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Poudyal N, Takemoto JY, Lin YY, Chang CWT. An Alternative to Biliverdin, Mesobiliverdin IXα and Mesobiliverdin-Enriched Microalgae: A Review on the Production and Applications of Mesobiliverdin-Related Products. Molecules 2025; 30:1379. [PMID: 40142154 PMCID: PMC11945237 DOI: 10.3390/molecules30061379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/06/2025] [Accepted: 03/18/2025] [Indexed: 03/28/2025] Open
Abstract
Despite attracting interest for decades due to its anti-inflammatory and antioxidant capabilities, the use of biliverdin IXα (BV) in medicine and agriculture is hampered by uncertain purity and limited availability. A significant amount of effort has been devoted to the production and application of BV, but with limited success. Mesobiliverdin IXα (MBV), a natural BV analog derived from microalgae, offers a path to overcome the limitations of BV. MBV production is scalable, and it can be obtained at high purity. MBV and BV share important structural features (e.g., bridging propionate groups) and both are substrates of biliverdin reductase A (BVRA), and thus exert the same mechanisms and pathways for anti-inflammatory action. To enable the use of MBV in industry, especially in agriculture, a cost-effective product, mesobiliverdin-enriched microalgae (MEM), was developed. In this review, we focus on recent developments and investigations of MBV and MEM, and compare their effectiveness with BV and Spirulina. This review article highlights cost-effective and scalable production of MEM, the therapeutic potential of MBV in cytoprotection and anti-inflammation, and MEM as an animal feed additive for improved gut health and amelioration of osteoporosis. More studies are ongoing to expand the potential applications of both MBV and MEM from fundamental research to industrial and agricultural practices.
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Affiliation(s)
- Naveena Poudyal
- Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT 84322-0300, USA;
| | - Jon Y. Takemoto
- Department of Biology, Utah State University, 5305 Old Main Hill, Logan, UT 84322-5305, USA;
| | - Yuan-Yu Lin
- Department of Animal Science and Technology, National Taiwan University, Taipei City 106, Taiwan;
| | - Cheng-Wei T. Chang
- Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT 84322-0300, USA;
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Li Z, Liu Y, Wang H, Xu G. Transcription factor SMAD5 upregulates ALG5 to alleviate osteoporosis development by inducing osteogenic differentiation. J Orthop 2025; 61:140-149. [PMID: 39588532 PMCID: PMC11585819 DOI: 10.1016/j.jor.2024.10.047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 10/30/2024] [Indexed: 11/27/2024] Open
Abstract
Background Impaired osteogenic differentiation ability of mesenchymal stem cells (MSCs) plays a pathogenic role in osteoporosis (OP). ALG5, a key glucosyltransferase, participates in the synthesis of the glucose-residue donor. However, little is known about the role of ALG5 in OP pathogenesis and osteogenic differentiation. Methods The GSE35956 dataset was used to observe OP-associated factors. ALG5 and SMAD5 mRNA analysis was performed by quantitative PCR. Induction of osteoblastic differentiation of human MSCs (hMSCs) was done using specific media for 14 days. The ovariectomy (OVX)-induced osteoporotic mouse model was established. Calcium deposition was detected by alkaline phosphatase (ALP) activity assay and Alizarin Red staining. Protein expression was evaluated by immunoblot analysis. The relationship of SMAD5 with the ALG5 promoter was predicted by the online tool JASPAR and validated by luciferase assay. Results In bone marrow of OP, ALG5 and SMAD5 levels were decreased. Overexpression of ALG5 acted for in vitro enhancement of osteogenic differentiation and autophagy of hMSCs. Mechanistically, SMAD5 enhanced ALG5 transcription to increase ALG5 expression. Moreover, increased SMAD5 expression promoted in vitro osteogenic differentiation of hMSCs through ALG5. ALG5 and SMAD5 were also underexpressed in bone samples of OVX-osteoporotic mice. Furthermore, increased SMAD5 expression alleviated OP development of OVX mice by inducing osteogenic differentiation by upregulating ALG5. Conclusion Our findings demonstrate that increased SMAD5 expression upregulates ALG5 to enhance osteogenic differentiation of hMSCs and thus alleviates OP development, providing novel potential approaches to combat OP.
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Affiliation(s)
- Zhenhua Li
- Department of Outpatient, Shanghai Changzheng Hospital, Naval Medical University, 200003, Shanghai City, China
| | - Yifei Liu
- Department of Spine Surgery, Shanghai Changzheng Hospital, Naval Medical University, 200003, Shanghai City, China
| | - Haiping Wang
- Department of Outpatient, Shanghai Changzheng Hospital, Naval Medical University, 200003, Shanghai City, China
| | - Guohua Xu
- Department of Spine Surgery, Shanghai Changzheng Hospital, Naval Medical University, 200003, Shanghai City, China
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Fouladgar F, Powell R, Irukuvarjula V, Joy A, Li X, Habibi N. Osteogenic differentiation of mesenchymal stem cells in cell-laden culture of self-assembling peptide hydrogels. OPENNANO 2025; 22:100235. [PMID: 40124089 PMCID: PMC11928154 DOI: 10.1016/j.onano.2025.100235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/25/2025]
Abstract
Mesenchymal stem cell (MSC) osteogenic differentiation requires scaffolds to support multiple stages of growth and differentiation signals. Fluorenyl-9-methoxycarbonyl diphenylalanine (Fmoc-FF) peptides self-assemble to create 3D nanofibers. Here, we cultured MSC in 2D and 3D Fmoc-FF layers to support their osteogenic differentiation. The stiffness of the hydrogels was tunable between 100 and 10,000 Pa which allows precise modulation of the cellular microenvironment. Scaffold stiffness impacted cell viability which softer scaffolds (100 Pa) favored higher viability. MSC formed spheroids in 3D hydrogel and showed spread morphology in 2D overlayers. Our results demonstrate that the Fmoc-FF 3D cultures significantly enhanced osteogenic differentiation, as evidenced by increased calcium deposition, elevated phosphatase activity, and the secretion of osteocalcin. We propose that the peptides provide integrin-binding sites that activate a cytoplasmic feedback loop essential for differentiation. These findings suggest that self-assembled Fmoc-FF peptide hydrogels, is a promising platform for bone tissue engineering applications.
