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Givian A, Azizan A, Jamshidi A, Mahmoudi M, Farhadi E. Iron metabolism in rheumatic diseases. J Transl Autoimmun 2025; 10:100267. [PMID: 39867458 PMCID: PMC11763848 DOI: 10.1016/j.jtauto.2025.100267] [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: 11/09/2024] [Revised: 12/24/2024] [Accepted: 01/03/2025] [Indexed: 01/28/2025] Open
Abstract
Iron is a crucial element for living organism in terms of oxygen transport, hematopoiesis, enzymatic activity, mitochondrial respiratory chain function and also immune system function. The human being has evolved a mechanism to regulate body iron. In some rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematous (SLE), systemic sclerosis (SSc), ankylosing spondylitis (AS), and gout, this balanced iron regulation is impaired. Altered iron homeostasis can contribute to disease progression through ROS production, fibrosis, inflammation, abnormal bone homeostasis, NETosis and cell senescence. In this review, we have focused on the iron metabolism in rheumatic disease and its role in disease progression.
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Affiliation(s)
- Aliakbar Givian
- Rheumatology Research Center, Tehran University of Medical Science, Tehran, Iran
- Department of Immunology, School of Medicine, Semnan University of Medical Science, Semnan, Iran
| | - Amin Azizan
- Rheumatology Research Center, Tehran University of Medical Science, Tehran, Iran
- Research Center for Chronic Inflammatory Diseases, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmadreza Jamshidi
- Rheumatology Research Center, Tehran University of Medical Science, Tehran, Iran
| | - Mahdi Mahmoudi
- Rheumatology Research Center, Tehran University of Medical Science, Tehran, Iran
- Research Center for Chronic Inflammatory Diseases, Tehran University of Medical Sciences, Tehran, Iran
| | - Elham Farhadi
- Rheumatology Research Center, Tehran University of Medical Science, Tehran, Iran
- Research Center for Chronic Inflammatory Diseases, Tehran University of Medical Sciences, Tehran, Iran
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2
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Xiao L, He W, Hurley MM. Fibroblast growth factor 23 neutralizing antibody partially rescues bone loss and increases hematocrit in sickle cell disease mice. Sci Rep 2025; 15:10727. [PMID: 40155665 PMCID: PMC11953280 DOI: 10.1038/s41598-025-95335-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: 02/04/2025] [Accepted: 03/20/2025] [Indexed: 04/01/2025] Open
Abstract
Fibroblast Growth Factor 23 (FGF23) is increased in serum of humanized Sickle Cell Disease (SCD) mice. Since FGF23 is associated with impaired bone formation, we examined the effect of FGF23-neutralizing antibody (FGF23Ab) on bone loss in SCD mice. Healthy control (Ctrl) and SCD 5-months-old female mice were treated with FGF23Ab or isotype-specific IgG for 6 weeks. Significantly reduced hematocrit in SCD mice was increased by FGF23Ab. MicroCT of SCD femurs revealed no significant reduction in metaphyseal bone volume/total volume vs. Ctrl mice. However, histomorphometry of SCD femur revealed significantly reduced mineral apposition rate, bone formation rate, inter-label thickness, and osteoid surface, which were increased by FGF23Ab. Significantly increased osteoclast number/bone perimeter in SCD mice was reduced by FGF23Ab. Bone marrow stromal cells (BMSC) cultured in osteogenic media revealed significantly reduced mineralized nodules in SCD-IgG-BMSC that was increased in SCD-FGF23Ab-BMSC. FGF23 and αKlotho protein was significantly increased in SCD-IgG-BMSC and was not reduced by FGF23Ab. However, phosphorylated FGF Receptor-1, the receptor through which FGF23 signals, was significantly reduced by FGF23Ab. The mineralization inhibitor osteopontin was significantly increased in SCD-IgG-BMSC cultures and was reduced by FGF23Ab. We conclude that FGF23Ab may be efficacious in improving some parameters of reduced bone formation in female SCD mice.
