and understanding its implications in disease progression and therapeutic responses may pave the way for novel targeted therapies and personalized treatment approaches for liver cancer patients. Further research is warranted to unravel the full potential of the EPH/ephrin system in liver cancer and its clinical translation.
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Affiliation(s)
- Stavros P. Papadakos
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Ioanna E. Stergiou
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Nikolina Gkolemi
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Konstantinos Arvanitakis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636 Thessaloniki, Greece;
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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12
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Zhao J, Li J, Xu A, Xu Y, He F, Mao Y. IRAK4 inhibition: an effective strategy for immunomodulating peri-implant osseointegration via reciprocally-shifted polarization in the monocyte-macrophage lineage cells. BMC Oral Health 2023; 23:265. [PMID: 37158847 PMCID: PMC10169473 DOI: 10.1186/s12903-023-03011-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 05/03/2023] [Indexed: 05/10/2023] Open
Abstract
BACKGROUND The biomaterial integration depends on its interaction with the host immune system. Monocyte-macrophage lineage cells are immediately recruited to the implant site, polarized into different phenotypes, and fused into multinucleated cells, thus playing roles in tissue regeneration. IL-1R-associated kinase 4 (IRAK4) inhibition was reported to antagonize inflammatory osteolysis and regulate osteoclasts and foreign body giant cells (FBGCs), which may be a potential target in implant osseointegration. METHODS In in-vitro experiments, we established simulated physiological and inflammatory circumstances in which bone-marrow-derived macrophages were cultured on sand-blasted and acid-etched (SLA) titanium surfaces to evaluate the induced macrophage polarization, multinucleated cells formation, and biological behaviors in the presence or absence of IRAK4i. Then, bone marrow stromal stem cells (BMSCs) were cultured in the conditioned media collected from the aforementioned induced osteoclasts or FBGCs cultures to clarify the indirect coupling effect of multinucleated cells on BMSCs. We further established a rat implantation model, which integrates IRAK4i treatment with implant placement, to verify the positive effect of IRAK4 inhibition on the macrophage polarization, osteoclast differentiation, and ultimately the early peri-implant osseointegration in vivo. RESULTS Under inflammatory conditions, by transforming the monocyte-macrophage lineage cells from M1 to M2, IRAK4i treatment could down-regulate the formation and activity of osteoclast and relieve the inhibition of FBGC generation, thus promoting osteogenic differentiation in BMSCs and improve the osseointegration. CONCLUSION This study may improve our understanding of the function of multinucleated cells and offer IRAK4i as a therapeutic strategy to improve early implant osseointegration and help to eliminate the initial implant failure.
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Affiliation(s)
- Juan Zhao
- Department of ProsthodonticsSchool of StomatologyZhejiang Provincial Clinical Research Center for Oral Diseases, Stomatology HospitalZhejiang University School of MedicineKey Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, 31000, China
- Department of Prosthodontics, The Affiliated Stomatology Hospital, Zhejiang University School of Medicine, 166 QiuTao Rd(N), Hangzhou, 310000, China
| | - Jia Li
- Department of ProsthodonticsSchool of StomatologyZhejiang Provincial Clinical Research Center for Oral Diseases, Stomatology HospitalZhejiang University School of MedicineKey Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, 31000, China
- Department of Prosthodontics, The Affiliated Stomatology Hospital, Zhejiang University School of Medicine, 166 QiuTao Rd(N), Hangzhou, 310000, China
| | - Antian Xu
- Department of ProsthodonticsSchool of StomatologyZhejiang Provincial Clinical Research Center for Oral Diseases, Stomatology HospitalZhejiang University School of MedicineKey Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, 31000, China
- Department of Prosthodontics, The Affiliated Stomatology Hospital, Zhejiang University School of Medicine, 166 QiuTao Rd(N), Hangzhou, 310000, China
| | - Yangbo Xu
- Department of ProsthodonticsSchool of StomatologyZhejiang Provincial Clinical Research Center for Oral Diseases, Stomatology HospitalZhejiang University School of MedicineKey Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, 31000, China
- Department of Prosthodontics, The Affiliated Stomatology Hospital, Zhejiang University School of Medicine, 166 QiuTao Rd(N), Hangzhou, 310000, China
| | - Fuming He
- Department of ProsthodonticsSchool of StomatologyZhejiang Provincial Clinical Research Center for Oral Diseases, Stomatology HospitalZhejiang University School of MedicineKey Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, 31000, China.
- Department of Prosthodontics, The Affiliated Stomatology Hospital, Zhejiang University School of Medicine, 166 QiuTao Rd(N), Hangzhou, 310000, China.
| | - Yingjie Mao
- Department of ProsthodonticsSchool of StomatologyZhejiang Provincial Clinical Research Center for Oral Diseases, Stomatology HospitalZhejiang University School of MedicineKey Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, 31000, China.
- Department of Prosthodontics, The Affiliated Stomatology Hospital, Zhejiang University School of Medicine, 166 QiuTao Rd(N), Hangzhou, 310000, China.
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13
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Keever AL, Collins KM, Clark RA, Framstad AL, Ashley JW. RANK signaling in osteoclast precursors results in a more permissive epigenetic landscape and sexually divergent patterns of gene expression. PeerJ 2023; 11:e14814. [PMID: 36788807 PMCID: PMC9922499 DOI: 10.7717/peerj.14814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 01/06/2023] [Indexed: 02/11/2023] Open
Abstract
Background Sex is an important risk factor in the development of osteoporosis and other bone loss disorders, with women often demonstrating greater susceptibility than men. While variation in sex steroids, such as estradiol, accounts for much of the risk, there are likely additional non-endocrine factors at transcriptional and epigenetic levels that result in a higher rate of bone loss in women. Identification of these factors could improve risk assessment and therapies to preserve and improve bone health. Methods Osteoclast precursors were isolated male and female C57Bl/6 mice and cultured with either MCSF alone or MCSF and RANKL. Following the culture period RNA was isolated for RNA sequencing and DNA was isolated for tagmentation and ATAC sequencing. RNA-Seq and ATAC-seq were evaluated via pathway analysis to identify sex- and RANKL-differential transcription and chromatin accessibility. Results Osteoclasts demonstrated significant alterations in gene expression compared to macrophages with both shared and differential pathways between the sexes. Transcriptional pathways differentially regulated between male and female cells were associated with immunological functions with evidence of greater sensitivity in male macrophages and female osteoclasts. ATAC-Seq revealed a large increase in chromatin accessibility following RANKL treatment with few alterations attributable to sex. Comparison of RNA-Seq and ATAC-seq data revealed few common pathways suggesting that many of the transcriptional changes of osteoclastogenesis occur independently of chromatin remodeling.
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Affiliation(s)
- Abigail L. Keever
- Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States,Department of Biology, Eastern Washington University, Cheney, WA, United States
| | - Kathryn M. Collins
- Department of Biology, Eastern Washington University, Cheney, WA, United States
| | - Rachel A. Clark
- Department of Biology, Eastern Washington University, Cheney, WA, United States
| | - Amber L. Framstad
- Department of Biology, Eastern Washington University, Cheney, WA, United States
| | - Jason W. Ashley
- Department of Biology, Eastern Washington University, Cheney, WA, United States
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14
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Molecular Features of the Mesenchymal and Osteoblastic Cells in Multiple Myeloma. Int J Mol Sci 2022; 23:ijms232415448. [PMID: 36555090 PMCID: PMC9779562 DOI: 10.3390/ijms232415448] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/02/2022] [Accepted: 12/04/2022] [Indexed: 12/12/2022] Open
Abstract
Multiple myeloma (MM) is a monoclonal gammopathy characterized by biological heterogeneity and unregulated proliferation of plasma cells (PCs) in bone marrow (BM). MM is a multistep process based on genomic instability, epigenetic dysregulation and a tight cross-talk with the BM microenvironment that plays a pivotal role supporting the proliferation, survival, drug-resistance and homing of PCs. The BM microenvironment consists of a hematopoietic and a non-hematopoietic compartment, which cooperate to create a tumor environment. Among the non-hematopoietic component, mesenchymal stromal cells (MSCs) and osteoblasts (OBs) appear transcriptionally and functionally different in MM patients compared to healthy donors (HDs) and to patients with pre-malignant monoclonal gammopathies. Alterations of both MSCs and OBs underly the osteolytic lesions that characterize myeloma-associated bone disease. In this review, we will discuss the different characteristics of MSCs and OBs in MM patients, analyzing the transcriptome, the deregulated molecular pathways and the role performed by miRNAs and exosome in the pathophysiology of MM.
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15
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Xu H, Tao L, Cao J, Zhang P, Zeng H, Zhao H. Yi Shen Juan Bi Pill alleviates bone destruction in inflammatory arthritis under postmenopausal conditions by regulating ephrinB2 signaling. Front Pharmacol 2022; 13:1010640. [PMID: 36249763 PMCID: PMC9561306 DOI: 10.3389/fphar.2022.1010640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/16/2022] [Indexed: 11/13/2022] Open
Abstract
Yi Shen Juan Bi Pill (YSJB) is a traditional Chinese medicine (TCM) formulation that has a therapeutic effect upon rheumatoid arthritis (RA), but how YSJB affects bone destruction in arthritis under postmenopausal conditions is not known. We evaluated the therapeutic role of YSJB in bone destruction in postmenopausal arthritis, We used collagen-induced arthritis (CIA) rats who had been ovariectomized (OVX) as models and explored the possible mechanism from the synovium and bone marrow (BM). Arthritis was generated after ovariectomy or sham surgery for 12 weeks. After 14 days of primary immunization, rats were administered YSJB or estradiol valerate (EV) for 28 days. YSJB could prevent bone destruction in the inflamed joints of rats in the OVX + CIA group. CIA promoted osteoclast differentiation significantly in the synovial membrane according to tartrate resistant acid phosphatase (TRACP) staining, and OVX tended to aggravate the inflammatory reaction of CIA rats according to hematoxylin-and-eosin staining. Immunohistochemistry revealed that the synovium did not have significant changes in erythropoietin-producing hepatocellular interactor (ephrin)B2 or erythropoietin-producing hepatocellular (eph) B4 expression after YSJB treatment, but YSJB treatment reduced nuclear factor of activated T cells (NFATc)1 expression. The BM of rats in the OVX + CIA exhibited remarkable increases in the number of osteoclasts and NFATc1 expression, as well as significantly reduced expression of ephrinB2 and ephB4 compared with the CIA group and sham group. YSJB treatment reduced NFATc1 expression significantly but also increased ephrinB2 expression in the BM markedly. These data suggest that YSJB exhibit a bone-protective effect, it may be a promising therapeutic strategy for alleviating bone destruction in arthritis under postmenopausal conditions, and one of the mechanisms is associated with the modulation of ephrinB2 signaling.
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Affiliation(s)
- Huihui Xu
- Department of Bone & Joint Surgery and National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, China
- Center for Translational Medicine Research and Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Beijing Key Laboratory of Research of Chinese Medicine on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Science, Beijing, China
| | - Li Tao
- Beijing Key Laboratory of Research of Chinese Medicine on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Science, Beijing, China
| | - Jinfeng Cao
- Beijing Key Laboratory of Research of Chinese Medicine on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Science, Beijing, China
| | - Peng Zhang
- Center for Translational Medicine Research and Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- *Correspondence: Peng Zhang, ; Hui Zeng, ; Hongyan Zhao,
| | - Hui Zeng
- Department of Bone & Joint Surgery and National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, China
- *Correspondence: Peng Zhang, ; Hui Zeng, ; Hongyan Zhao,
| | - Hongyan Zhao
- Beijing Key Laboratory of Research of Chinese Medicine on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Science, Beijing, China
- *Correspondence: Peng Zhang, ; Hui Zeng, ; Hongyan Zhao,
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16
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Bolamperti S, Villa I, Rubinacci A. Bone remodeling: an operational process ensuring survival and bone mechanical competence. Bone Res 2022; 10:48. [PMID: 35851054 PMCID: PMC9293977 DOI: 10.1038/s41413-022-00219-8] [Citation(s) in RCA: 162] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 05/02/2022] [Accepted: 05/15/2022] [Indexed: 12/12/2022] Open
Abstract
Bone remodeling replaces old and damaged bone with new bone through a sequence of cellular events occurring on the same surface without any change in bone shape. It was initially thought that the basic multicellular unit (BMU) responsible for bone remodeling consists of osteoclasts and osteoblasts functioning through a hierarchical sequence of events organized into distinct stages. However, recent discoveries have indicated that all bone cells participate in BMU formation by interacting both simultaneously and at different differentiation stages with their progenitors, other cells, and bone matrix constituents. Therefore, bone remodeling is currently considered a physiological outcome of continuous cellular operational processes optimized to confer a survival advantage. Bone remodeling defines the primary activities that BMUs need to perform to renew successfully bone structural units. Hence, this review summarizes the current understanding of bone remodeling and future research directions with the aim of providing a clinically relevant biological background with which to identify targets for therapeutic strategies in osteoporosis.