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Affiliation(s)
- Faye Fouladgar
- Department of Biomedical Engineering, University of North Texas, TX, USA
| | - Robert Powell
- Department of Biomedical Engineering, University of North Texas, TX, USA
| | | | - Akhila Joy
- Department of Material Science & Engineering, University of North Texas, TX, USA
| | - Xiao Li
- Department of Material Science & Engineering, University of North Texas, TX, USA
| | - Neda Habibi
- Department of Biomedical Engineering, University of North Texas, TX, USA
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Wang W, Wang Y, Bao S, He F, Li G, Yang G, Chen J, Yang X, Xiao Y, Tong Y, Zhao X, Hu J, You D. iPSCs-derived iMSCs prevent osteoporotic bone loss and affect bone metabolites in ovariectomized mice. J Cell Mol Med 2024; 28:e70200. [PMID: 39580790 PMCID: PMC11586054 DOI: 10.1111/jcmm.70200] [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: 06/25/2024] [Revised: 10/14/2024] [Accepted: 10/22/2024] [Indexed: 11/26/2024] Open
Abstract
Osteoporosis is a metabolic bone disease that seriously jeopardizes the health of middle-aged and elderly people. Mesenchymal stem cell-based transplantation for osteoporosis is a promising new therapeutic strategy. Induced mesenchymal stem cells (iMSCs) are a new option for stem cell transplantation therapy. Acquired mouse skin fibroblasts were transduced and reprogrammed into induced pluripotent cells and further induced to differentiate into iMSCs. The iMSCs were tested for pluripotency markers, trilineage differentiation ability, cell surface molecular marker tests, and gene expression patterns. The iMSCs were injected into the tail vein of mice by tail vein injection, and the distribution of cells in various organs was observed. The effect of iMSCs on the bone mass of mice was detected after injection into the mouse osteoporosis model. The effects of iMSCs infusion on metabolites in femoral tissue and peripheral blood plasma were detected based on LC-MS untargeted metabolomics. iMSCs have similar morphology, immunophenotype, in vitro differentiation potential, and gene expression patterns as mesenchymal stem cells. The iMSCs were heavily distributed in the lungs after infusion and gradually decreased over time. The iMSCs in the femoral bone marrow cavity gradually increased with time. iMSCs infusion significantly avoided bone loss due to oophorectomy. The results of untargeted metabolomics suggest that amino acid and lipid metabolic pathways are key factors involved in iMSCs bone protection and prevention of osteoporosis formation. iMSCs obtained by reprogramming-induced differentiation had cellular properties similar to those of bone marrow mesenchymal stem cells. The iMSCs could promote the remodelling of bone structure in ovariectomy-induced osteoporotic mice and affect the changes of several key metabolites in bone and peripheral blood. Some of these metabolites can serve as potential biomarkers and therapeutic targets for iMSCs intervention in osteoporosis. Investigating the effects of iMSCs on osteoporosis and the influence of metabolic pathways will provide new ideas and methods for the clinical treatment of osteoporosis.
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Affiliation(s)
- Wei‐Zhou Wang
- Yunnan Provincial Key Laboratory of Public Health and Biosafety and School of Public HealthThe First Affiliated Hospital of Kunming Medical UniversityKunmingYunnanChina
- Department of OrthopedicsThe First Affiliated Hospital of Kunming Medical UniversityKunmingYunnanChina
| | - Yang‐Hao Wang
- Department of PathologyThe First Affiliated Hospital of Kunming Medical UniversityKunmingYunnanChina
| | - Sha‐Sha Bao
- Department of RadiologyYan'an Hospital Affiliated to Kunming Medical UniversityKunmingYunnanChina
| | - Fei He
- Department of OrthopedicsKunming Medical University Affiliated Qujing HospitalQujingYunnanChina
| | - Guoyu Li
- Department of Colorectal Surgery, Yunnan Cancer HospitalThe Third Affiliated Hospital of Kunming Medical UniversityKunmingYunnanChina
- Kunming Medical UniversityKunmingYunnanChina
| | - Guang Yang
- Trauma Medicine CentreThe First Affiliated Hospital of Kunming Medical UniversityKunmingYunnanChina
| | - Jing Chen
- Department of Pathology and Pathophysiology, Faculty of Basic Medical ScienceKunming Medical UniversityKunmingYunnanChina
| | - Xin‐Yu Yang
- Kunming Medical UniversityKunmingYunnanChina
| | - Ya Xiao
- Kunming Medical UniversityKunmingYunnanChina
| | | | | | - Jun Hu
- Department of OrthopedicsKunming First People's HospitalKunmingYunnanChina
| | - Ding‐You You
- Yunnan Provincial Key Laboratory of Public Health and Biosafety and School of Public HealthKunming Medical UniversityKunmingYunnanChina
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Yang G, Ye J, Wang J, Liu H, Long Y, Jiang J, Miao X, Deng J, Wu T, Li T, Cheng X, Wang X. "Three birds, one stone" strategy of NIR-responsive CO/H 2S dual-gas Nanogenerator for efficient treatment of osteoporosis. Mater Today Bio 2024; 28:101179. [PMID: 39221209 PMCID: PMC11364908 DOI: 10.1016/j.mtbio.2024.101179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 07/09/2024] [Accepted: 07/27/2024] [Indexed: 09/04/2024] Open
Abstract
Osteoporosis (OP), the most prevalent bone degenerative disease, has become a significant public health challenge globally. Current therapies primarily target inhibiting osteoclast activity or stimulating osteoblast activation, but their effectiveness remains suboptimal. This paper introduced a "three birds, one stone" therapeutic approach for osteoporosis, employing upconversion nanoparticles (UCNPs) to create a dual-gas storage nanoplatform (UZPA-CP) targeting bone tissues, capable of concurrently generating carbon monoxide (CO) and hydrogen sulfide (H2S). Through the precise modulation of 808 nm near-infrared (NIR) light, the platform could effectively control the release of CO and H2S in the OP microenvironment, and realize the effective combination of promoting osteogenesis, inhibiting osteoclast activity, and improving the immune microenvironment to achieve the therapeutic effect of OP. High-throughput sequencing results further confirmed the remarkable effectiveness of the nanoplatform in inhibiting apoptosis, modulating inflammatory response, inhibiting osteoclast differentiation and regulating multiple immune signaling pathways. The gas storage nanoplatform not only optimized the OP microenvironment with the assistance of NIR, but also restored the balance between osteoblasts and osteoclasts. This comprehensive therapeutic strategy focused on improving the bone microenvironment, promoting osteogenesis and inhibiting osteoclast activity provides an ideal new solution for the treatment of metabolic bone diseases.