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Affiliation(s)
- Liping Xiao
- Division of Endocrinology and Metabolism, Department of Medicine, UConn Health School of Medicine, Farmington, CT, 06030, USA.
| | - Wei He
- Division of Endocrinology and Metabolism, Department of Medicine, UConn Health School of Medicine, Farmington, CT, 06030, USA
| | - Marja M Hurley
- Division of Endocrinology and Metabolism, Department of Medicine, UConn Health School of Medicine, Farmington, CT, 06030, USA.
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Arosio P, Cairo G, Bou-Abdallah F. A Brief History of Ferritin, an Ancient and Versatile Protein. Int J Mol Sci 2024; 26:206. [PMID: 39796064 PMCID: PMC11719527 DOI: 10.3390/ijms26010206] [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: 11/24/2024] [Revised: 12/26/2024] [Accepted: 12/27/2024] [Indexed: 01/13/2025] Open
Abstract
Ferritin, a highly conserved iron storage protein, is among the earliest proteins that have been purified, named, and characterized due to its unique properties that continue to captivate researchers. Ferritin is composed of 24 subunits that form an almost spherical shell delimiting a cavity where thousands of iron atoms can be stored in a nontoxic ferric form, thereby preventing cytosolic iron from catalyzing oxidative stress. Mitochondrial and extracellular ferritin have also been described and characterized, with the latter being associated with several signaling functions. In addition, serum ferritin serves as a reliable indicator of both iron stores and inflammatory conditions. First identified and purified through crystallization in 1937, ferritin has since drawn significant attention for its critical role in iron metabolism and regulation. Its unique structural features have recently been exploited for many diverse biological and technological applications. To date, more than 40,000 publications have explored this remarkable protein. Here, we present a historical overview, tracing its journey from discovery to current applications and highlighting the evolution of biochemical techniques developed for its structure-function characterization over the past eight decades.
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Affiliation(s)
- Paolo Arosio
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Gaetano Cairo
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy;
| | - Fadi Bou-Abdallah
- Department of Chemistry, State University of New York at Potsdam, Potsdam, NY 13676, USA;
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Passin V, Ledesma-Colunga MG, Altamura S, Muckenthaler MU, Baschant U, Hofbauer LC, Rauner M. Depletion of macrophages and osteoclast precursors mitigates iron overload-mediated bone loss. IUBMB Life 2024. [PMID: 39555707 DOI: 10.1002/iub.2928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 10/16/2024] [Indexed: 11/19/2024]
Abstract
Iron is an essential element for physiological cellular processes, but is toxic in excess. Iron overload diseases are commonly associated with low bone mass. Increased bone resorption by osteoclasts as well as decreased bone formation by osteoblasts have been implicated in bone loss under iron overload conditions. However, the exact contribution of individual cell types has not yet been formally tested. In this study, we aimed to investigate the role of osteoclast precursors in iron overload-induced bone loss. To that end, we used clodronate liposomes to deplete phagocytic cells (including macrophages and osteoclast precursors) in male C57BL/6J mice that were exposed to ferric derisomaltose. Bone microarchitecture and bone turnover were assessed after 4 weeks. The application of clodronate resulted in the efficient depletion of circulating myeloid-lineage cells by about 70%. Depletion of osteoclast precursors mitigated iron overload-induced trabecular bone loss at the lumbar vertebrae and distal femur. While clodronate treatment led to a profound inhibition of bone turnover in control mice, it significantly reduced osteoclast numbers in iron-treated mice without further impacting the bone formation rate or serum PINP levels. Our observations suggest that even though bone formation is markedly suppressed by iron overload, osteoclasts also play a key role in iron overload-induced bone loss and highlight them as potential therapeutic targets.