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Affiliation(s)
- Simona Bolamperti
- Osteoporosis and Bone and Mineral Metabolism Unit, IRCCS San Raffaele Hospital, Via Olgettina 60, 20132, Milano, Italy
| | - Isabella Villa
- Osteoporosis and Bone and Mineral Metabolism Unit, IRCCS San Raffaele Hospital, Via Olgettina 60, 20132, Milano, Italy
| | - Alessandro Rubinacci
- Osteoporosis and Bone and Mineral Metabolism Unit, IRCCS San Raffaele Hospital, Via Olgettina 60, 20132, Milano, Italy.
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17
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Hill EW, Stoffel MA, McGivney BA, MacHugh DE, Pemberton JM. Inbreeding depression and the probability of racing in the Thoroughbred horse. Proc Biol Sci 2022; 289:20220487. [PMID: 35765835 PMCID: PMC9240673 DOI: 10.1098/rspb.2022.0487] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Small effective population sizes and active inbreeding can lead to inbreeding depression due to deleterious recessive mutations exposed in the homozygous state. The Thoroughbred racehorse has low levels of population genetic diversity, but the effects of genomic inbreeding in the population are unknown. Here, we quantified inbreeding based on runs of homozygosity (ROH) using 297 K SNP genotypes from 6128 horses born in Europe and Australia, of which 13.2% were unraced. We show that a 10% increase in inbreeding (FROH) is associated with a 7% lower probability of ever racing. Moreover, a ROH-based genome-wide association study identified a haplotype on ECA14 which, in its homozygous state, is linked to a 32.1% lower predicted probability of ever racing, independent of FROH. The haplotype overlaps a candidate gene, EFNA5, that is highly expressed in cartilage tissue, which when damaged is one of the most common causes of catastrophic musculoskeletal injury in racehorses. Genomics-informed breeding aiming to reduce inbreeding depression and avoid damaging haplotype carrier matings will improve population health and racehorse welfare.
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Affiliation(s)
- Emmeline W. Hill
- Plusvital Ltd, The Highline, Dún Laoghaire Industrial Estate, Pottery Road, Dún Laoghaire, Co. Dublin, Ireland,UCD School of Agriculture and Food Science, University College Dublin, Belfield, Dublin D04 V1W8, Ireland
| | - Martin A. Stoffel
- Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK
| | - Beatrice A. McGivney
- Plusvital Ltd, The Highline, Dún Laoghaire Industrial Estate, Pottery Road, Dún Laoghaire, Co. Dublin, Ireland
| | - David E. MacHugh
- UCD School of Agriculture and Food Science, University College Dublin, Belfield, Dublin D04 V1W8, Ireland,UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin D04 V1W8, Ireland
| | - Josephine M. Pemberton
- Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK
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18
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Ahmadzadeh K, Vanoppen M, Rose CD, Matthys P, Wouters CH. Multinucleated Giant Cells: Current Insights in Phenotype, Biological Activities, and Mechanism of Formation. Front Cell Dev Biol 2022; 10:873226. [PMID: 35478968 PMCID: PMC9035892 DOI: 10.3389/fcell.2022.873226] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 03/17/2022] [Indexed: 12/21/2022] Open
Abstract
Monocytes and macrophages are innate immune cells with diverse functions ranging from phagocytosis of microorganisms to forming a bridge with the adaptive immune system. A lesser-known attribute of macrophages is their ability to fuse with each other to form multinucleated giant cells. Based on their morphology and functional characteristics, there are in general three types of multinucleated giant cells including osteoclasts, foreign body giant cells and Langhans giant cells. Osteoclasts are bone resorbing cells and under physiological conditions they participate in bone remodeling. However, under pathological conditions such as rheumatoid arthritis and osteoporosis, osteoclasts are responsible for bone destruction and bone loss. Foreign body giant cells and Langhans giant cells appear only under pathological conditions. While foreign body giant cells are found in immune reactions against foreign material, including implants, Langhans giant cells are associated with granulomas in infectious and non-infectious diseases. The functionality and fusion mechanism of osteoclasts are being elucidated, however, our knowledge on the functions of foreign body giant cells and Langhans giant cells is limited. In this review, we describe and compare the phenotypic aspects, biological and functional activities of the three types of multinucleated giant cells. Furthermore, we provide an overview of the multinucleation process and highlight key molecules in the different phases of macrophage fusion.
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Affiliation(s)
- Kourosh Ahmadzadeh
- Laboratory of Immunobiology, Department Microbiology and Immunology, Rega Institute, KU Leuven – University of Leuven, Leuven, Belgium
- *Correspondence: Kourosh Ahmadzadeh, ; Carine Helena Wouters,
| | - Margot Vanoppen
- Laboratory of Immunobiology, Department Microbiology and Immunology, Rega Institute, KU Leuven – University of Leuven, Leuven, Belgium
| | - Carlos D. Rose
- Division of Pediatric Rheumatology Nemours Children’s Hospital, Thomas Jefferson University, Philadelphia, PA, United States
| | - Patrick Matthys
- Laboratory of Immunobiology, Department Microbiology and Immunology, Rega Institute, KU Leuven – University of Leuven, Leuven, Belgium
| | - Carine Helena Wouters
- Laboratory of Immunobiology, Department Microbiology and Immunology, Rega Institute, KU Leuven – University of Leuven, Leuven, Belgium
- Division Pediatric Rheumatology, UZ Leuven, Leuven, Belgium
- European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) at University Hospital Leuven, Leuven, Belgium
- *Correspondence: Kourosh Ahmadzadeh, ; Carine Helena Wouters,
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19
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Hrkac S, Novak R, Salai G, Grazio S, Vlahovic T, Grgurevic L. Heterotopic ossification vs. fracture healing: Extracellular vesicle cargo proteins shed new light on bone formation. Bone Rep 2022; 16:101177. [PMID: 35252484 PMCID: PMC8892095 DOI: 10.1016/j.bonr.2022.101177] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/19/2022] [Accepted: 02/22/2022] [Indexed: 02/08/2023] Open
Abstract
Fibrodysplasia ossificans progressiva (FOP) is an extremely rare disease in which bone tissue forms in extraskeletal sites, which is known as heterotopic ossification (HO). Extracellular vesicles (EVs) are small phospholipid-enclosed particles released by various cells which have an emerging, but not completely understood role in various (patho)physiological processes. In order to further study the pathophysiology of FOP we conducted a small observational study comparing the proteomic profiles of EV cargo, derived from pooled plasma of four patient groups: FOP patient (N = 1) during active disease phase (flare-up), FOP patients during remission (N = 2), patients after long bone fracture (N = 20) and healthy controls (N = 10). After isolation of EVs – their protein cargo was determined using liquid chromatography / mass spectrometry, after which a functional gene enrichment analysis was performed. Our results show a sizeable difference of the proteomics profiles in which EVs from the bone fracture group show significant activity of integrin interactions, Wnt, VEGF, IGF-1 and PDGF pathways; conversely, FOP patients' EVs indicate that HO occurs via processes of innate immunity and the Ephrin B signaling pathway. We hypothesize that the Ephrin B signaling (expressed in EVs) contributes to HO by aiding in mesenchymal stem cell recruitment and osteogenic differentiation, as well as by contributing to the inflammatory response, including macrophage chemotaxis and activation. This is, to our knowledge, the first published analysis of EV protein cargo in FOP.
Proteomics-based analysis of extracellular vesicles’ protein cargo in FOP patients, bone fracture healing and controls. Marked differences in signaling pathways expressed in extracellular vesicles in FOP vs. patients with bone fractures. Ephrin B signaling pathway expressed in extracellular vesicles identified as a likely cogwheel in heterotopic ossification.
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20
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Pan D, Yang F, Zhu S, Li Y, Ning G, Feng S. Inhibition of TGF-β repairs spinal cord injury by attenuating EphrinB2 expressing through inducing miR-484 from fibroblast. Cell Death Discov 2021; 7:319. [PMID: 34711831 PMCID: PMC8553751 DOI: 10.1038/s41420-021-00705-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 09/27/2021] [Accepted: 10/07/2021] [Indexed: 12/27/2022] Open
Abstract
Spinal cord injury (SCI) can lead to severe loss of motor and sensory function with high disability and mortality. The effective treatment of SCI remains unknown. Here we find systemic injection of TGF-β neutralizing antibody induces the protection of axon growth, survival of neurons, and functional recovery, whereas erythropoietin-producing hepatoma interactor B2 (EphrinB2) expression and fibroblasts distribution are attenuated. Knockout of TGF-β type II receptor in fibroblasts can also decrease EphrinB2 expression and improve spinal cord injury recovery. Moreover, miR-488 was confirmed to be the most upregulated gene related to EphrinB2 releasing in fibroblasts after SCI and miR-488 initiates EphrinB2 expression and physical barrier building through MAPK signaling after SCI. Our study points toward elevated levels of active TGF-β as inducer and promoters of fibroblasts distribution, fibrotic scar formation, and EphrinB2 expression, and deletion of global TGF-β or the receptor of TGF-β in Col1α2 lineage fibroblasts significantly improve functional recovery after SCI, which suggest that TGF-β might be a therapeutic target in SCI.
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Affiliation(s)
- Dayu Pan
- Department of Orthopedics, Tianjin Medical University General Hospital, Heping District, Tianjin, 300052, PR China.,International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Fuhan Yang
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China
| | - Shibo Zhu
- Department of Orthopedics, Tianjin Medical University General Hospital, Heping District, Tianjin, 300052, PR China.,International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Yongjin Li
- Department of Orthopedics, Tianjin Medical University General Hospital, Heping District, Tianjin, 300052, PR China.,International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Guangzhi Ning
- Department of Orthopedics, Tianjin Medical University General Hospital, Heping District, Tianjin, 300052, PR China. .,International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China.
| | - Shiqing Feng
- Department of Orthopedics, Tianjin Medical University General Hospital, Heping District, Tianjin, 300052, PR China. .,International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China.
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21
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Crous A, Abrahamse H. The Signalling Effects of Photobiomodulation on Osteoblast Proliferation, Maturation and Differentiation: A Review. Stem Cell Rev Rep 2021; 17:1570-1589. [PMID: 33686595 DOI: 10.1007/s12015-021-10142-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/21/2021] [Indexed: 02/06/2023]
Abstract
Proliferation of osteoblasts is essential for maturation and mineralization of bone matrix. Ossification, the natural phase of bone-forming and hardening is a carefully regulated phase where deregulation of this process may result in insufficient or excessive bone mineralization or ectopic calcification. Osteoblasts can also be differentiated into osteocytes, populating short interconnecting passages within the bone matrix. Over the past few decades, we have seen a significant improvement in awareness and techniques using photobiomodulation (PBM) to stimulate cell function. One of the applications of PBM is the promotion of osteoblast proliferation and maturation. PBM research results on osteoblasts showed increased mitochondrial ATP production, increased osteoblast activity and proliferation, increased and pro-osteoblast expression in the presence of red and NIR radiation. Osteocyte differentiation was also accomplished using blue and green light, showing that different light parameters have various signalling effects. The current review addresses osteoblast function and control, a new understanding of PBM on osteoblasts and its therapeutic impact using various parameters to optimize osteoblast function that may be clinically important. Graphical Abstract.