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Affiliation(s)
- Guoyu Yang
- Department of Orthopedics, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330088, PR China
| | - Jing Ye
- Department of Orthopedics, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330088, PR China
| | - Jingcheng Wang
- Department of Orthopedics, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330088, PR China
| | - Huijie Liu
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330088, PR China
| | - Yanli Long
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330088, PR China
| | - Junkai Jiang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330088, PR China
| | - Xinxin Miao
- Department of Orthopedics, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330088, PR China
| | - Jianjian Deng
- Department of Orthopedics, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330088, PR China
| | - Tianlong Wu
- Department of Orthopedics, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330088, PR China
| | - Tao Li
- Department of Orthopedics, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330088, PR China
| | - Xigao Cheng
- Department of Orthopedics, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330088, PR China
| | - Xiaolei Wang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330088, PR China
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García-Guerrero CA, Fuentes P, Araya MJ, Djouad F, Luz-Crawford P, Vega-Letter AM, Altamirano C. How to enhance MSCs therapeutic properties? An insight on potentiation methods. Stem Cell Res Ther 2024; 15:331. [PMID: 39334487 PMCID: PMC11438163 DOI: 10.1186/s13287-024-03935-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) have emerged as a promising tool in the field of regenerative medicine due to their unique therapeutic properties as they can differentiate into multiple cell types and exert paracrine effects. However, despite encouraging results obtained in preclinical studies, clinical trials have not achieved the same levels of efficacy. To improve the therapeutic properties of MSCs, several strategies have been explored. Therefore, in this review, the therapeutic properties of MSCs will be analyzed, and an update and overview of the most prominent approaches used to enhance their therapeutic capabilities will be provided. These approaches include using drugs, molecules, strategies based on biomaterials, and modification parameters in culture. The strategy described shows several common factors among those affected by these strategies that lead to an enhancement of the MSCs therapeutic properties such as the activation of the PI3K/AKT pathway and the increased expression of Heat Shock Proteins and Hypoxia-Inducible Factor. The combined effect of these elements shift MSCs towards a glycolytic state, suggesting this shift is essential for their enhancement.
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Affiliation(s)
- Cynthia Aylín García-Guerrero
- Doctorado en Biomedicina, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Paloma Fuentes
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
- Escuela de Ingeniería Bioquímica, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - María Jesús Araya
- Doctorado en Biomedicina, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Farida Djouad
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de La Santé Et de La Recherche Médicale, Montpellier, France
| | - Patricia Luz-Crawford
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile.
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile.
| | - Ana María Vega-Letter
- Escuela de Ingeniería Bioquímica, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile.
| | - Claudia Altamirano
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile.
- Escuela de Ingeniería Bioquímica, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile.
- Centro Regional de Estudios en Alimentos Saludables, Av. Universidad 330, Curauma-Placilla, Valparaíso, Chile.
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7
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Zhang Y, Chen J, Sun Y, Wang M, Liu H, Zhang W. Endogenous Tissue Engineering for Chondral and Osteochondral Regeneration: Strategies and Mechanisms. ACS Biomater Sci Eng 2024; 10:4716-4739. [PMID: 39091217 DOI: 10.1021/acsbiomaterials.4c00603] [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] [Indexed: 08/04/2024]
Abstract
Increasing attention has been paid to the development of effective strategies for articular cartilage (AC) and osteochondral (OC) regeneration due to their limited self-reparative capacities and the shortage of timely and appropriate clinical treatments. Traditional cell-dependent tissue engineering faces various challenges such as restricted cell sources, phenotypic alterations, and immune rejection. In contrast, endogenous tissue engineering represents a promising alternative, leveraging acellular biomaterials to guide endogenous cells to the injury site and stimulate their intrinsic regenerative potential. This review provides a comprehensive overview of recent advancements in endogenous tissue engineering strategies for AC and OC regeneration, with a focus on the tissue engineering triad comprising endogenous stem/progenitor cells (ESPCs), scaffolds, and biomolecules. Multiple types of ESPCs present within the AC and OC microenvironment, including bone marrow-derived mesenchymal stem cells (BMSCs), adipose-derived mesenchymal stem cells (AD-MSCs), synovial membrane-derived mesenchymal stem cells (SM-MSCs), and AC-derived stem/progenitor cells (CSPCs), exhibit the ability to migrate toward injury sites and demonstrate pro-regenerative properties. The fabrication and characteristics of scaffolds in various formats including hydrogels, porous sponges, electrospun fibers, particles, films, multilayer scaffolds, bioceramics, and bioglass, highlighting their suitability for AC and OC repair, are systemically summarized. Furthermore, the review emphasizes the pivotal role of biomolecules in facilitating ESPCs migration, adhesion, chondrogenesis, osteogenesis, as well as regulating inflammation, aging, and hypertrophy-critical processes for endogenous AC and OC regeneration. Insights into the applications of endogenous tissue engineering strategies for in vivo AC and OC regeneration are provided along with a discussion on future perspectives to enhance regenerative outcomes.