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Affiliation(s)
- Vanessa Passin
- Department of Medicine III & Center for Healthy Aging, Medical Faculty and University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
| | - Maria G Ledesma-Colunga
- Department of Medicine III & Center for Healthy Aging, Medical Faculty and University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
| | - Sandro Altamura
- Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, Heidelberg, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Martina U Muckenthaler
- Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, Heidelberg, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Ulrike Baschant
- Department of Medicine III & Center for Healthy Aging, Medical Faculty and University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
| | - Lorenz C Hofbauer
- Department of Medicine III & Center for Healthy Aging, Medical Faculty and University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
| | - Martina Rauner
- Department of Medicine III & Center for Healthy Aging, Medical Faculty and University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
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von Brackel FN, Oheim R. Iron and bones: effects of iron overload, deficiency and anemia treatments on bone. JBMR Plus 2024; 8:ziae064. [PMID: 38957399 PMCID: PMC11215550 DOI: 10.1093/jbmrpl/ziae064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 04/24/2024] [Accepted: 05/10/2024] [Indexed: 07/04/2024] Open
Abstract
Iron is a vital trace element and exerts opposing effects on bone in both iron overload and iron deficiency situations. Remarkably, iron supplementation through intravenous infusion in patients with iron deficiency can also have detrimental effects on bone in special cases. The diverse mechanisms underlying these effects and their manifestations contribute to the complexity of this relationship. Iron overload impacts both bone resorption and formation, accelerating bone resorption while reducing bone formation. These effects primarily result from the direct action of reactive oxygen species (ROS), which influence the proliferation, differentiation, and activity of both osteoclasts and osteoblasts differently. This imbalance favors osteoclasts and inhibits the osteoblasts. Simultaneously, multiple pathways, including bone morphogenic proteins, RANK ligand, and others, contribute to these actions, leading to a reduction in bone mass and an increased susceptibility to fractures. In contrast, iron deficiency induces low bone turnover due to energy and co-factor deficiency, both of which require iron. Anemia increases the risk of fractures in both men and women. This effect occurs at various levels, reducing muscular performance and, on the bone-specific level, decreasing bone mineral density. Crucially, anemia increases the synthesis of the phosphaturic hormone iFGF23, which is subsequently inactivated by cleavage under physiological conditions. Thus, iFGF23 levels and phosphate excretion are not increased. However, in specific cases where anemia has to be managed with intravenous iron treatment, constituents-particularly maltoses-of the iron infusion suppress the cleavage of iFGF23. As a result, patients can experience severe phosphate wasting and, consequently, hypophosphatemic osteomalacia. This condition is often overlooked in clinical practice and is often caused by ferric carboxymaltose. Ending iron infusions or changing the agent, along with phosphate and vitamin D supplementation, can be effective in addressing this issue.
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Affiliation(s)
- Felix N von Brackel
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 22529 Hamburg, Germany
| | - Ralf Oheim
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 22529 Hamburg, Germany
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Ma HD, Shi L, Li HT, Wang XD, Yang MW. Polycytosine RNA-binding protein 1 regulates osteoblast function via a ferroptosis pathway in type 2 diabetic osteoporosis. World J Diabetes 2024; 15:977-987. [PMID: 38766437 PMCID: PMC11099367 DOI: 10.4239/wjd.v15.i5.977] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/22/2024] [Accepted: 03/15/2024] [Indexed: 05/10/2024] Open
Abstract
BACKGROUND Recently, type 2 diabetic osteoporosis (T2DOP) has become a research hotspot for the complications of diabetes, but the specific mechanism of its occurrence and development remains unknown. Ferroptosis caused by iron overload is con-sidered an important cause of T2DOP. Polycytosine RNA-binding protein 1 (PCBP1), an iron ion chaperone, is considered a protector of ferroptosis. AIM To investigate the existence of ferroptosis and specific role of PCBP1 in the development of type 2 diabetes. METHODS A cell counting kit-8 assay was used to detect changes in osteoblast viability under high glucose (HG) and/or ferroptosis inhibitors at different concentrations and times. Transmission electron microscopy was used to examine the morphological changes in the mitochondria of osteoblasts under HG, and western blotting was used to detect the expression levels of PCBP1, ferritin, and the ferroptosis-related protein glutathione peroxidase 4 (GPX4). A lentivirus silenced and overexpressed PCBP1. Western blotting was used to detect the expression levels of the osteoblast functional proteins osteoprotegerin (OPG) and osteocalcin (OCN), whereas flow cytometry was used to detect changes in reactive oxygen species (ROS) levels in each group. RESULTS Under HG, the viability of osteoblasts was considerably decreased, the number of mitochondria undergoing atrophy was considerably increased, PCBP1 and ferritin expression levels were increased, and GPX4 expression was decreased. Western blotting results demonstrated that infection with lentivirus overexpressing PCBP1, increased the expression levels of ferritin, GPX4, OPG, and OCN, compared with the HG group. Flow cytometry results showed a reduction in ROS, and an opposite result was obtained after silencing PCBP1. CONCLUSION PCBP1 may protect osteoblasts and reduce the harm caused by ferroptosis by promoting ferritin expression under a HG environment. Moreover, PCBP1 may be a potential therapeutic target for T2DOP.