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Affiliation(s)
- Anine Crous
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, PO Box 17011, Johannesburg, 2028, South Africa.
| | - Heidi Abrahamse
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, PO Box 17011, Johannesburg, 2028, South Africa
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22
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Liang B, Wang H, Wu D, Wang Z. Macrophage M1/M2 polarization dynamically adapts to changes in microenvironment and modulates alveolar bone remodeling after dental implantation. J Leukoc Biol 2021; 110:433-447. [PMID: 34254348 DOI: 10.1002/jlb.1ma0121-001r] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 04/01/2021] [Accepted: 04/18/2021] [Indexed: 12/27/2022] Open
Abstract
As one of the first arriving immune cells after dental implantation, Mϕs own the abilities to polarize into to a spectrum of diverse phenotypes, from "classically activated" M1 Mϕs to "alternatively activated" M2 Mϕs. Herein, it was hypothesized that Mϕ phenotypes dynamically adapt after dental implantation, and the changes ensue a cascade of coordinated interplay with the bone-forming osteoblast and the bone-resorbing osteoclast. Results showed that the remodelling process after dental implantation was similar with the standard response to tissue injury (exampled by tooth extraction models), only with the delay of bone regeneration phases. Additionally, Mϕ activation in both groups underwent a transition from M1 Mϕs dominated to M2-type dominated stage, but the persistence of M1 Mϕs occurred in rat model of dental implantation. Further research in vitro showed that M1 Mϕs are involved in osteoclast activities via secreting the highest levels of TNF-α and IL-1β, as well as being the potential precursor of osteoclasts. Besides, they also recruited BMSCs by secreting the highest levels of chemoattractants, CCL2 and VEGF. M2 Mϕs accelerated osteogenesis in the subsequent stage via their capability to secrete osteogenesis-related proteins, BMP-2 and TGF-β1. However, the osteogenic differentiation of BMSCs was inhibited when cultured in a high concentration of conditioned media from each Mϕ phenotype, meaning that the immune strategies should be controlled within the proper ranges. These results suggest that coordinated efforts by both M1 and M2 Mϕs for bone remodelling, which may highlight an optimization strategy for tissue engineering implants.
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Affiliation(s)
- Beilei Liang
- Department of Implantology, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, P. R. China
| | - Haicheng Wang
- Department of Pathology, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, P. R. China
| | - Di Wu
- Department of Implantology, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, P. R. China
| | - Zuolin Wang
- Department of Implantology, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, P. R. China
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The expression of Netrin-1 in the MIA-induced osteoarthritic temporomandibular joint in mice. Sci Rep 2021; 11:15695. [PMID: 34344989 PMCID: PMC8333414 DOI: 10.1038/s41598-021-95251-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 07/14/2021] [Indexed: 11/09/2022] Open
Abstract
Subchondral bone degeneration is the main pathological change during temporomandibular joint (TMJ) osteoarthritis (OA) development. Netrin-1, an axon-guiding factor, might play roles in OA development and pain. The purpose of this study was to investigate the expression of Netrin-1 in TMJ OA and its possible role in the progression of TMJ OA and pain. The synovial fluids of temporomandibular joint disorders (TMDs) patients were collected for Netrin-1 by enzyme linked immunosorbent assay (ELISA). TMJ OA model was built by MIA joint injection, and then the von Frey test, hematoxylin & eosin (H&E) staining, toluidine blue (TB) staining, immunohistochemical (IHC) staining and micro-CT were performed. After induction of osteoclast differentiation of raw264.7 cells, immunofluorescence (IF) was used to detect the Netrin-1 and its receptors on osteoclast membrane. The concentration of Netrin-1 increased in the synovial fluid of TMJ OA patients. After MIA injection to TMJ, the head withdrawal threshold (HWT) was significantly decreased. Microscopically, the structural disorder of subchondral bone was the most obvious at the 2nd week after MIA injection. In addition, Netrin-1 expression increased in the subchondral bone at the 2nd week after MIA injection. In vitro, the expressions of Netrin-1 and its receptor Unc5B were upregulated on the osteoclast membrane. Netrin-1 might be an important regulator during bone degeneration and pain in the process of TMJ OA.
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Kawatsu M, Takeshita N, Takimoto A, Yoshimoto Y, Seiryu M, Ito A, Kimura S, Kawamoto T, Hiraki Y, Shukunami C, Takano-Yamamoto T. Scleraxis upregulated by transforming growth factor-β1 signaling inhibits tension-induced osteoblast differentiation of priodontal ligament cells via ephrin A2. Bone 2021; 149:115969. [PMID: 33892176 DOI: 10.1016/j.bone.2021.115969] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 04/06/2021] [Accepted: 04/18/2021] [Indexed: 11/25/2022]
Abstract
During tooth movement in orthodontic treatment, bone formation and resorption occur on the tension and compression sides of the alveolar bone, respectively. Although the bone formation activity increases in the periodontal ligament (PDL) on the tension side, the PDL itself is not ossified and maintains its homeostasis, indicating that there are negative regulators of bone formation in the PDL. Our previous report suggested that scleraxis (Scx) has an inhibitory effect on ossification of the PDL on the tension side through the suppression of calcified extracellular matrix formation. However, the molecular biological mechanisms of Scx-modulated inhibition of ossification in the tensioned PDL are not fully understood. The aim of the present study is to clarify the inhibitory role of Scx in osteoblast differentiation of PDL cells and its underlying mechanism. Our in vivo experiment using a mouse experimental tooth movement model showed that Scx expression was increased during early response of the PDL to tensile force. Scx knockdown upregulated expression of alkaline phosphatase, an early osteoblast differentiation marker, in the tensile force-loaded PDL cells in vitro. Transforming growth factor (TGF)-β1-Smad3 signaling in the PDL was activated by tensile force and inhibitors of TGF-β receptor and Smad3 suppressed the tensile force-induced Scx expression in PDL cells. Tensile force induced ephrin A2 (Efna2) expression in the PDL and Efna2 knockdown upregulated alkaline phosphatase expression in PDL cells under tensile force loading. Scx knockdown eliminated the tensile force-induced Efna2 expression in PDL cells. These findings suggest that the TGF-β1-Scx-Efna2 axis is a novel molecular mechanism that negatively regulates the tensile force-induced osteoblast differentiation of PDL cells.
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Affiliation(s)
- Masayoshi Kawatsu
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi 980-0875, Japan; Laboratory of Cellular Differentiation, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
| | - Nobuo Takeshita
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi 980-0875, Japan
| | - Aki Takimoto
- Laboratory of Cellular Differentiation, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
| | - Yuki Yoshimoto
- Laboratory of Cellular Differentiation, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan; Department of Molecular Biology and Biochemistry, Biomedical Sciences Major, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
| | - Masahiro Seiryu
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi 980-0875, Japan
| | - Arata Ito
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi 980-0875, Japan
| | - Seiji Kimura
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi 980-0875, Japan
| | - Tadafumi Kawamoto
- Radioisotope Research Institute, Tsurumi University School of Dental Medicine, Tsurumi, Yokohama, 230-8501, Japan
| | - Yuji Hiraki
- Laboratory of Cellular Differentiation, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
| | - Chisa Shukunami
- Laboratory of Cellular Differentiation, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan; Department of Molecular Biology and Biochemistry, Biomedical Sciences Major, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
| | - Teruko Takano-Yamamoto
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi 980-0875, Japan; Department of Biomaterials and Bioengineering, Faculty of Dental Medicine, Hokkaido University, Sapporo, Hokkaido 060-8586, Japan.
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Shafiei M, Ansari MNM, Razak SIA, Khan MUA. A Comprehensive Review on the Applications of Exosomes and Liposomes in Regenerative Medicine and Tissue Engineering. Polymers (Basel) 2021; 13:2529. [PMID: 34372132 PMCID: PMC8347192 DOI: 10.3390/polym13152529] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022] Open
Abstract
Tissue engineering and regenerative medicine are generally concerned with reconstructing cells, tissues, or organs to restore typical biological characteristics. Liposomes are round vesicles with a hydrophilic center and bilayers of amphiphiles which are the most influential family of nanomedicine. Liposomes have extensive research, engineering, and medicine uses, particularly in a drug delivery system, genes, and vaccines for treatments. Exosomes are extracellular vesicles (EVs) that carry various biomolecular cargos such as miRNA, mRNA, DNA, and proteins. As exosomal cargo changes with adjustments in parent cells and position, research of exosomal cargo constituents provides a rare chance for sicknesses prognosis and care. Exosomes have a more substantial degree of bioactivity and immunogenicity than liposomes as they are distinctly chiefly formed by cells, which improves their steadiness in the bloodstream, and enhances their absorption potential and medicinal effectiveness in vitro and in vivo. In this review, the crucial challenges of exosome and liposome science and their functions in disease improvement and therapeutic applications in tissue engineering and regenerative medicine strategies are prominently highlighted.
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Affiliation(s)
- Mojtaba Shafiei
- Bioinspired Device and Tissue Engineering Research Group, School of Biomedical Engineering and Health Sciences, Faculty of Engineering, Universiti Teknologi Malaysia, Skudai 81300, Johor, Malaysia; (M.S.); (M.U.A.K.)
| | | | - Saiful Izwan Abd Razak
- Bioinspired Device and Tissue Engineering Research Group, School of Biomedical Engineering and Health Sciences, Faculty of Engineering, Universiti Teknologi Malaysia, Skudai 81300, Johor, Malaysia; (M.S.); (M.U.A.K.)
| | - Muhammad Umar Aslam Khan
- Bioinspired Device and Tissue Engineering Research Group, School of Biomedical Engineering and Health Sciences, Faculty of Engineering, Universiti Teknologi Malaysia, Skudai 81300, Johor, Malaysia; (M.S.); (M.U.A.K.)
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Cellular Effects of Rhynchophylline and Relevance to Sleep Regulation. Clocks Sleep 2021; 3:312-341. [PMID: 34207633 PMCID: PMC8293156 DOI: 10.3390/clockssleep3020020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/25/2021] [Accepted: 06/03/2021] [Indexed: 01/06/2023] Open
Abstract
Uncaria rhynchophylla is a plant highly used in the traditional Chinese and Japanese medicines. It has numerous health benefits, which are often attributed to its alkaloid components. Recent studies in humans show that drugs containing Uncaria ameliorate sleep quality and increase sleep time, both in physiological and pathological conditions. Rhynchophylline (Rhy) is one of the principal alkaloids in Uncaria species. Although treatment with Rhy alone has not been tested in humans, observations in rodents show that Rhy increases sleep time. However, the mechanisms by which Rhy could modulate sleep have not been comprehensively described. In this review, we are highlighting cellular pathways that are shown to be targeted by Rhy and which are also known for their implications in the regulation of wakefulness and sleep. We conclude that Rhy can impact sleep through mechanisms involving ion channels, N-methyl-d-aspartate (NMDA) receptors, tyrosine kinase receptors, extracellular signal-regulated kinases (ERK)/mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K)/RAC serine/threonine-protein kinase (AKT), and nuclear factor-kappa B (NF-κB) pathways. In modulating multiple cellular responses, Rhy impacts neuronal communication in a way that could have substantial effects on sleep phenotypes. Thus, understanding the mechanisms of action of Rhy will have implications for sleep pharmacology.