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Affiliation(s)
- Yanan Zhang
- School of Medicine, Southeast University, 210009 Nanjing, China
| | - Jialin Chen
- School of Medicine, Southeast University, 210009 Nanjing, China
- Jiangsu Key Laboratory for Biomaterials and Devices, Southeast University, 210096 Nanjing, China
- China Orthopedic Regenerative Medicine Group (CORMed), 310058 Hangzhou, China
| | - Yuzhi Sun
- Department of Orthopaedic Surgery, Institute of Digital Medicine, Nanjing First Hospital, Nanjing Medical University, 210006 Nanjing, China
| | - Mingyue Wang
- School of Medicine, Southeast University, 210009 Nanjing, China
| | - Haoyang Liu
- School of Medicine, Southeast University, 210009 Nanjing, China
| | - Wei Zhang
- School of Medicine, Southeast University, 210009 Nanjing, China
- Jiangsu Key Laboratory for Biomaterials and Devices, Southeast University, 210096 Nanjing, China
- China Orthopedic Regenerative Medicine Group (CORMed), 310058 Hangzhou, China
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8
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Gao Y, Huang A, Zhao Y, Du Y. PMAIP1 regulates autophagy in osteoblasts via the AMPK/mTOR pathway in osteoporosis. Hum Cell 2024; 37:1024-1038. [PMID: 38691334 DOI: 10.1007/s13577-024-01067-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: 11/28/2023] [Accepted: 04/22/2024] [Indexed: 05/03/2024]
Abstract
Osteoporosis (OP) is a highly prevalent disorder characterized by low bone mass that severely reduces patient quality of life. Although numerous treatments for OP have been introduced in clinic, many have side effects and high costs. Therefore, there is still an unmet need for optimal solutions. Here, raw signal analysis was used to identify potential high-risk factors for OP, and the biological functions and possible mechanisms of action (MOAs) of these factors were explored via gene set enrichment analysis (GSEA). Subsequently, molecular biological experiments were performed to verify and analyze the discovered risk factors in vitro and in vivo. PMAIP1 was identified as a potential risk factor for OP and significantly suppressed autophagy in osteoblasts via the AMPK/mTOR pathway, thereby inhibiting the proliferation and differentiation of osteoblasts. Furthermore, we constructed an ovariectomy (OVX) model of OP in rats and simultaneously applied si-PMAIP1 for in vivo interference. si-PMAIP1 upregulated the expression of LC3B and p-AMPK and downregulated the expression of p-mTOR, and these effects were reversed by the autophagy inhibitor. Micro-CT revealed that, si-PMAIP1 significantly inhibited the development of osteoporosis in OVX model rats, and this therapeutic effect was attenuated by treatment with an autophagy inhibitor. This study explored the role and mechanism of PMAIP1 in OP and demonstrated that PMAIP1 may serve as a novel target for OP treatment.
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Affiliation(s)
- Yijie Gao
- Department of Rehabilitation Medicine, The Second Hospital of Dalian Medical University, Dalian, Liaoning, People's Republic of China
- Dalian Medical University, Dalian, Liaoning, People's Republic of China
| | - Anquan Huang
- Department of Joint Surgery, Dalian Municipal Central Hospital, Dalian, Liaoning, People's Republic of China
| | - Yantao Zhao
- Department of Joint Surgery, Dalian Municipal Central Hospital, Dalian, Liaoning, People's Republic of China.
| | - Yunxia Du
- Department of Rehabilitation Medicine, The Second Hospital of Dalian Medical University, Dalian, Liaoning, People's Republic of China.
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9
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Huo K, Chen T, Kong D, Zhang W, Shao J. Comprehensive analysis of circRNA expression profiles in postmenopausal women differing in bone mineral density. Medicine (Baltimore) 2024; 103:e37813. [PMID: 38640297 PMCID: PMC11029967 DOI: 10.1097/md.0000000000037813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 03/09/2024] [Accepted: 03/15/2024] [Indexed: 04/21/2024] Open
Abstract
Postmenopausal osteoporosis (PMOP) seriously endangers the bone health of older women. Although there are currently indicators to diagnose PMOP, early diagnostic biomarkers are lacking. Circular ribonucleic acid (circRNA) has a stable structure, regulates gene expression, participates in the pathological process of disease, and has the potential to become a biomarker. The purpose of this study was to investigate circRNAs that could be used to predict patients with early PMOP. Ribonucleic acid (RNA) sequencing was performed on peripheral blood leukocytes from 15 female patients to identify differential circRNAs between different groups. Using bioinformatics analysis, enrichment analysis was performed to discover relevant functions and pathways. CircRNA-micro ribonucleic acid (miRNA) interaction analysis and messenger ribonucleic acid (mRNA) prediction and network construction help us to understand the relationship between circRNA, miRNA, and mRNA. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the gene expression of candidate circRNAs. We screened out 2 co-expressed differential circRNAs, namely hsa_circ_0060849 and hsa_circ_0001394. By analyzing the regulatory network, a total of 54 miRNAs and 57 osteoporosis-related mRNAs were identified, which, as potential downstream target genes of hsa_circ_0060849 and hsa_circ_0001394, may play a key role in the occurrence and development of PMOP. The occurrence and development of PMOP is regulated by circRNAs, and hsa_circ_0060849 and hsa_circ_0001394 can be used as new diagnostic markers and therapeutic targets for early PMOP.