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Affiliation(s)
- Hong-Dong Ma
- Department of Orthopedics, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Lei Shi
- Department of Orthopedics, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Hai-Tian Li
- Department of Orthopedics, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Xin-Dong Wang
- Department of Orthopedics, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Mao-Wei Yang
- Department of Orthopedics, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Chen Y, Zhao W, Hu A, Lin S, Chen P, Yang B, Fan Z, Qi J, Zhang W, Gao H, Yu X, Chen H, Chen L, Wang H. Type 2 diabetic mellitus related osteoporosis: focusing on ferroptosis. J Transl Med 2024; 22:409. [PMID: 38693581 PMCID: PMC11064363 DOI: 10.1186/s12967-024-05191-x] [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: 01/21/2024] [Accepted: 04/12/2024] [Indexed: 05/03/2024] Open
Abstract
With the aging global population, type 2 diabetes mellitus (T2DM) and osteoporosis(OP) are becoming increasingly prevalent. Diabetic osteoporosis (DOP) is a metabolic bone disorder characterized by abnormal bone tissue structure and reduced bone strength in patients with diabetes. Studies have revealed a close association among diabetes, increased fracture risk, and disturbances in iron metabolism. This review explores the concept of ferroptosis, a non-apoptotic cell death process dependent on intracellular iron, focusing on its role in DOP. Iron-dependent lipid peroxidation, particularly impacting pancreatic β-cells, osteoblasts (OBs) and osteoclasts (OCs), contributes to DOP. The intricate interplay between iron dysregulation, which comprises deficiency and overload, and DOP has been discussed, emphasizing how excessive iron accumulation triggers ferroptosis in DOP. This concise overview highlights the need to understand the complex relationship between T2DM and OP, particularly ferroptosis. This review aimed to elucidate the pathogenesis of ferroptosis in DOP and provide a prospective for future research targeting interventions in the field of ferroptosis.
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Affiliation(s)
- Yili Chen
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Wen Zhao
- Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006, China
| | - An Hu
- Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006, China
| | - Shi Lin
- Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006, China
| | - Ping Chen
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Bing Yang
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Zhirong Fan
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Ji Qi
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Wenhui Zhang
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Huanhuan Gao
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Xiubing Yu
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Haiyun Chen
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Luyuan Chen
- Stomatology Center, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, 510086, China.