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Povoroznyuk VV, Dedukh NV, Bystrytska MA, Shapovalov VS. Bone remodeling stages under physiological conditions and glucocorticoid in excess: Focus on cellular and molecular mechanisms. REGULATORY MECHANISMS IN BIOSYSTEMS 2021. [DOI: 10.15421/022130] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
This review provides a rationale for the cellular and molecular mechanisms of bone remodeling stages under physiological conditions and glucocorticoids (GCs) in excess. Remodeling is a synchronous process involving bone resorption and formation, proceeding through stages of: (1) resting bone, (2) activation, (3) bone resorption, (4) reversal, (5) formation, (6) termination. Bone remodeling is strictly controlled by local and systemic regulatory signaling molecules. This review presents current data on the interaction of osteoclasts, osteoblasts and osteocytes in bone remodeling and defines the role of osteoprogenitor cells located above the resorption area in the form of canopies and populating resorption cavities. The signaling pathways of proliferation, differentiation, viability, and cell death during remodeling are presented. The study of signaling pathways is critical to understanding bone remodeling under normal and pathological conditions. The main signaling pathways that control bone resorption and formation are RANK / RANKL / OPG; M-CSF – c-FMS; canonical and non-canonical signaling pathways Wnt; Notch; MARK; TGFβ / SMAD; ephrinB1/ephrinB2 – EphB4, TNFα – TNFβ, and Bim – Bax/Bak. Cytokines, growth factors, prostaglandins, parathyroid hormone, vitamin D, calcitonin, and estrogens also act as regulators of bone remodeling. The role of non-encoding microRNAs and long RNAs in the process of bone cell differentiation has been established. MicroRNAs affect many target genes, have both a repressive effect on bone formation and activate osteoblast differentiation in different ways. Excess of glucocorticoids negatively affects all stages of bone remodeling, disrupts molecular signaling, induces apoptosis of osteocytes and osteoblasts in different ways, and increases the life cycle of osteoclasts. Glucocorticoids disrupt the reversal stage, which is critical for the subsequent stages of remodeling. Negative effects of GCs on signaling molecules of the canonical Wingless (WNT)/β-catenin pathway and other signaling pathways impair osteoblastogenesis. Under the influence of excess glucocorticoids biosynthesis of biologically active growth factors is reduced, which leads to a decrease in the expression by osteoblasts of molecules that form the osteoid. Glucocorticoids stimulate the expression of mineralization inhibitor proteins, osteoid mineralization is delayed, which is accompanied by increased local matrix demineralization. Although many signaling pathways involved in bone resorption and formation have been discovered and described, the temporal and spatial mechanisms of their sequential turn-on and turn-off in cell proliferation and differentiation require additional research.
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Patil KC, Soekmadji C. Extracellular Vesicle-Mediated Bone Remodeling and Bone Metastasis: Implications in Prostate Cancer. Subcell Biochem 2021; 97:297-361. [PMID: 33779922 DOI: 10.1007/978-3-030-67171-6_12] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Bone metastasis is the tendency of certain primary tumors to spawn and dictate secondary neoplasia in the bone. The process of bone metastasis is regulated by the dynamic crosstalk between metastatic cancer cells, cellular components of the bone marrow microenvironment (osteoblasts, osteoclasts, and osteocytes), and the bone matrix. The feed-forward loop mechanisms governs the co-option of homeostatic bone remodeling by cancer cells in bone. Recent developments have highlighted the discovery of extracellular vesicles (EVs) and their diverse roles in distant outgrowths. Several studies have implicated EV-mediated interactions between cancer cells and the bone microenvironment in synergistically promoting pathological skeletal metabolism in the metastatic site. Nevertheless, the potential role that EVs serve in arbitrating intricate sequences of coordinated events within the bone microenvironment remains an emerging field. In this chapter, we review the role of cellular participants and molecular mechanisms in regulating normal bone physiology and explore the progress of current research into bone-derived EVs in directly triggering and coordinating the processes of physiological bone remodeling. In view of the emerging role of EVs in interorgan crosstalk, this review also highlights the multiple systemic pathophysiological processes orchestrated by the EVs to direct organotropism in bone in prostate cancer. Given the deleterious consequences of bone metastasis and its clinical importance, in-depth knowledge of the multifarious role of EVs in distant organ metastasis is expected to open new possibilities for prognostic evaluation and therapeutic intervention for advanced bone metastatic prostate cancer.
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Affiliation(s)
- Kalyani C Patil
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Carolina Soekmadji
- Department of Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. .,School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
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Li M, Tang Z, Zhang C, Jin L, Matsuo K, Yang Y. Lipopolysaccharides affect compressed periodontal ligament cells via Eph-ephrin signaling. Oral Dis 2021; 28:1662-1673. [PMID: 33872438 PMCID: PMC9544889 DOI: 10.1111/odi.13875] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 03/25/2021] [Accepted: 04/01/2021] [Indexed: 11/27/2022]
Abstract
OBJECTIVES The aim of this study is to investigate the underlying mechanism of the recovery of periodontal ligament cells (PDLCs) sequentially exposed to inflammation and mechanical loading. MATERIALS AND METHODS We divided PDLCs into four groups: control; compressive force (CF) alone (2.0 g/cm2 ); lipopolysaccharides (LPS) pretreatment (0.1 μg/ml) followed by simultaneous LPS and CF stimulation, simulating uncontrolled periodontitis; and LPS pretreatment followed by CF exposure, simulating controlled periodontitis. The expression of EphB4-ephrinB2 and EphA2-ephrinA2, and the level of osteoclastogenesis and osteogenesis were evaluated. RESULTS Simultaneous stimulation by LPS and CF, compared with CF alone and sequential LPS and CF exposure, significantly suppressed EphB4 and enhanced ephrinA2 expression. Similarly, the most intense osteoclastic differentiation was observed under simultaneous LPS and CF stimulation, while sequential exposure to LPS and CF only slightly increased osteoclastic cell numbers. Both the activation of EphB4 signaling and ephrinA2 silencing lowered osteoclastic differentiation, which had previously been upregulated by simultaneous LPS and CF stimulation. These treatments also increased osteogenic differentiation. CONCLUSIONS Simultaneous LPS and CF stimulation critically enhances osteoclastogenesis in PDLCs through the suppression of EphB4 and the induction of ephrinA2 signaling. Sequential LPS and CF exposure partially abolishes the osteolytic effects of simultaneous stimulation.
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Affiliation(s)
- Minjie Li
- Faculty of Dentistry, University of Hong Kong, Hong Kong, China.,Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Zhongyuan Tang
- Faculty of Dentistry, University of Hong Kong, Hong Kong, China
| | - Chengfei Zhang
- Faculty of Dentistry, University of Hong Kong, Hong Kong, China
| | - Lijian Jin
- Faculty of Dentistry, University of Hong Kong, Hong Kong, China
| | | | - Yanqi Yang
- Faculty of Dentistry, University of Hong Kong, Hong Kong, China
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Vaught DB, Merkel AR, Lynch CC, Edwards J, Tantawy MN, Hilliard T, Wang S, Peterson T, Johnson RW, Sterling JA, Brantley‐Sieders D. EphA2 Is a Clinically Relevant Target for Breast Cancer Bone Metastatic Disease. JBMR Plus 2021; 5:e10465. [PMID: 33869989 PMCID: PMC8046157 DOI: 10.1002/jbm4.10465] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/22/2020] [Accepted: 01/12/2021] [Indexed: 11/23/2022] Open
Abstract
EphA2 receptor tyrosine kinase (RTK) is highly expressed in breast tumor cells across multiple molecular subtypes and correlates with poor patient prognosis. In this study, the potential role of EphA2 in this clinically relevant phenomenon is investigated as metastasis of breast cancer to bone is a major cause of morbidity and mortality in patients. It was found that the EphA2 function in breast cancer cells promotes osteoclast activation and the development of osteolytic bone disease. Blocking EphA2 function molecularly and pharmacologically in breast tumors reduced the number and size of bone lesions and the degree of osteolytic disease in intratibial and intracardiac mouse models, which correlated with a significant decrease in the number of osteoclasts at the tumor-bone interface. EphA2 loss of function in tumor cells impaired osteoclast progenitor differentiation in coculture, which is mediated, at least in part, by reduced expression of IL-6. EPHA2 transcript levels are enriched in human breast cancer bone metastatic lesions relative to visceral metastatic sites; EphA2 protein expression was detected in breast tumor cells in bone metastases in patient samples, supporting the clinical relevance of the study's findings. These data provide a strong rationale for the development and application of molecularly targeted therapies against EphA2 for the treatment of breast cancer bone metastatic disease. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- David B Vaught
- Department of Cancer BiologyVanderbilt University School of MedicineNashvilleTNUSA
| | - Alyssa R Merkel
- Vanderbilt Center for Bone BiologyVanderbilt University School of MedicineNashvilleTNUSA
| | - Conor C Lynch
- Department of Tumor BiologyH. Lee Moffitt Cancer CenterTampaFLUSA
| | | | - Mohammed Noor Tantawy
- Radiology and Vanderbilt Institute of Imaging SciencesVanderbilt University School of MedicineNashvilleTNUSA
| | - Timothy Hilliard
- Radiology and Vanderbilt Institute of Imaging SciencesVanderbilt University School of MedicineNashvilleTNUSA
| | - Shan Wang
- Department of Medicine, Division of Rheumatology and ImmunologyVanderbilt University School of MedicineNashvilleTNUSA
| | - Todd Peterson
- Radiology and Vanderbilt Institute of Imaging SciencesVanderbilt University School of MedicineNashvilleTNUSA
| | - Rachelle W Johnson
- Vanderbilt Center for Bone BiologyVanderbilt University School of MedicineNashvilleTNUSA
- Vanderbilt‐Ingram Cancer CenterVanderbilt University School of MedicineNashvilleTNUSA
- Department of Tumor BiologyH. Lee Moffitt Cancer CenterTampaFLUSA
- Division of Clinical PharmacologyVanderbilt University School of MedicineNashvilleTNUSA
| | - Julie A Sterling
- Vanderbilt Center for Bone BiologyVanderbilt University School of MedicineNashvilleTNUSA
- Department of Veterans Affairs, Tennessee Valley Healthcare System (VISN 9)Vanderbilt UniversityNashvilleTNUSA
| | - Dana Brantley‐Sieders
- Vanderbilt‐Ingram Cancer CenterVanderbilt University School of MedicineNashvilleTNUSA
- Department of Tumor BiologyH. Lee Moffitt Cancer CenterTampaFLUSA
- Radiology and Vanderbilt Institute of Imaging SciencesVanderbilt University School of MedicineNashvilleTNUSA
- Department of Medicine, Division of Rheumatology and ImmunologyVanderbilt University School of MedicineNashvilleTNUSA
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The Osteocyte: From "Prisoner" to "Orchestrator". J Funct Morphol Kinesiol 2021; 6:jfmk6010028. [PMID: 33802907 PMCID: PMC8006231 DOI: 10.3390/jfmk6010028] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/04/2021] [Accepted: 03/11/2021] [Indexed: 02/07/2023] Open
Abstract
Osteocytes are the most abundant bone cells, entrapped inside the mineralized bone matrix. They derive from osteoblasts through a complex series of morpho-functional modifications; such modifications not only concern the cell shape (from prismatic to dendritic) and location (along the vascular bone surfaces or enclosed inside the lacuno-canalicular cavities, respectively) but also their role in bone processes (secretion/mineralization of preosseous matrix and/or regulation of bone remodeling). Osteocytes are connected with each other by means of different types of junctions, among which the gap junctions enable osteocytes inside the matrix to act in a neuronal-like manner, as a functional syncytium together with the cells placed on the vascular bone surfaces (osteoblasts or bone lining cells), the stromal cells and the endothelial cells, i.e., the bone basic cellular system (BBCS). Within the BBCS, osteocytes can communicate in two ways: by means of volume transmission and wiring transmission, depending on the type of signals (metabolic or mechanical, respectively) received and/or to be forwarded. The capability of osteocytes in maintaining skeletal and mineral homeostasis is due to the fact that it acts as a mechano-sensor, able to transduce mechanical strains into biological signals and to trigger/modulate the bone remodeling, also because of the relevant role of sclerostin secreted by osteocytes, thus regulating different bone cell signaling pathways. The authors want to emphasize that the present review is centered on the morphological aspects of the osteocytes that clearly explain their functional implications and their role as bone orchestrators.