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Affiliation(s)
- Kailun Huo
- Postgraduate Training Base in Shanghai Gongli Hospital, Ningxia Medical University, Yinchuan, Ningxia Hui-Autonomous Region, China
| | - Tianning Chen
- Postgraduate Training Base in Shanghai Gongli Hospital, Ningxia Medical University, Yinchuan, Ningxia Hui-Autonomous Region, China
| | - Dece Kong
- Department of Orthopedics, Pudong New Area Gongli Hospital, Shanghai, China
| | - Weiwei Zhang
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jin Shao
- Department of Orthopedics, Pudong New Area Gongli Hospital, Shanghai, China
- School of Gongli Hospital Medical Technology, University of Shanghai for Science and Technology, Shanghai, China
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10
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Li C, Liu Y, Deng M, Li J, Li S, Li X, Zuo Y, Shen C, Wang Y. Comparison of the therapeutic effects of mesenchymal stem cells derived from human dental pulp (DP), adipose tissue (AD), placental amniotic membrane (PM), and umbilical cord (UC) on postmenopausal osteoporosis. Front Pharmacol 2024; 15:1349199. [PMID: 38601464 PMCID: PMC11004311 DOI: 10.3389/fphar.2024.1349199] [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: 12/04/2023] [Accepted: 03/18/2024] [Indexed: 04/12/2024] Open
Abstract
Background: Osteoporosis is a systemic bone disease characterized by bone loss and microstructural degeneration. Recent preclinical and clinical trials have further demonstrated that the transplantation of mesenchymal stem cells (MSCs) derived from human adipose tissue (AD), dental pulp (DP), placental amniotic membrane (AM), and umbilical cord (UC) tissues can serve as an effective form of cell therapy for osteoporosis. However, MSC-mediated osteoimmunology and the ability of these cells to regulate osteoclast-osteoblast differentiation varies markedly among different types of MSCs. Methods: In this study, we investigated whether transplanted allogeneic MSCs derived from AD, DP, AM, and UC tissues were able to prevent osteoporosis in an ovariectomy (OVX)-induced mouse model of osteoporosis. The homing and immunomodulatory ability of these cells as well as their effects on osteoblastogenesis and the maintenance of bone formation were compared for four types of MSCs to determine the ideal source of MSCs for the cell therapy-based treatment of OVX-induced osteoporosis. The bone formation and bone resorption ability of these four types of MSCs were analyzed using micro-computed tomography analyses and histological staining. In addition, cytokine array-based analyses of serological markers and bioluminescence imaging assays were employed to evaluate cell survival and homing efficiency. Immune regulation was determined by flow cytometer assay to reflect the mechanisms of osteoporosis treatment. Conclusion: These analyses demonstrated that MSCs isolated from different tissues have the capacity to treat osteoporosis when transplanted in vivo. Importantly, DP-MSCs infusion was able to maintain trabecular bone mass more efficiently with corresponding improvements in trabecular bone volume, mineral density, number, and separation. Among the tested MSC types, DP-MSCs were also found to exhibit greater immunoregulatory capabilities, regulating the Th17/Treg and M1/M2 ratios. These data thus suggest that DP-MSCs may represent an effective tool for the treatment of osteoporosis.
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Affiliation(s)
- Chuncai Li
- Stem Cells Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- TCM Hospital of Sichuan Province, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yincong Liu
- Stem Cells Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Mingxing Deng
- Stem Cells Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jun Li
- Sichuan Provincial Cells Tissue Bank, Chengdu, China
| | - Shengqi Li
- Sichuan Provincial Cells Tissue Bank, Chengdu, China
| | - Xiaoyu Li
- Stem Cells Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuling Zuo
- Stem Cells Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- TCM Hospital of Sichuan Province, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chongyang Shen
- Stem Cells Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yichao Wang
- Department of Thyroid Surgery, West China Hospital, Sichuan University, Chengdu, China
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11
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Vimalraj S, Govindarajan D, Sudhakar S, Suresh R, Palanivel P, Sekaran S. Chitosan derived chito-oligosaccharides promote osteoblast differentiation and offer anti-osteoporotic potential: Molecular and morphological evidence from a zebrafish model. Int J Biol Macromol 2024; 259:129250. [PMID: 38199551 DOI: 10.1016/j.ijbiomac.2024.129250] [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: 08/31/2023] [Revised: 12/15/2023] [Accepted: 01/03/2024] [Indexed: 01/12/2024]
Abstract
This study delves into the potential of chito-oligosaccharides (COS) to promote osteoblast differentiation and prevent osteoporosis, utilizing experiments with mouse MSCs and the zebrafish model. The preliminary biocompatibility study affirms the non-toxic nature of COS across various concentrations. In the osteoblast differentiation study, COS enhances ALP activity and calcium deposition at the cellular level. Moreover, COS induces the upregulation of molecular markers, including Runx2, Type I collagen, ALP, osteocalcin, and osteonectin in mouse MSCs. Zebrafish studies further demonstrate COS's anti-osteoporotic effects, showcasing its ability to expedite fin fracture repair, vertebral mineralization, and bone mineralization in dexamethasone-induced osteoporosis models. The scale regenerative study reveals that COS mitigates the detrimental effects of dexamethasone induced osteoclastic activity, reducing TRAP and hydroxyproline levels while elevating the expression of Runx2a MASNA isoform, collagen2α, OC, and ON mRNAs. Additionally, COS enhances calcium and phosphorus levels in regenerated scales, impacting the bone-healthy calcium-to‑phosphorus ratio. The study also suggests that COS modulates the MMP3-Osteopontin-MAPK signaling pathway. Overall, this comprehensive investigation underscores the potential of COS to prevent and treat osteoporosis. Its multifaceted cellular and molecular effects, combined with in vivo bone regeneration and repair, propose that COS may be effective in addressing osteoporosis and related bone disorders. Nonetheless, further research is imperative to unravel underlying mechanisms and optimize clinical applications.
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Affiliation(s)
- Selvaraj Vimalraj
- Department of Applied Mechanics and Biomedical Engineering, Indian Institute of Technology-Madras, Chennai 600 036, Tamil Nadu, India; Department of Prosthodontics, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Science (SIMATS), Saveetha University, Chennai 600 077, Tamil Nadu, India.