| | - Haizhou Wang
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
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Yu N, Wang N, Zhang W, Xue J, zhou Q, Hu F, Bai X, Liu N. Dihydroartemisinin (DHA) inhibits myofibroblast differentiation through inducing ferroptosis mediated by ferritinophagy. Heliyon 2024; 10:e27276. [PMID: 38463857 PMCID: PMC10923727 DOI: 10.1016/j.heliyon.2024.e27276] [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: 10/23/2023] [Revised: 02/24/2024] [Accepted: 02/27/2024] [Indexed: 03/12/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is caused by persistent micro-injuries and aberrant repair processes. Myofibroblast differentiation in lung is a key event for abnormal repair. Dihydroartemisinin(DHA), a well-known anti-malarial drug, have been shown to alleviate pulmonary fibrosis, but its mechanism is not clear. Ferroptosis is involved in the pathgenesis of many diseases, including IPF. Ferritinophagy is a form of cellular autophagy which regulates intracellular iron homeostasis. The function of DHA on myofibroblasts differentiation of pulmonary and whether related with ferroptosis and ferritinophagy are unknown now. Using human fetal lung fibroblast 1(HFL1) cell line and the qRT-PCR, immunofluorescent and Western blotting techniques, we found that after TGF-β1 treatment, the levels of ɑ-SMA expression and ROS increased; the mRNA and protein levels of FTH1 and NCOA4, the content of Fe2+ and 4-HNE increased significantly at 6h, then gradually reduced with time. After DHA treatment, FHL1 cells appeared ferroptosis; the levels of α-SMA mRNA and protein reduced and the levels of ROS and 4-HNE increased; the Fe2+ levels decreased sharply at 6h, then increased with time, and were higher than normal since 24h; the mRNA and protein levels of FTH1 and NCOA4 decreased, exhibited a downward trend. These results show that Fe2+, ROS and lipid peroxidation are involved in and ferritinophagy is inhibited during fibroblast-to-myofibroblast differentiation; The depletion of Fe2+ at early stage induced by DHA treatment triggers the ferritinophagy in HFL1 cells, leading to degradation of FTH1 and NCOA4 and following increase of Fe2+ levels. DHA may inhibit the fibroblast-to-myofibroblast differentiation through inducing ferroptosis mediated by ferritinophagy.
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Affiliation(s)
- Ningning Yu
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, 256603, PR China
| | - Nan Wang
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, 256603, PR China
| | - Weiqun Zhang
- Dental Implant Department, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, PR China
| | - Junyu Xue
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, 256603, PR China
| | - Quan zhou
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, 256603, PR China
| | - Fengai Hu
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, 256603, PR China
| | - Xuelian Bai
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, 256603, PR China
| | - Naiguo Liu
- Medical Research Center, Binzhou Medical University Hospital, Binzhou, 256603, PR China
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Zhang H, Yang F, Cao Z, Xu Y, Wang M. The influence of iron on bone metabolism disorders. Osteoporos Int 2024; 35:243-253. [PMID: 37857915 DOI: 10.1007/s00198-023-06937-x] [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: 01/05/2023] [Accepted: 09/29/2023] [Indexed: 10/21/2023]
Abstract
Iron is a necessary trace element in the human body, and it participates in many physiological processes. Disorders of iron metabolism can cause lesions in many tissues and organs, including bone. Recently, iron has gained attention as an independent factor influencing bone metabolism disorders, especially the involvement of iron overload in osteoporosis. The aim of this review was to summarize the findings from clinical and animal model research regarding the involvement of iron in bone metabolism disorders and to elucidate the mechanisms behind iron overload and osteoporosis. Lastly, we aimed to describe the association between bone loss and iron overload. We believe that a reduction in iron accumulation can be used as an alternative treatment to assist in the treatment of osteoporosis, to improve bone mass, and to improve the quality of life of patients.
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Affiliation(s)
- Hui Zhang
- Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Fan Yang
- Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Zihou Cao
- Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Youjia Xu
- Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
| | - Mingyong Wang
- Murui Biological Technology Co., Ltd, Suzhou Industrial Park, Suzhou, China.