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Rowe DW, Hong SH, Zhang C, Shin DG, Adams DJ, Youngstrom DW, Chen L, Wu Z, Zhou Y, Maye P. Skeletal screening IMPC/KOMP using μCT and computer automated cryohistology: Application to the Efna4 KO mouse line. Bone 2021; 144:115688. [PMID: 33065355 DOI: 10.1016/j.bone.2020.115688] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 10/09/2020] [Indexed: 01/01/2023]
Abstract
The IMPC/KOMP program provides the opportunity to screen mice harboring well defined gene-inactivation mutations in a uniform genetic background. The program performs a global tissue phenotyping survey that includes skeletal x-rays and bone density measurements. Because of the relative insensitivity of the two screening tests for detecting variance in bone architecture, we initiated a secondary screen based on μCT and a cryohistolomorphological workflow that was performed on the femur and vertebral compartments on 220 randomly selected knockouts (KOs) and 36 control bone samples over a 2 1/2 year collection period provided by one of the production/phenotyping centers. The performance of the screening protocol was designed to balance throughput and cost versus sensitivity and informativeness such that the output would be of value to the skeletal biology community. Here we report the reliability of this screening protocol to establish criteria for control skeletal variance at the architectural, dynamic and cellular histomorphometric level. Unexpected properties of the control population include unusually high variance in BV/TV in male femurs and greater bone formation and bone turnover rates in the female femur and vertebral trabeculae bone compartments. However, the manner for maintaining bone formation differed between these two bone sites. The vertebral compartment relies on maintaining a greater number of bone forming surfaces while the femoral compartment utilized more matrix production per cell. The comparison of the architectural properties obtained by μCT and histomorphology revealed significant differences in values for BV/TV, Tb.Th and Tb.N which is attributable to sampling density of the two methods. However, as a screening tool, expressing the ratio of KO to the control line as obtained by either method was remarkably similar. It identified KOs with significant variance which led to a more detailed histological analysis. Our findings are exemplified by the Efna4 KO, in which a high BV/TV was identified by μCT and confirmed by histomorphometry in the femur but not in the vertebral compartment. Dynamic labeling showed a marked increase in BFR which was attributable to increased labeling surfaces. Cellular analysis confirmed partitioning of osteoblast to labeling surfaces and a marked decrease in osteoclastic activity on both labeling and quiescent surfaces. This pattern of increased bone modeling would not be expected based on prior studies of the Ephrin-Ephrin receptor signaling pathways between osteoblasts and osteoclasts. Overall, our findings underscore why unbiased screening is needed because it can reveal unknown or unanticipated genes that impact skeletal variation.
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Affiliation(s)
- David W Rowe
- Regenerative Medicine and Skeletal Development, Department of Reconstructive Sciences, Biomaterials and Skeletal Development, School of Dental Medicine, University of Connecticut Health, Farmington, CT 06030, United States of America.
| | - Seung-Hyun Hong
- Computer Science & Engineering, School of Engineering, University of Connecticut, Storrs, CT 06269, United States of America
| | - Caibin Zhang
- Regenerative Medicine and Skeletal Development, Department of Reconstructive Sciences, Biomaterials and Skeletal Development, School of Dental Medicine, University of Connecticut Health, Farmington, CT 06030, United States of America
| | - Dong-Guk Shin
- Computer Science & Engineering, School of Engineering, University of Connecticut, Storrs, CT 06269, United States of America
| | - Douglas J Adams
- Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States of America
| | - Daniel W Youngstrom
- Department of Orthopaedic Surgery, School of Medicine, University of Connecticut Health, Farmington, CT 06030, United States of America
| | - Li Chen
- Regenerative Medicine and Skeletal Development, Department of Reconstructive Sciences, Biomaterials and Skeletal Development, School of Dental Medicine, University of Connecticut Health, Farmington, CT 06030, United States of America
| | - Zhihua Wu
- Regenerative Medicine and Skeletal Development, Department of Reconstructive Sciences, Biomaterials and Skeletal Development, School of Dental Medicine, University of Connecticut Health, Farmington, CT 06030, United States of America
| | - Yueying Zhou
- Regenerative Medicine and Skeletal Development, Department of Reconstructive Sciences, Biomaterials and Skeletal Development, School of Dental Medicine, University of Connecticut Health, Farmington, CT 06030, United States of America
| | - Peter Maye
- Regenerative Medicine and Skeletal Development, Department of Reconstructive Sciences, Biomaterials and Skeletal Development, School of Dental Medicine, University of Connecticut Health, Farmington, CT 06030, United States of America
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Arthur A, Gronthos S. Eph-Ephrin Signaling Mediates Cross-Talk Within the Bone Microenvironment. Front Cell Dev Biol 2021; 9:598612. [PMID: 33634116 PMCID: PMC7902060 DOI: 10.3389/fcell.2021.598612] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 01/15/2021] [Indexed: 12/18/2022] Open
Abstract
Skeletal integrity is maintained through the tightly regulated bone remodeling process that occurs continuously throughout postnatal life to replace old bone and to repair skeletal damage. This is maintained primarily through complex interactions between bone resorbing osteoclasts and bone forming osteoblasts. Other elements within the bone microenvironment, including stromal, osteogenic, hematopoietic, endothelial and neural cells, also contribute to maintaining skeletal integrity. Disruption of the dynamic interactions between these diverse cellular systems can lead to poor bone health and an increased susceptibility to skeletal diseases including osteopenia, osteoporosis, osteoarthritis, osteomalacia, and major fractures. Recent reports have implicated a direct role for the Eph tyrosine kinase receptors and their ephrin ligands during bone development, homeostasis and skeletal repair. These membrane-bound molecules mediate contact-dependent signaling through both the Eph receptors, termed forward signaling, and through the ephrin ligands, referred to as reverse signaling. This review will focus on Eph/ ephrin cross-talk as mediators of hematopoietic and stromal cell communication, and how these interactions contribute to blood/ bone marrow function and skeletal integrity during normal steady state or pathological conditions.
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Affiliation(s)
- Agnieszka Arthur
- Mesenchymal Stem Cell Laboratory, Faculty of Health and Medical Sciences, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.,Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Stan Gronthos
- Mesenchymal Stem Cell Laboratory, Faculty of Health and Medical Sciences, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.,Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
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Qu F, Song Y, Wu Y, Huang Y, Zhong Q, Zhang Y, Fan Z, Xu C. The protective role of Ephrin-B2/EphB4 signaling in osteogenic differentiation under inflammatory environment. Exp Cell Res 2021; 400:112505. [PMID: 33516666 DOI: 10.1016/j.yexcr.2021.112505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 01/21/2021] [Accepted: 01/24/2021] [Indexed: 12/01/2022]
Abstract
Inflammation and alveolar bone destruction constitute the main pathological process of periodontitis. However, the molecular mechanisms of bone destruction under the inflammation environment remain unclear. This study aims to explore the role of Ephrin-B2/EphB4 signaling in osteogenic differentiation under the inflammation environment. Mouse pre-osteoblasts MC3T3-E1 were pretreated with lipopolysaccharide of Porphyromonas gingivalis (Pg-LPS). The Ephrin-B2/EphB4 signaling was activated, and the osteogenic differentiation of cells was examined. The results showed that activation of Ephrin-B2/EphB4 signaling promoted the expression levels of osteogenic differentiation-related genes, and also relieved the inhibitory effect of Pg-LPS on osteogenesis. Noticeably, the effect of Ephrin-B2/EphB4 signaling might be related to the mitogen-activated protein kinase (MAPK) pathway. While applying Ephrin-B2-Fc and EphB4-Fc to periodontitis mice, we observed the reduction of alveolar crest destruction. The current study revealed the possible role of Ephrin-B2/EphB4 signaling in reducing bone destruction in periodontitis and suggested its potential values for further research.
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Affiliation(s)
- Fang Qu
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, No.639 Zhizaoju Road, Shanghai, 200011, China; National Clinical Research Center for Oral Diseases, No.639 Zhizaoju Road, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, No.639 Zhizaoju Road, Shanghai, 200011, China
| | - Yingshuang Song
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, No.639 Zhizaoju Road, Shanghai, 200011, China; National Clinical Research Center for Oral Diseases, No.639 Zhizaoju Road, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, No.639 Zhizaoju Road, Shanghai, 200011, China
| | - Yaqin Wu
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, No.639 Zhizaoju Road, Shanghai, 200011, China; National Clinical Research Center for Oral Diseases, No.639 Zhizaoju Road, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, No.639 Zhizaoju Road, Shanghai, 200011, China
| | - Yujie Huang
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, No.639 Zhizaoju Road, Shanghai, 200011, China; National Clinical Research Center for Oral Diseases, No.639 Zhizaoju Road, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, No.639 Zhizaoju Road, Shanghai, 200011, China
| | - Qi Zhong
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, No.639 Zhizaoju Road, Shanghai, 200011, China; National Clinical Research Center for Oral Diseases, No.639 Zhizaoju Road, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, No.639 Zhizaoju Road, Shanghai, 200011, China
| | - Yifan Zhang
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, No.639 Zhizaoju Road, Shanghai, 200011, China; National Clinical Research Center for Oral Diseases, No.639 Zhizaoju Road, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, No.639 Zhizaoju Road, Shanghai, 200011, China
| | - Zhen Fan
- Department of Oral Implantology, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, No. 399 Yanchang Middle Road, Shanghai, 200072, China.
| | - Chun Xu
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, No.639 Zhizaoju Road, Shanghai, 200011, China; National Clinical Research Center for Oral Diseases, No.639 Zhizaoju Road, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, No.639 Zhizaoju Road, Shanghai, 200011, China.
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Li T, Wang H, Liu R, Wang X, Huang L, Wu Z, Yin X, Zou S, Duan P. The role of EphB4/ephrinB2 signaling in root repair after orthodontically-induced root resorption. Am J Orthod Dentofacial Orthop 2021; 159:e217-e232. [PMID: 33487501 DOI: 10.1016/j.ajodo.2020.07.035] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 07/01/2020] [Accepted: 07/01/2020] [Indexed: 12/28/2022]
Abstract
INTRODUCTION This study aimed to investigate the effect of EphB4/ephrinB2 signaling on orthodontically-induced root resorption repair and the possible molecular mechanism behind it. METHODS Seventy-two 6-week-old male Wistar rats were randomly divided into 3 groups: blank control group, physiological regeneration group (PHY), and EphB4 inhibitor local injection group (INH). A root repair model was built on experimental rats of the PHY and INH groups. The animals in the INH groups received a daily periodontal local injection of EphB4 inhibitor NVP-BHG712, whereas the blank control group and PHY groups received only the vehicle. RESULTS Histologic staining and microcomputed tomography analysis showed that root regeneration was inhibited in the INH group compared with the PHY group with a greater number of osteoclasts. Immunohistochemical staining showed active EphB4/ephrinB2 signaling activities during root regeneration. The cementogenesis-related factors cementum attachment protein, alkaline phosphatase, osteopontin, and runt-related transcription factor 2, and osteoclastic-related factors RANKL and osteoprotegerin were affected by regulated EphB4/ephrinB2 signaling. CONCLUSIONS These findings demonstrated that the EphB4/ephrinB2 signaling might be a promising therapeutic target for novel therapeutic approaches to reduce orthodontically-induced root resorption through enhancement of cementogenesis.
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Affiliation(s)
- Tiancheng Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China School and Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Han Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China School and Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ruojing Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China School and Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xin Wang
- Oral Diagnosis and Treatment Center, Aviation General Hospital, China Medical University, Beijing, China
| | - Li Huang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China School and Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zuping Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China School and Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xing Yin
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China School and Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Shujuan Zou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China School and Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Peipei Duan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China School and Hospital of Stomatology, Sichuan University, Chengdu, China.
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36
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Dixit M, Poudel SB, Yakar S. Effects of GH/IGF axis on bone and cartilage. Mol Cell Endocrinol 2021; 519:111052. [PMID: 33068640 PMCID: PMC7736189 DOI: 10.1016/j.mce.2020.111052] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 09/29/2020] [Accepted: 10/01/2020] [Indexed: 12/11/2022]
Abstract
Growth hormone (GH) and its mediator, the insulin-like growth factor-1 (IGF-1) regulate somatic growth, metabolism and many aspects of aging. As such, actions of GH/IGF have been studied in many tissues and organs over decades. GH and IGF-1 are part of the hypothalamic/pituitary somatotrophic axis that consists of many other regulatory hormones, receptors, binding proteins, and proteases. In humans, GH/IGF actions peak during pubertal growth and regulate skeletal acquisition through stimulation of extracellular matrix production and increases in bone mineral density. During aging the activity of these hormones declines, a state called somatopaguss, which associates with deleterious effects on the musculoskeletal system. In this review, we will focus on GH/IGF-1 action in bone and cartilage. We will cover many studies that have utilized congenital ablation or overexpression of members of this axis, as well as cell-specific gene-targeting approaches used to unravel the nature of the GH/IGF-1 actions in the skeleton in vivo.