| | - Dharunya Govindarajan
- Department of Biotechnology, Stem Cell and Molecular Biology Laboratory, Bhupat & Jyoti Mehta School of Biosciences, Indian Institute of Technology, Madras, Chennai 600 036, Tamil Nadu, India
| | - Swathi Sudhakar
- Department of Applied Mechanics and Biomedical Engineering, Indian Institute of Technology-Madras, Chennai 600 036, Tamil Nadu, India
| | - Renugaa Suresh
- Department of Applied Mechanics and Biomedical Engineering, Indian Institute of Technology-Madras, Chennai 600 036, Tamil Nadu, India
| | | | - Saravanan Sekaran
- Department of Prosthodontics, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Science (SIMATS), Saveetha University, Chennai 600 077, Tamil Nadu, India
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12
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Liang G, Zhao J, Pan J, Yang Y, Dou Y, Yang W, Zeng L, Liu J. Network pharmacology identifies fisetin as a treatment for osteoporosis that activates the Wnt/β-catenin signaling pathway in BMSCs. J Orthop Surg Res 2023; 18:312. [PMID: 37087476 PMCID: PMC10122799 DOI: 10.1186/s13018-023-03761-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 03/29/2023] [Indexed: 04/24/2023] Open
Abstract
BACKGROUND Although fisetin may exist widely in many natural herbs, its anti-OP mechanism is still unclear. The aim of this study is to explore the molecular anti-osteoporosis (OP) mechanism of fisetin based on network pharmacology and cell experiments. METHODS The target of fisetin was extracted by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The targets of OP were obtained by DisGeNET, GeneCards and the Comparative Toxicogenomics Database, and the targets of fisetin in OP were screened by cross-analysis. The protein-protein interaction (PPI) network was constructed by STRING, and the core targets were obtained. We performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses on common targets via the Database for Annotation, Visualization and Integrated Discovery. Finally, an in vitro cell experiment was used to verify the anti-OP effect and mechanism of fisetin. RESULTS There are 44 targets of fisetin related to the treatment of OP. The PPI results suggest that CTNNB1, CCND1, TP53, JUN, and AKT1 are the core targets. A total of 259 biological process, 57 molecular function and 26 cell component terms were obtained from GO enrichment analysis. The results of KEGG pathway enrichment analysis suggested that fisetin treatment of OP may be related to the Wnt signaling pathway, estrogen signaling pathway, PI3K-Akt signaling pathway and other signaling pathways. In vitro cell experiments showed that fisetin significantly increased the expression levels of ALP, collagen I, osteopontin and RUNX2 in bone marrow mesenchymal stem cells (BMSCs) (p < 0.05). Fisetin also increased the gene expression levels of Wnt3 and β-catenin (CTNNB1) in BMSCs, which indicates that fisetin can regulate the Wnt/β-catenin signaling pathway and promote the osteogenic differentiation of BMSCs. CONCLUSIONS Fisetin acts on multiple targets and pathways in the treatment of OP; mechanistically, it regulates the Wnt/β-catenin signaling pathway, which promotes the osteogenic differentiation of BMSCs and maintains bone homeostasis. The results of this study provide a theoretical basis for further study on the complex anti-OP mechanism of fisetin.
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Affiliation(s)
- Guihong Liang
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405 China
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120 China
- The Research Team on Bone and Joint Degeneration and Injury of Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, 510120 China
| | - Jinlong Zhao
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405 China
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120 China
- The Research Team on Bone and Joint Degeneration and Injury of Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, 510120 China
| | - Jianke Pan
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120 China
| | - Yuan Yang
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405 China
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120 China
- The Research Team on Bone and Joint Degeneration and Injury of Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, 510120 China
| | - Yaoxing Dou
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405 China
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120 China
- The Research Team on Bone and Joint Degeneration and Injury of Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, 510120 China
| | - Weiyi Yang
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120 China
| | - Lingfeng Zeng
- The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405 China
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120 China
- The Research Team on Bone and Joint Degeneration and Injury of Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, 510120 China
| | - Jun Liu
- The Research Team on Bone and Joint Degeneration and Injury of Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, 510120 China
- The Fifth Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405 China
- Guangdong Second Traditional Chinese Medicine Hospital (Guangdong Province Engineering Technology Research Institute of Traditional Chinese Medicine), Guangzhou, 510095 China
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13
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Huo KL, Yang TY, Zhang WW, Shao J. Mesenchymal stem/stromal cells-derived exosomes for osteoporosis treatment. World J Stem Cells 2023; 15:83-89. [PMID: 37007454 PMCID: PMC10052342 DOI: 10.4252/wjsc.v15.i3.83] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/17/2023] [Accepted: 03/17/2023] [Indexed: 03/23/2023] Open
Abstract
Osteoporosis is a systemic bone disease, which leads to decreased bone mass and an increased risk of fragility fractures. Currently, there are many anti-resorption drugs and osteosynthesis drugs, which are effective in the treatment of osteoporosis, but their usage is limited due to their contraindications and side effects. In regenerative medicine, the unique repair ability of mesenchymal stem cells (MSCs) has been favored by researchers. The exosomes secreted by MSCs have signal transduction and molecular delivery mechanisms, which may have therapeutic effects. In this review, we describe the regulatory effects of MSCs-derived exosomes on osteoclasts, osteoblasts, and bone immunity. We aim to summarize the preclinical studies of exosome therapy in osteoporosis. Furthermore, we speculate that exosome therapy can be a future direction to improve bone health.
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Affiliation(s)
- Kai-Lun Huo
- Postgraduate Training Base in Shanghai Gongli Hospital, Ningxia Medical University, Yinchuan 750004, the Ningxia Hui Autonomous Region, China
| | - Tie-Yi Yang
- Department of Orthopedics, Pudong New Area Gongli Hospital, School of Medical Technology, University of Shanghai for Science and Technology, Shanghai 200135, China
| | - Wei-Wei Zhang
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Jin Shao
- Department of Orthopedics, Pudong New Area Gongli Hospital, School of Medical Technology, University of Shanghai for Science and Technology, Shanghai 200135, China
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14
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Downregulation of METTL14 improves postmenopausal osteoporosis via IGF2BP1 dependent posttranscriptional silencing of SMAD1. Cell Death Dis 2022; 13:919. [PMID: 36319624 PMCID: PMC9626483 DOI: 10.1038/s41419-022-05362-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 09/19/2022] [Accepted: 10/20/2022] [Indexed: 11/21/2022]
Abstract
Osteoporosis (OP) tends to occur in postmenopausal women, making them prone to fractures. N6-methyladenosine (m6A) methylation plays a crucial role in OP. Herein, we aimed to explore the effects of METTL14 on osteogenesis and the underlying mechanism. Osteogenic differentiation was assessed through osteoblast markers expression, cell proliferation, ALP activity, and mineralization, which were detected by qRT-PCR, CCK-8, EdU assay, ALP staining assay, and ARS staining assay, respectively. Osteoporosis was evaluated in OVX mice using qRT-PCR, microcomputed tomography, and H&E staining assay. The levels of METTL14 and SMAD1 were measured using qRT-PCR and western blot, and their interaction was assessed using RIP and luciferase reporter assay. M6A methylation was analyzed using the Me-RIP assay. The results indicated that m6A, METTL14, and SMAD1 levels were downregulated in patients with OP and OVX mice, and upregulated in osteogenic BMSCs. Knockdown of METTL14 suppressed osteogenesis of BMSCs and reduced bone mass of OVX mice. Moreover, silencing of METTL14 positively related to SMAD1 and inhibited m6A modification of SMAD1 by suppressing its stability. IGF2BP1 was identified as the methylation reader, and which knockdown reversed the upregulation induced by SMAD1. Overexpression of SMAD1 reversed the suppression of osteogenic differentiation induced by METTL14 knockdown. In conclusion, interference with METTL14 inhibited osteogenic differentiation of BSMCs by m6A modification of SMAD1 in an IGFBP1 manner, suggesting that METTL14 might be a novel approach for improving osteoporosis.