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González-Cejudo T, Villa-Suárez JM, Ferrer-Millán M, Andújar-Vera F, Contreras-Bolívar V, Andreo-López MC, Gómez-Vida JM, Martínez-Heredia L, González-Salvatierra S, de Haro Muñoz T, García-Fontana C, Muñoz-Torres M, García-Fontana B. Mild hypophosphatasia may be twice as prevalent as previously estimated: an effective clinical algorithm to detect undiagnosed cases. Clin Chem Lab Med 2024; 62:128-137. [PMID: 37440753 DOI: 10.1515/cclm-2023-0427] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 07/04/2023] [Indexed: 07/15/2023]
Abstract
OBJECTIVES Since the prevalence of hypophosphatasia (HPP), a rare genetic disease, seems to be underestimated in clinical practice, in this study, a new diagnostic algorithm to identify missed cases of HPP was developed and implemented. METHODS Analytical determinations recorded in the Clinical Analysis Unit of the Hospital Universitario Clínico San Cecilio in the period June 2018 - December 2020 were reviewed. A new clinical algorithm to detect HPP-misdiagnosed cases was used including the following steps: confirmation of persistent hypophosphatasemia, exclusion of secondary causes of hypophosphatasemia, determination of serum pyridoxal-5'-phosphate (PLP) and genetic study of ALPL gene. RESULTS Twenty-four subjects were selected to participate in the study and genetic testing was carried out in 20 of them following clinical algorithm criteria. Eighty percent of patients was misdiagnosed with HPP following the current standard clinical practice. Extrapolating these results to the current Spanish population means that there could be up to 27,177 cases of undiagnosed HPP in Spain. In addition, we found a substantial proportion of HPP patients affected by other comorbidities, such as autoimmune diseases (∼40 %). CONCLUSIONS This new algorithm was effective in detecting previously undiagnosed cases of HPP, which appears to be twice as prevalent as previously estimated for the European population. In the near future, our algorithm could be globally applied routinely in clinical practice to minimize the underdiagnosis of HPP. Additionally, some relevant findings, such as the high prevalence of autoimmune diseases in HPP-affected patients, should be investigated to better characterize this disorder.
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Affiliation(s)
- Trinidad González-Cejudo
- Clinical Analysis Unit, University Hospital Clínico San Cecilio, Granada, Spain
- Department of Medicine, University of Granada, Granada, Spain
| | | | - María Ferrer-Millán
- Instituto de Investigación Biosanitaria de Granada (ibs. GRANADA), Granada, Spain
| | - Francisco Andújar-Vera
- Department of Computer Science and Artificial Intelligence, University of Granada, Granada, Spain
- CIBER on Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
- Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI Institute), Granada, Spain
| | - Victoria Contreras-Bolívar
- Instituto de Investigación Biosanitaria de Granada (ibs. GRANADA), Granada, Spain
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, Granada, Spain
| | | | | | | | - Sheila González-Salvatierra
- Instituto de Investigación Biosanitaria de Granada (ibs. GRANADA), Granada, Spain
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain
| | - Tomás de Haro Muñoz
- Clinical Analysis Unit, University Hospital Clínico San Cecilio, Granada, Spain
| | - Cristina García-Fontana
- Instituto de Investigación Biosanitaria de Granada (ibs. GRANADA), Granada, Spain
- CIBER on Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, Granada, Spain
| | - Manuel Muñoz-Torres
- Department of Medicine, University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (ibs. GRANADA), Granada, Spain
- CIBER on Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, Granada, Spain
| | - Beatriz García-Fontana
- Instituto de Investigación Biosanitaria de Granada (ibs. GRANADA), Granada, Spain
- CIBER on Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
- Department of Cell Biology, University of Granada, Granada, Spain
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Yuan W, Yang Y, Wei Y, Yu X, Bao J, Zhong J, Wang Z, Chen L. Ferritin was involved in interleukin-17A enhanced osteogenesis through autophagy activation. Int Immunopharmacol 2023; 124:110916. [PMID: 37713787 DOI: 10.1016/j.intimp.2023.110916] [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: 04/07/2023] [Revised: 09/05/2023] [Accepted: 09/06/2023] [Indexed: 09/17/2023]
Abstract
Periodontitis is a prevalent inflammatory immune disease that involves tissue inflammation and excessive bone loss. In murine periodontitis models and periodontitis patients, upregulated interleukin-17A (IL-17A) expression was observed, and its level seemed to correlate with the disease severity. In this study, we intended to investigate the specific role of ferritin, a critical iron storage protein, in IL-17A enhanced osteogenic differentiation as well as the underlying mechanism. Under osteogenic induction, IL-17A stimulation promoted differentiation and mineralization of murine calvarial osteoblasts. In addition, increased iron accumulation and ferritin expression were detected in osteoblasts treated with IL-17A, indicating an alteration in iron metabolism during osteogenesis. Administration of iron chelator deferoxamine (DFO) and transfection with small interfering RNA (siRNA) targeting ferritin heavy chain (FTH) further revealed that ferritin suppression consequently inhibited osteoblast differentiation. Autophagy activation was also found upon IL-17A stimulation, which played a positive role in osteogenic differentiation and was subsequently suppressed by DFO or siRNA targeting FTH. In conclusion, IL-17A induced ferritin expression in osteoblasts, which further enhanced osteogenic differentiation via autophagy activation. These findings may provide further insight into the role of IL-17A in osteoblast differentiation and demonstrate ferritin as a potential target in modulating alveolar bone homeostasis.