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Affiliation(s)
- Manisha Dixit
- David B. Kriser Dental Center, Department of Molecular Pathobiology, New York University College of Dentistry, NY, 10010, USA
| | - Sher Bahadur Poudel
- David B. Kriser Dental Center, Department of Molecular Pathobiology, New York University College of Dentistry, NY, 10010, USA
| | - Shoshana Yakar
- David B. Kriser Dental Center, Department of Molecular Pathobiology, New York University College of Dentistry, NY, 10010, USA.
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Wang Y, Ling L, Tian F, Won Kim SH, Ho S, Bikle DD. Ablation of Ephrin B2 in Col2 Expressing Cells Delays Fracture Repair. Endocrinology 2020; 161:5912608. [PMID: 32987403 PMCID: PMC7609132 DOI: 10.1210/endocr/bqaa179] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 09/23/2020] [Indexed: 01/15/2023]
Abstract
Ephrin B2 is critical for endochondral bone development. In this study, we investigated its role in fracture repair by deleting ephrin B2 in type II collagen (Col.2) expressing cells. We used a nonstable tibia fracture model to evaluate fracture repair at 3 sites: intramembranous bone formation, endochondral bone formation, and intramedullary bone formation. We observed that during fracture repair, deletion of ephrin B2 impaired periosteal stem cell activation, inhibited their proliferation, decreased their survival, and blocked their differentiation into osteoblasts and chondrocytes. In addition, deletion of ephrin B2 decreased vascular endothelial growth factor production as well as vascular invasion into the fracture site. These changes led to reduced cartilage to bone conversion in the callus with decreased new bone formation, resulting in impaired fracture repair. Our data indicate that ephrin B2 in Col2-expressing cells is a critical regulator of fracture repair, pointing to a new and potentially targetable mechanism to enhance fracture repair.
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Affiliation(s)
- Yongmei Wang
- Endocrine Unit, University of California, San Francisco and Veterans Affairs Health Care System, San Francisco, California, USA
- Correspondence: Yongmei Wang, MD, PhD, Endocrine Unit (111N), VAMC, 1700 Owens Street, San Francisco, CA 94158. E-mail:
| | - Lin Ling
- Endocrine Unit, University of California, San Francisco and Veterans Affairs Health Care System, San Francisco, California, USA
| | - Faming Tian
- Endocrine Unit, University of California, San Francisco and Veterans Affairs Health Care System, San Francisco, California, USA
| | - Sun Hee Won Kim
- Endocrine Unit, University of California, San Francisco and Veterans Affairs Health Care System, San Francisco, California, USA
| | - Sunita Ho
- Bioengineering & Biomaterials Micro-CT and Imaging Facility, University of California, San Francisco, San Francisco, California, USA
| | - Daniel D Bikle
- Endocrine Unit, University of California, San Francisco and Veterans Affairs Health Care System, San Francisco, California, USA
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Broggini T, Piffko A, Hoffmann CJ, Ghori A, Harms C, Adams RH, Vajkoczy P, Czabanka M. Ephrin-B2-EphB4 communication mediates tumor-endothelial cell interactions during hematogenous spread to spinal bone in a melanoma metastasis model. Oncogene 2020; 39:7063-7075. [PMID: 32989254 DOI: 10.1038/s41388-020-01473-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 08/21/2020] [Accepted: 09/15/2020] [Indexed: 11/09/2022]
Abstract
Metastases account for the majority of cancer deaths. Bone represents one of the most common sites of distant metastases, and spinal bone metastasis is the most common source of neurological morbidity in cancer patients. During metastatic seeding of cancer cells, endothelial-tumor cell interactions govern extravasation to the bone and potentially represent one of the first points of action for antimetastatic treatment. The ephrin-B2-EphB4 pathway controls cellular interactions by inducing repulsive or adhesive properties, depending on forward or reverse signaling. Here, we report that in an in vivo metastatic melanoma model, ephrin-B2-mediated activation of EphB4 induces tumor cell repulsion from bone endothelium, translating in reduced spinal bone metastatic loci and improved neurological function. Selective ephrin-B2 depletion in endothelial cells or EphB4 inhibition increases bone metastasis and shortens the time window to hind-limb locomotion deficit from spinal cord compression. EphB4 overexpression in melanoma cells ameliorates the metastatic phenotype and improves neurological outcome. Timely harvesting of bone tissue after tumor cell injection and intravital bone microscopy revealed less tumor cells attached to ephrin-B2-positive endothelial cells. These results suggest that ephrin-B2-EphB4 communication influences bone metastasis formation by altering melanoma cell repulsion/adhesion to bone endothelial cells, and represents a molecular target for therapeutic intervention.
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Affiliation(s)
- Thomas Broggini
- Department of Neurosurgery, Universitätsmedizin Charite, D-10117, Berlin, Germany.,Department of Physics, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Andras Piffko
- Department of Neurosurgery, Universitätsmedizin Charite, D-10117, Berlin, Germany.,Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - Christian J Hoffmann
- Department of Experimental Neurology, Center for Stroke Research Berlin, Universitätsmedizin Charite, D-10117, Berlin, Germany
| | - Adnan Ghori
- Department of Neurosurgery, Universitätsmedizin Charite, D-10117, Berlin, Germany
| | - Christoph Harms
- Department of Experimental Neurology, Center for Stroke Research Berlin, Universitätsmedizin Charite, D-10117, Berlin, Germany
| | - Ralf H Adams
- Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Münster, Faculty of Medicine, D-48149, Münster, Germany
| | - Peter Vajkoczy
- Department of Neurosurgery, Universitätsmedizin Charite, D-10117, Berlin, Germany
| | - Marcus Czabanka
- Department of Neurosurgery, Universitätsmedizin Charite, D-10117, Berlin, Germany.
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The Recombinant Protein EphB4-Fc Changes the Ti Particle-Mediated Imbalance of OPG/RANKL via EphrinB2/EphB4 Signaling Pathway and Inhibits the Release of Proinflammatory Factors In Vivo. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:1404915. [PMID: 32587656 PMCID: PMC7294355 DOI: 10.1155/2020/1404915] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 02/12/2020] [Accepted: 02/26/2020] [Indexed: 12/18/2022]
Abstract
Aseptic loosening caused by wear particles is one of the common complications after total hip arthroplasty. We investigated the effect of the recombinant protein ephB4-Fc (erythropoietin-producing human hepatocellular receptor 4) on wear particle-mediated inflammatory response. In vitro, ephrinB2 expression was analyzed using siRNA-NFATc1 (nuclear factor of activated T-cells 1) and siRNA-c-Fos. Additionally, we used Tartrate-resistant acid phosphatase (TRAP) staining, bone pit resorption, Enzyme-linked immunosorbent assay (ELISA), as well as ephrinB2 overexpression and knockdown experiments to verify the effect of ephB4-Fc on osteoclast differentiation and function. In vivo, a mouse skull model was constructed to test whether the ephB4-Fc inhibits osteolysis and inhibits inflammation by micro-CT, H&E staining, immunohistochemistry, and immunofluorescence. The gene expression of ephrinB2 was regulated by c-Fos/NFATc1. Titanium wear particles activated this signaling pathway to the promoted expression of the ephrinB2 gene. However, ephrinB2 protein can be activated by osteoblast membrane receptor ephB4 to inhibit osteoclast differentiation. In in vivo experiments, we found that ephB4 could regulate Ti particle-mediated imbalance of OPG/RANKL, and the most important finding was that ephB4 relieved the release of proinflammatory factors. The ephB4-Fc inhibits wear particle-mediated osteolysis and inflammatory response through the ephrinB2/EphB4 bidirectional signaling pathway, and ephrinB2 ligand is expected to become a new clinical drug therapeutic target.
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Zhang Y, Luo G, Yu X. Cellular Communication in Bone Homeostasis and the Related Anti-osteoporotic Drug Development. Curr Med Chem 2020; 27:1151-1169. [PMID: 30068268 DOI: 10.2174/0929867325666180801145614] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 06/28/2018] [Accepted: 07/19/2018] [Indexed: 02/08/2023]
Abstract
Background：Intercellular crosstalk among osteoblast, osteoclast, osteocyte and chondrocyte is involved in the precise control of bone homeostasis. Disruption of this cellular and molecular signaling would lead to metabolic bone diseases such as osteoporosis. Currently a number of anti-osteoporosis interventions are restricted by side effects, complications and long-term intolerance. This review aims to summarize the bone cellular communication involved in bone remodeling and its usage to develop new drugs for osteoporosis. Methods：We searched PubMed for publications from 1 January 1980 to 1 January 2018 to identify relevant and latest literatures, evaluation and prospect of osteoporosis medication were summarized. Detailed search terms were 'osteoporosis', 'osteocyte', 'osteoblast', 'osteoclast', 'bone remodeling', 'chondrocyte', 'osteoporosis treatment', 'osteoporosis therapy', 'bisphosphonates', 'denosumab', 'Selective Estrogen Receptor Modulator (SERM)', 'PTH', 'romosozumab', 'dkk-1 antagonist', 'strontium ranelate'. Results：A total of 170 papers were included in the review. About 80 papers described bone cell interactions involved in bone remodeling. The remaining papers were focused on the novel advanced and new horizons in osteoporosis therapies. Conclusion：There exists a complex signal network among bone cells involved in bone remodeling. The disorder of cell-cell communications may be the underlying mechanism of osteoporosis. Current anti-osteoporosis therapies are effective but accompanied by certain drawbacks simultaneously. Restoring the abnormal signal network and individualized therapy are critical for ideal drug development.
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Affiliation(s)
- Yi Zhang
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Guojing Luo
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xijie Yu
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
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Corre I, Verrecchia F, Crenn V, Redini F, Trichet V. The Osteosarcoma Microenvironment: A Complex But Targetable Ecosystem. Cells 2020; 9:cells9040976. [PMID: 32326444 PMCID: PMC7226971 DOI: 10.3390/cells9040976] [Citation(s) in RCA: 293] [Impact Index Per Article: 58.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 04/06/2020] [Accepted: 04/11/2020] [Indexed: 01/08/2023] Open
Abstract
Osteosarcomas are the most frequent primary bone sarcomas, affecting mainly children, adolescents, and young adults, and with a second peak of incidence in elderly individuals. The current therapeutic management, a combined regimen of poly-chemotherapy and surgery, still remains largely insufficient, as patient survival has not improved in recent decades. Osteosarcomas are very heterogeneous tumors, both at the intra- and inter-tumor level, with no identified driver mutation. Consequently, efforts to improve treatments using targeted therapies have faced this lack of specific osteosarcoma targets. Nevertheless, these tumors are inextricably linked to their local microenvironment, composed of bone, stromal, vascular and immune cells and the osteosarcoma microenvironment is now considered to be essential and supportive for growth and dissemination. This review describes the different actors of the osteosarcoma microenvironment and gives an overview of the past, current, and future strategies of therapy targeting this complex ecosystem, with a focus on the role of extracellular vesicles and on the emergence of multi-kinase inhibitors.