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15
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Cao C, Zhang L, Liu F, Shen J. Therapeutic Benefits of Mesenchymal Stem Cells in Acute Respiratory Distress Syndrome: Potential Mechanisms and Challenges. J Inflamm Res 2022; 15:5235-5246. [PMID: 36120184 PMCID: PMC9473549 DOI: 10.2147/jir.s372046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 08/31/2022] [Indexed: 11/23/2022] Open
Abstract
Acute respiratory distress syndrome (ARDS) presents as a form of acute respiratory failure resulting from non-cardiogenic pulmonary edema due to excessive alveolocapillary permeability, which may be pulmonary or systemic in origin. In the last 3 years, the coronavirus disease 2019 pandemic has resulted in an increase in ARDS cases and highlighted the challenges associated with this syndrome, as well as the unacceptably high mortality rates and lack of effective treatments. Currently, clinical treatment remains primarily supportive, including mechanical ventilation and drug-based therapy. Mesenchymal stem cell (MSC) therapies are emerging as a promising intervention in patients with ARDS and have promising therapeutic effects and safety. The therapeutic mechanisms include modifying the immune response and assisting with tissue repair. This review provides an overview of the general properties of MSCs and outlines their role in mitigating lung injury and promoting tissue repair in ARDS. Finally, we summarize the current challenges in the study of translational MSC research and identify avenues by which the discipline may progress in the coming years.
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Affiliation(s)
- Chao Cao
- Research Center for Chemical Injury, Emergency and Critical Medicine of Fudan University, Shanghai, People's Republic of China.,Key Laboratory of Chemical Injury, Emergency and Critical Medicine of Shanghai Municipal Health Commission, Shanghai, People's Republic of China.,Center of Emergency and Critical Medicine in Jinshan Hospital of Fudan University, Shanghai, People's Republic of China.,Shanghai Medical College Fudan University, Shanghai, People's Republic of China
| | - Lin Zhang
- Key Laboratory of Chemical Injury, Emergency and Critical Medicine of Shanghai Municipal Health Commission, Shanghai, People's Republic of China.,Center of Emergency and Critical Medicine in Jinshan Hospital of Fudan University, Shanghai, People's Republic of China
| | - Fuli Liu
- Key Laboratory of Chemical Injury, Emergency and Critical Medicine of Shanghai Municipal Health Commission, Shanghai, People's Republic of China.,Center of Emergency and Critical Medicine in Jinshan Hospital of Fudan University, Shanghai, People's Republic of China
| | - Jie Shen
- Research Center for Chemical Injury, Emergency and Critical Medicine of Fudan University, Shanghai, People's Republic of China.,Key Laboratory of Chemical Injury, Emergency and Critical Medicine of Shanghai Municipal Health Commission, Shanghai, People's Republic of China.,Center of Emergency and Critical Medicine in Jinshan Hospital of Fudan University, Shanghai, People's Republic of China.,Shanghai Medical College Fudan University, Shanghai, People's Republic of China
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16
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Cai H, Guo H, Deng Y, Jiang J, Liu S, He W, Jian H. RRM2 regulates osteogenesis of mouse embryo fibroblasts via the Wnt/β‑catenin signaling pathway. Exp Ther Med 2022; 24:605. [PMID: 36160885 PMCID: PMC9468855 DOI: 10.3892/etm.2022.11542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 07/13/2022] [Indexed: 11/06/2022] Open
Abstract
Osteoporosis is a widespread bone metabolic disease characterized by reduced bone mass and bone microstructure deterioration. Ribonucleotide reductase M2 (RRM2) is a key enzyme in DNA synthesis and repair. The present study investigated the effect of RRM2 on osteogenesis of mouse embryo fibroblasts (MEFs) and its molecular mechanism. Bioinformatics analysis revealed that RRM2 expression was increased during osteogenesis of MEFs triggered by bone morphogenetic protein 9. Subsequently, MEFs were used as a mesenchymal stem cell model and osteogenic inducing medium was used to induce osteogenic differentiation. RRM2 protein expression was measured by western blotting during osteogenic differentiation induction of MEFs. RRM2 levels in MEFs were upregulated and downregulated by RRM2-overexpressing recombinant adenovirus and small interfering RNA-RRM2, respectively. Bone formation markers (RUNX family transcription factor 2, osterix, distal-less homeobox 5, collagen type I α1 chain, osteopontin and osteocalcin) were detected by reverse transcription-quantitative (RT-q) PCR and alkaline phosphatase (ALP) and Alizarin Red S staining were examined. The protein expression levels of β-catenin and the ratio of phosphorylated (p-)GSK-3β to GSK-3β were detected by western blotting and the RNA expression of downstream related target genes (β-catenin, axis inhibition protein 2 (AXIN2), transcription factor 7 like 2, lymphoid enhancer binding factor 1, c-MYC and Cyclin D1) in the Wnt/β-catenin signaling pathway was measured by RT-qPCR. RRM2 protein expression increased as the osteogenic differentiation induction period was extended. RRM2 overexpression increased osteogenic marker RNA expression, ALP activity, bone mineralization, the protein expression levels of β-catenin, the ratio of p-GSK-3β to GSK-3β and the RNA expression of downstream related target genes in the Wnt/β-catenin signaling pathway, whereas RRM2 knockdown had the opposite effect. The findings of the present study revealed that RRM2 overexpression enhanced osteogenic differentiation, while RRM2 knockdown reduced osteogenic differentiation. RRM2 may regulate osteogenic differentiation of MEFs via the canonical Wnt/β-catenin signaling pathway, providing a possible therapeutic target for osteoporosis.