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Affiliation(s)
- Isabelle Corre
- INSERM, Nantes University, UMR1238 Phy-Os “Bone Sarcomas and Remodeling of Calcified Tissues”, F-44035 Nantes, France
- CNRS GDR3697 MicroNit, F-37044 Tours, France
- Correspondence: (I.C.); (V.T.)
| | - Franck Verrecchia
- INSERM, Nantes University, UMR1238 Phy-Os “Bone Sarcomas and Remodeling of Calcified Tissues”, F-44035 Nantes, France
| | - Vincent Crenn
- INSERM, Nantes University, UMR1238 Phy-Os “Bone Sarcomas and Remodeling of Calcified Tissues”, F-44035 Nantes, France
- Department of Orthopedic, Nantes Hospital, CHU Hotel-Dieu, F-44035 Nantes, France
| | - Francoise Redini
- INSERM, Nantes University, UMR1238 Phy-Os “Bone Sarcomas and Remodeling of Calcified Tissues”, F-44035 Nantes, France
| | - Valérie Trichet
- INSERM, Nantes University, UMR1238 Phy-Os “Bone Sarcomas and Remodeling of Calcified Tissues”, F-44035 Nantes, France
- CNRS GDR3697 MicroNit, F-37044 Tours, France
- Correspondence: (I.C.); (V.T.)
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Wang Q, Liu Y, Zhao Y, Sun LZ, Wang LX, Han M, Mi FL. [Research progress on the expression and function of erythropoietin-producing hepatomocellular receptors and their receptor-interacting proteins in oral-related diseases]. HUA XI KOU QIANG YI XUE ZA ZHI = HUAXI KOUQIANG YIXUE ZAZHI = WEST CHINA JOURNAL OF STOMATOLOGY 2020; 38:218-223. [PMID: 32314898 DOI: 10.7518/hxkq.2020.02.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Erythropoietin-producing hepatomocellular receptors and their receptor-interacting proteins (Eph/ephrin) can participate in the regulation of growth and development and promote the development of diseases through short-distance signal transduction between cells. To study the mechanism of Eph/ephrin and oral-related diseases, we provided a new theoretical basis and a strategy for the treatment of oral diseases. The Eph/ephrin pathway has been used to regulate oral diseases, especially in periodontal disease prevention, orthodontic bone reconstruction, and biological treatment of oral tumors. This paper reviews the research progress of Eph/ephrin pathway in oral-related diseases.
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Affiliation(s)
- Qi Wang
- Dept. of Stomatology, North Sichuan Medical College, Nanchong 637000, China
| | - Yan Liu
- Dept. of Prosthodontics, the Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China
| | - Yun Zhao
- Dept. of Stomatology, North Sichuan Medical College, Nanchong 637000, China
| | - Li-Zhong Sun
- Dept. of Stomatology, North Sichuan Medical College, Nanchong 637000, China
| | - Lin-Xuan Wang
- Dept. of Stomatology, North Sichuan Medical College, Nanchong 637000, China
| | - Mei Han
- Dept. of Stomatology, North Sichuan Medical College, Nanchong 637000, China
| | - Fang-Lin Mi
- Dept. of Stomatology, North Sichuan Medical College, Nanchong 637000, China
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Miyagawa K, Ohata Y, Delgado-Calle J, Teramachi J, Zhou H, Dempster DD, Subler MA, Windle JJ, Chirgwin JM, Roodman GD, Kurihara N. Osteoclast-derived IGF1 is required for pagetic lesion formation in vivo. JCI Insight 2020; 5:133113. [PMID: 32078587 PMCID: PMC7213785 DOI: 10.1172/jci.insight.133113] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 02/19/2020] [Indexed: 01/12/2023] Open
Abstract
We report that transgenic mice expressing measles virus nucleocapsid protein (MVNP) in osteoclasts (OCLs) (MVNP mice) are Paget's disease (PD) models and that OCLs from patients with PD and MVNP mice express high levels of OCL-derived IGF1 (OCL-IGF1). To determine OCL-IGF1's role in PD and normal bone remodeling, we generated WT and MVNP mice with targeted deletion of Igf1 in OCLs (Igf1-cKO) and MVNP/Igf1-cKO mice, and we assessed OCL-IGF1's effects on bone mass, bone formation rate, EphB2/EphB4 expression on OCLs and osteoblasts (OBs), and pagetic bone lesions (PDLs). A total of 40% of MVNP mice, but no MVNP/Igf1-cKO mice, had PDLs. Bone volume/tissue volume (BV/TV) was decreased by 60% in lumbar vertebrae and femurs of MVNP/Igf1-cKO versus MVNP mice with PDLs and by 45% versus all MVNP mice tested. Bone formation rates were decreased 50% in Igf1-cKO and MVNP/Igf1-cKO mice versus WT and MVNP mice. MVNP mice had increased EphB2 and EphB4 levels in OCLs/OBs versus WT and MVNP/Igf1-cKO, with none detectable in OCLs/OBs of Igf1-cKO mice. Mechanistically, IL-6 induced the increased OCL-IGF1 in MVNP mice. These results suggest that high OCL-IGF1 levels increase bone formation and PDLs in PD by enhancing EphB2/EphB4 expression in vivo and suggest OCL-IGF1 may contribute to normal bone remodeling.
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Affiliation(s)
- Kazuaki Miyagawa
- Division of Hematology and Oncology, Department of Medicine, Indiana University (IU), Indianapolis, Indiana, USA
| | - Yasuhisa Ohata
- Division of Hematology and Oncology, Department of Medicine, Indiana University (IU), Indianapolis, Indiana, USA
| | - Jesus Delgado-Calle
- Division of Hematology and Oncology, Department of Medicine, Indiana University (IU), Indianapolis, Indiana, USA
| | - Jumpei Teramachi
- Division of Hematology and Oncology, Department of Medicine, Indiana University (IU), Indianapolis, Indiana, USA
| | - Hua Zhou
- Regional Bone Center, Helen Hayes Hospital, West Haverstraw, New York, USA
| | - David D Dempster
- Department of Clinical Pathology and Cell Biology, Columbia University, New York, New York, USA
| | - Mark A Subler
- Department of Human and Molecular Genetics, Virginia Commonwealth University (VCU), Richmond, Virginia, USA
| | - Jolene J Windle
- Department of Human and Molecular Genetics, Virginia Commonwealth University (VCU), Richmond, Virginia, USA
| | - John M Chirgwin
- Division of Hematology and Oncology, Department of Medicine, Indiana University (IU), Indianapolis, Indiana, USA
| | - G David Roodman
- Division of Hematology and Oncology, Department of Medicine, Indiana University (IU), Indianapolis, Indiana, USA
- Roudebush VA Medical Center, Indianapolis, Indiana, USA
| | - Noriyoshi Kurihara
- Division of Hematology and Oncology, Department of Medicine, Indiana University (IU), Indianapolis, Indiana, USA
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Gandolfi MG, Gardin C, Zamparini F, Ferroni L, Esposti MD, Parchi G, Ercan B, Manzoli L, Fava F, Fabbri P, Prati C, Zavan B. Mineral-Doped Poly(L-lactide) Acid Scaffolds Enriched with Exosomes Improve Osteogenic Commitment of Human Adipose-Derived Mesenchymal Stem Cells. NANOMATERIALS (BASEL, SWITZERLAND) 2020; 10:E432. [PMID: 32121340 PMCID: PMC7153699 DOI: 10.3390/nano10030432] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/05/2020] [Accepted: 02/22/2020] [Indexed: 12/18/2022]
Abstract
Exosomes derived from mesenchymal stem cells are extracellular vesicles released to facilitate cell communication and function. Recently, polylactic acid (PLA), calcium silicates (CaSi), and dicalcium phosphate dihydrate (DCPD) have been used to produce bioresorbable functional mineral-doped porous scaffolds-through thermally induced phase separation technique, as materials for bone regeneration. The aim of this study was to investigate the effect of mineral-doped PLA-based porous scaffolds enriched with exosome vesicles (EVs) on osteogenic commitment of human adipose mesenchymal stem cells (hAD-MSCs). Two different mineral-doped scaffolds were produced: PLA-10CaSi-10DCPD and PLA-5CaSi-5DCPD. Scaffolds surface micromorphology was investigated by ESEM-EDX before and after 28 days immersion in simulated body fluid (HBSS). Exosomes were deposited on the surface of the scaffolds and the effect of exosome-enriched scaffolds on osteogenic commitment of hAD-MSCs cultured in proximity of the scaffolds has been evaluated by real time PCR. In addition, the biocompatibility was evaluated by direct-contact seeding hAD-MSCs on scaffolds surface-using MTT viability test. In both formulations, ESEM showed pores similar in shape (circular and elliptic) and size (from 10-30 µm diameter). The porosity of the scaffolds decreased after 28 days immersion in simulated body fluid. Mineral-doped scaffolds showed a dynamic surface and created a suitable bone-forming microenvironment. The presence of the mineral fillers increased the osteogenic commitment of hAD-MSCs. Exosomes were easily entrapped on the surface of the scaffolds and their presence improved gene expression of major markers of osteogenesis such as collagen type I, osteopontin, osteonectin, osteocalcin. The experimental scaffolds enriched with exosomes, in particular PLA-10CaSi-10DCPD, increased the osteogenic commitment of MSCs. In conclusion, the enrichment of bioresorbable functional scaffolds with exosomes is confirmed as a potential strategy to improve bone regeneration procedures.
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Affiliation(s)
- Maria Giovanna Gandolfi
- Laboratory of Biomaterials and Oral Pathology, School of Dentistry, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40125 Bologna, Italy
| | - Chiara Gardin
- Medical Sciences Department, University of Ferrara, 44100 Ferrara, Italy
| | - Fausto Zamparini
- Laboratory of Biomaterials and Oral Pathology, School of Dentistry, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40125 Bologna, Italy
| | - Letizia Ferroni
- Medical Sciences Department, University of Ferrara, 44100 Ferrara, Italy
| | - Micaela Degli Esposti
- Department of Civil, Chemical, Environmental and Materials Engineering, University of Bologna, 40136 Bologna, Italy
| | - Greta Parchi
- Laboratory of Biomaterials and Oral Pathology, School of Dentistry, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40125 Bologna, Italy
| | - Batur Ercan
- Department of Metallurgical and Materials Engineering, 06800 Ankara, Turkey
| | - Lucia Manzoli
- Cellular Signaling Laboratory, Institute of Human Anatomy, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy
| | - Fabio Fava
- Department of Civil, Chemical, Environmental and Materials Engineering, University of Bologna, 40136 Bologna, Italy
| | - Paola Fabbri
- Department of Civil, Chemical, Environmental and Materials Engineering, University of Bologna, 40136 Bologna, Italy
| | - Carlo Prati
- Endodontic Clinical Section, School of Dentistry, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40125 Bologna, Italy
| | - Barbara Zavan
- Medical Sciences Department, University of Ferrara, 44100 Ferrara, Italy
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45
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Pang DD, Cai L, Zhang JR, Dai SM. IL-23 induces the expression of pro-osteogenic factors in
osteoclasts. AKTUEL RHEUMATOL 2020. [DOI: 10.1055/a-1099-9028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Abstract
Background The mechanism for the new bone formation in ankylosing
spondylitis (AS) is still unclear. Although it has been demonstrated that
IL-23 plays a pivotal role in the pathophysiology of AS, IL-23 has no direct
effects on osteoblasts but modulates the function of osteoclasts.
Aims To explore whether IL-23 indirectly facilitates new bone
formation through osteoclasts in AS, here we analyzed whether IL-23 enhances
the expression levels of pro-osteogenic factors by osteoclasts.
Methods Mononuclear cells were harvested from mouse bone marrow and
cultured in the presence of M-CSF (50 ng/ml) and RANKL
(30 ng/ml) to trigger the production of osteoclasts. Protein
and mRNA expression levels of Semaphorin 4D, Ephrin B2, BMP2, BMP6, SPHK1,
HtrA1 and Wnt10b were measured using Western blot and qRT-PCR.
Results Primary mononuclear cells were transformed into osteoclasts
with RANKL and M-CSF. The increased expression of NFATc1 and TRAP together
with TRAP staining of>3 nuclei were used to identify mature
osteoclasts. The mRNA expression levels of BMP2, Ephrin B2 and SPHK1 were
enhanced by 1.46, 2.1 and 2.46 folds after exposure to IL-23. Confirmation
of increased levels of Ephrin B2 and SPHK1 in IL-23-stimulated osteoclasts
was provided by Western blot analysis. IL-23 had no effects on the
expression of BMP6 or Wnt10b, or on the anti-osteogenic factors Semaphorin
4D or HtrA1.