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Affiliation(s)
- Haijun Cai
- Department of Emergency, The Second Affiliated Hospital, Chongqing Medical University, Yuzhong, Chongqing 400010, P.R. China
| | - Hui Guo
- Department of Emergency, The Second Affiliated Hospital, Chongqing Medical University, Yuzhong, Chongqing 400010, P.R. China
| | - Yixuan Deng
- Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China
| | - Jinhai Jiang
- Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China
| | - Siyuan Liu
- Department of Orthopedics, The Second Affiliated Hospital, Chongqing Medical University, Yuzhong, Chongqing 400010, P.R. China
| | - Wenge He
- Department of Orthopedics, The Second Affiliated Hospital, Chongqing Medical University, Yuzhong, Chongqing 400010, P.R. China
| | - Huagang Jian
- Department of Emergency, The Second Affiliated Hospital, Chongqing Medical University, Yuzhong, Chongqing 400010, P.R. China
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17
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Lin YY, Takemoto JY, Chang CWT, Peng CA. Mesobiliverdin IXα ameliorates osteoporosis via promoting osteogenic differentiation of mesenchymal stem cells. Biochem Biophys Res Commun 2022; 619:56-61. [PMID: 35738065 DOI: 10.1016/j.bbrc.2022.06.042] [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: 05/24/2022] [Revised: 06/10/2022] [Accepted: 06/14/2022] [Indexed: 11/16/2022]
Abstract
Heme oxygenase-1 (HO-1) expression promotes osteogenesis, but the mechanisms remain unclear and therapeutic strategies using it to target bone disorders such as osteoporosis have not progressed. Mesobiliverdin IXα is a naturally occurring bilin analog of HO-1 catalytic product biliverdin IXα. Inclusion of mesobiliverdin IXα in the feed diet of ovariectomized osteoporotic mice was observed to increase femur bone volume, trabecular thickness and osteogenesis serum markers osteoprotegrin and osteocalcin and to decrease bone resorption serum markers cross-linked N-teleopeptide and tartrate-resistant acid phosphatase 5b. Moreover, in vitro exposure of human bone marrow mesenchymal stem cells to mesobiliverdin IXα enhanced osteogenic differentiation efficiency by two-fold over non-exposed controls. Our results imply that mesobiliverdin IXα promotes osteogenesis in ways that reflect the potential therapeutic effects of induced HO-1 expression in alleviating osteoporosis.
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Affiliation(s)
- Yuan-Yu Lin
- Department of Animal Science and Technology, National Taiwan University, Taipei City, Taiwan
| | - Jon Y Takemoto
- Department of Biology, Utah State University, Logan, UT, United States
| | - Cheng-Wei T Chang
- Department of Chemistry and Biochemistry, Utah State University, Logan, UT, United States
| | - Ching-An Peng
- Department of Chemical and Biological Engineering, University of Idaho, Moscow, ID, United States.
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18
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Habib SA, Kamal MM, El-Maraghy SA, Senousy MA. Exendin-4 enhances osteogenic differentiation of adipose tissue mesenchymal stem cells through the receptor activator of nuclear factor-kappa B and osteoprotegerin signaling pathway. J Cell Biochem 2022; 123:906-920. [PMID: 35338509 DOI: 10.1002/jcb.30236] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 02/26/2022] [Accepted: 03/03/2022] [Indexed: 12/11/2022]
Abstract
The capability of mesenchymal stem cells (MSCs) to repair bone damage and defects has long been investigated. The receptor activator of nuclear factor-kappa B (RANK), its ligand (RANKL) and the decoy receptor osteoprotegerin (OPG) axis is crucial to keep the equilibrium between osteoblastic and osteoclastic activity. Exendin-4 utilization increased bone formation and enhanced bone integrity. This study aimed to investigate the mentioned axis and determine the effect of exendin-4 upon adipose mesenchymal stem cells (Ad-MSCs) osteogenic differentiation. Ad-MSCs were isolated from rat epididymal fat, followed by characterization and then differentiation into osteocytes both in the presence or absence of exendin-4. Osteogenic differentiation was evaluated by alizarin red staining and the expression of osteogenic markers; using reverse transcriptase-quantitative polymerase chain reaction, western blotting and enzyme-linked immunoassay. MSCs derived from rat epididymal fat were isolated and characterized, along with their differentiation into osteocytes. The differentiated cells were alizarin red-stained, showing increased staining intensity upon addition of exendin-4. Moreover, the addition of exendin-4 elevated the messenger RNA expression levels of osteogenic markers; runt-related transcription factor-2 (RUNX-2), osteocalcin, and forkhead box protein O-1 while reducing the expression of the adipogenic marker peroxisome-proliferator-activated receptor-gamma. Exendin-4 addition elevated OPG levels in the supernatant of osteogenic differentiated cells. Moreover, exendin-4 elevated the protein levels of glucagon-like peptide-1 receptor and RUNX-2, while decreasing both RANK and RANKL. In conclusion, osteogenic differentiation of Ad-MSCs is associated with increased osteoblastic rather than osteoclastic activity. The findings of this study suggest that exendin-4 can enhance Ad-MSCs osteogenic differentiation partially through the RANK/RANKL/OPG axis.
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Affiliation(s)
- Sarah A Habib
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt
| | - Mohamed M Kamal
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
- Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt
| | - Shohda A El-Maraghy
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Mahmoud A Senousy
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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