Conclusions IL-23 induces osteoclasts to express pro-osteogenic
factors rather than anti-osteogenic factors, suggesting IL-23 might
indirectly promote the differentiation of osteoblasts through activated
osteoclasts in ankylosing spondylitis.
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Affiliation(s)
- Dan-Dan Pang
- Department of Rheumatology & Immunology, Changhai Hospital,
Second Military Medical University, Shanghai, China
- Department of Rheumatology & Immunology, Shanghai Jiao Tong
University Affiliated Sixth People’s Hospital, Shanghai,
China
| | - Li Cai
- Department of Rheumatology & Immunology, Shanghai Jiao Tong
University Affiliated Sixth People’s Hospital, Shanghai,
China
| | - Jing-Ru Zhang
- Department of Rheumatology & Immunology, Changhai Hospital,
Second Military Medical University, Shanghai, China
- Department of Rheumatology & Immunology, First Affiliated
Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Sheng-Ming Dai
- Department of Rheumatology & Immunology, Shanghai Jiao Tong
University Affiliated Sixth People’s Hospital, Shanghai,
China
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46
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Zhu S, Liu Z, Yuan C, Lin Y, Yang Y, Wang H, Zhang C, Wang P, Gu M. Bidirectional ephrinB2‑EphB4 signaling regulates the osteogenic differentiation of canine periodontal ligament stem cells. Int J Mol Med 2020; 45:897-909. [PMID: 31985015 PMCID: PMC7015143 DOI: 10.3892/ijmm.2020.4473] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 12/23/2019] [Indexed: 12/28/2022] Open
Abstract
The aim of the present study was to evaluate the effect of ephrinB2 gene-transfected canine periodontal ligament stem cells (cPDLSCs) on the regulation of osteogenic differentiation. cPDLSCs were transfected with a transgenic null-control green fluorescent protein (GFP) vector (termed Vector-cPDLSCs) or with NFNB2 GFP-Blasticidin (termed EfnB2-cPDLSCs). Subsequently, the osteogenic differentiation of Vector-cPDLSCs and EfnB2-cPDLSCs was assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), alkaline phosphatase (ALP) assay and Alizarin Red S staining. The migratory abilities of cPDLSCs, Vector-cPDLSCs and EfnB2-cPDLSCs were also assessed. Following osteogenic induction of Vector-cPDLSCs and EfnB2-cPDLSCs, the protein expression levels of collagen I, Runt-related transcription factor 2, osteocalcin, ephrin type-B receptor 4 (EphB4), phospho-EphB4, ephrinB2 and phosphoephrinB2 were analyzed by western blot assays. Following gene transfection, the RT-qPCR and western blotting results revealed that the mRNA and protein expression levels of ephrinB2, respectively, were significantly increased in EfnB2-cPDLSCs compared with that in Vector-cPDLSCs (P<0.05). ALP and Alizarin Red S staining assays revealed increased ALP activity and mineralization nodules, respectively, in EfnB2-cPDLSCs. Cell proliferation and migration assays revealed that EfnB2-cPDLSCs exhibited enhanced proliferation and migration compared with Vector-cPDLSCs (P<0.05). In conclusion, the findings of the current study indicated that ephrinB2 gene-modified cPDLSCs exhibited enhanced osteogenic differentiation, with the ephrinB2 reverse signaling and EphB4 forward signaling pathways serving a key role in this process. Furthermore, ephrinB2 gene modification was observed to promote the migration and proliferation of cPDLSCs.
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Affiliation(s)
- Shaoyue Zhu
- Discipline of Orthodontics and Paediatric Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR 999077, P.R. China
| | - Zongxiang Liu
- Discipline of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China
| | - Changyong Yuan
- Discipline of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China
| | - Yifan Lin
- Discipline of Orthodontics and Paediatric Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR 999077, P.R. China
| | - Yanqi Yang
- Discipline of Orthodontics and Paediatric Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR 999077, P.R. China
| | - Haiming Wang
- Discipline of Orthodontics and Paediatric Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR 999077, P.R. China
| | - Chengfei Zhang
- Department of Endodontology, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR 999077, P.R. China
| | - Penglai Wang
- Dental Implant Center, Affiliated Stomatological Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China
| | - Min Gu
- Discipline of Orthodontics and Paediatric Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR 999077, P.R. China
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47
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Zhu GG, Nafa K, Agaram N, Zehir A, Benayed R, Sadowska J, Borsu L, Kelly C, Tap WD, Fabbri N, Athanasian E, Boland PJ, Healey JH, Berger MF, Ladanyi M, Hameed M. Genomic Profiling Identifies Association of IDH1/IDH2 Mutation with Longer Relapse-Free and Metastasis-Free Survival in High-Grade Chondrosarcoma. Clin Cancer Res 2019; 26:419-427. [PMID: 31615936 DOI: 10.1158/1078-0432.ccr-18-4212] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Revised: 05/02/2019] [Accepted: 10/10/2019] [Indexed: 12/12/2022]
Abstract
PURPOSE Chondrosarcomas are the second most common primary malignant bone tumors. Although histologic grade is the most important factor predicting the clinical outcome of chondrosarcoma, it is subject to interobserver variability. Isocitrate dehydrogenase 1 (IDH1) and IDH2 hotspot mutations were recently found to be frequently mutated in central chondrosarcomas. However, a few published articles have been controversial regarding the association between IDH1/IDH2 mutation status and clinical outcomes in chondrosarcomas. EXPERIMENTAL DESIGN We performed hotspot sequencing of IDH1 and IDH2 genes in 89 central chondrosarcomas and targeted next-generation sequencing in 54 of them, and then correlated the IDH1/IDH2 mutation status with the patient's clinical outcome. RESULTS Although no association was discovered between IDH mutation status and the patient's overall survival, IDH1/IDH2 mutation was found to be associated with longer relapse-free and metastasis-free survival in high-grade chondrosarcomas. Genomic profiling reveals TERT gene amplification and ATRX mutation, for the first time, in addition to TERT promoter mutation in a subset (6/30, 20%) of high-grade and dedifferentiated chondrosarcomas. These abnormalities in telomere genes are concurrent with IDH1/IDH2 mutation and with CDKN2A/2B deletion or TP53 mutation, suggesting a possible association and synergy among these genes in chondrosarcoma progression. We found 21% of patients with chondrosarcoma also had histories of second malignancies unrelated to cartilaginous tumors, suggesting possible unknown genetic susceptibility to chondrosarcoma. CONCLUSIONS IDH1/IDH2 mutations are associated with longer relapse-free and metastasis-free survival in high-grade chondrosarcomas, and they tend to co-occur with TERT mutations and with CDKN2A/2B and TP53 alterations in a subset of high-grade chondrosarcomas.
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Affiliation(s)
- Guo Gord Zhu
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Pathology, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, New Jersey
| | - Khedoudja Nafa
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Narasimhan Agaram
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ahmet Zehir
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ryma Benayed
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Justyna Sadowska
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Laetitia Borsu
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ciara Kelly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - William D Tap
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nicola Fabbri
- Orthopaedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Edward Athanasian
- Orthopaedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Patrick J Boland
- Orthopaedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - John H Healey
- Orthopaedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Michael F Berger
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.,Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Marc Ladanyi
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Meera Hameed
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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48
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Alfieri R, Vassalli M, Viti F. Flow-induced mechanotransduction in skeletal cells. Biophys Rev 2019; 11:729-743. [PMID: 31529361 DOI: 10.1007/s12551-019-00596-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 09/03/2019] [Indexed: 12/15/2022] Open
Abstract
Human body is subject to many and variegated mechanical stimuli, actuated in different ranges of force, frequency, and duration. The process through which cells "feel" forces and convert them into biochemical cascades is called mechanotransduction. In this review, the effects of fluid shear stress on bone cells will be presented. After an introduction to present the major players in bone system, we describe the mechanoreceptors in bone tissue that can feel and process fluid flow. In the second part of the review, we present an overview of the biological processes and biochemical cascades initiated by fluid shear stress in bone cells.
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Affiliation(s)
- Roberta Alfieri
- Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza" - National Research Council (IGM-CNR), Via Abbiategrasso, 207, 27100, Pavia, Italy
| | - Massimo Vassalli
- Institute of Biophysics - National Research Council (IBF-CNR), Via De Marini, 6, 16149, Genoa, Italy
| | - Federica Viti
- Institute of Biophysics - National Research Council (IBF-CNR), Via De Marini, 6, 16149, Genoa, Italy.
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49
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The Paradoxical Role of Uric Acid in Osteoporosis. Nutrients 2019; 11:nu11092111. [PMID: 31491937 PMCID: PMC6769742 DOI: 10.3390/nu11092111] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 09/01/2019] [Accepted: 09/03/2019] [Indexed: 12/16/2022] Open
Abstract
Because of its high prevalence worldwide, osteoporosis is considered a serious public health concern. Many known risk factors for developing osteoporosis have been identified and are crucial if planning health care needs. Recently, an association between uric acid (UA) and bone fractures had been explored. Extracellular UA exhibits antioxidant properties by effectively scavenging free radicals in human plasma, but this benefit might be disturbed by the hydrophobic lipid layer of the cell membrane. In contrast, intracellular free oxygen radicals are produced during UA degradation, and superoxide is further enhanced by interacting with NADPH oxidase. This intracellular oxidative stress, together with inflammatory cytokines induced by UA, stimulates osteoclast bone resorption and inhibits osteoblast bone formation. UA also inhibits vitamin D production and thereby results in hyper-parathyroidism, which causes less UA excretion in the intestines and renal proximal tubules by inhibiting the urate transporter ATP-binding cassette subfamily G member 2 (ABCG2). At normal or high levels, UA is associated with a reduction in bone mineral density and protects against bone fracture. However, in hyperuricemia or gout arthritis, UA increases bone fracture risk because oxidative stress and inflammatory cytokines can increase bone resorption and decrease bone formation. Vitamin D deficiency, and consequent secondary hyperparathyroidism, can further increase bone resorption and aggravated bone loss in UA-induced osteoporosis.
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50
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Ruan Z, Zhu Y, Lin Z, Long H, Zhao R, Sun B, Cheng L, Zhao S. Association between rs12742784 polymorphism and hip fracture, bone mineral density, and EPHB2 mRNA expression levels in elderly Chinese women. Climacteric 2019; 23:93-98. [PMID: 31352841 DOI: 10.1080/13697137.2019.1640195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Objective: This study aimed to determine the association between rs12742784 polymorphism in the non-coding area and hip fracture, bone mineral density (BMD), and EPHB2 mRNA expression levels in elderly Chinese women.Methods: We investigated 250 Chinese women (mean age: 63.5 ± 8.3 years) including 123 hip fracture patients and 127 non-fracture controls. All participants underwent clinical examination to meet the inclusion criteria. Lumbar and hip BMD were detected by dual-energy X-ray absorptiometry. rs12742784 polymorphism was determined by restriction fragment length polymorphism and EPHB2 mRNA expression levels were measured by real-time polymerase chain reaction.Results: Distribution of rs12742784 genotypes agreed with Hardy-Weinberg equilibrium. The frequency of the CT + TT genotype was significantly associated with decreased risk of hip fracture (adjusted odds ratio = 0.57, p < 0.01) after adjusting for age and body mass index, and with increased BMD and EPHB2 mRNA expression levels. The T allele of the rs12742784 single nucleotide polymorphism (SNP) was a protective factor for hip fracture (adjusted odds ratio = 0.56, p < 0.01).Conclusion: rs12742784 polymorphism was associated with EPHB2 mRNA expression levels, BMD, and hip fracture in Chinese women. The T allele of the rs12742784 SNP was a protective factor for osteoporosis and hip fracture.
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Affiliation(s)
- Z Ruan
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, P.R. China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, P.R. China
| | - Y Zhu
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, P.R. China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, P.R. China
| | - Z Lin
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, P.R. China
| | - H Long
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, P.R. China
| | - R Zhao
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, P.R. China
| | - B Sun
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, P.R. China
| | - L Cheng
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, P.R. China
| | - S Zhao
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, P.R. China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, P.R. China
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