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Affiliation(s)
- Wenlin Yuan
- Department of Periodontology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China; Cancer Institute, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou 310009, China
| | - Yuting Yang
- Department of Periodontology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Yingming Wei
- Department of Periodontology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Xufei Yu
- Department of Periodontology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Jiaqi Bao
- Department of Periodontology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Jiahui Zhong
- Department of Periodontology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Zhongxiu Wang
- Department of Periodontology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China.
| | - Lili Chen
- Department of Periodontology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China.
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Robin F, Chappard D, Leroyer P, Latour C, Mabilleau G, Monbet V, Cavey T, Horeau M, Derbré F, Roth MP, Ropert M, Guggenbuhl P, Loréal O. Differences in bone microarchitecture between genetic and secondary iron-overload mouse models suggest a role for hepcidin deficiency in iron-related osteoporosis. FASEB J 2023; 37:e23245. [PMID: 37874260 DOI: 10.1096/fj.202301184r] [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: 07/03/2023] [Revised: 09/04/2023] [Accepted: 09/25/2023] [Indexed: 10/25/2023]
Abstract
Iron overload is one of the secondary osteoporosis etiologies. Cellular and molecular mechanisms involved in iron-related osteoporosis are not fully understood. AIM The aim of the study was to investigate the respective roles of iron excess and hepcidin, the systemic iron regulator, in the development of iron-related osteoporosis. MATERIAL AND METHODS We used mice models with genetic iron overload (GIO) related to hepcidin deficiency (Hfe-/- and Bmp6-/- ) and secondary iron overload (SIO) exhibiting a hepcidin increase secondary to iron excess. Iron concentration and transferrin saturation levels were evaluated in serum and hepatic, spleen, and bone iron concentrations were assessed by ICP-MS and Perl's staining. Gene expression was evaluated by quantitative RT-PCR. Bone micro-architecture was evaluated by micro-CT. The osteoblastic MC3T3 murine cells that are able to mineralize were exposed to iron and/or hepcidin. RESULTS Despite an increase of bone iron concentration in all overloaded mice models, bone volume/total volume (BV/TV) and trabecular thickness (Tb.Th) only decreased significantly in GIO, at 12 months for Hfe-/- and from 6 months for Bmp6-/- . Alterations in bone microarchitecture in the Bmp6-/- model were positively correlated with hepcidin levels (BV/TV (ρ = +.481, p < .05) and Tb.Th (ρ = +.690, p < .05). Iron deposits were detected in the bone trabeculae of Hfe-/- and Bmp6-/- mice, while iron deposits were mainly visible in bone marrow macrophages in secondary iron overload. In cell cultures, ferric ammonium citrate exposure abolished the mineralization process for concentrations above 5 μM, with a parallel decrease in osteocalcin, collagen 1, and alkaline phosphatase mRNA levels. Hepcidin supplementation of cells had a rescue effect on the collagen 1 and alkaline phosphatase expression level decrease. CONCLUSION Together, these data suggest that iron in excess alone is not sufficient to induce osteoporosis and that low hepcidin levels also contribute to the development of osteoporosis.
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Affiliation(s)
- François Robin
- INSERM, Univ Rennes, INRAE, CHU Rennes, U 1241, Institut NuMeCan (Nutrition Metabolisms and Cancer), Rennes, France
| | - Daniel Chappard
- GEROM, LHEA, IRIS-IBS Biology Institut, Angers cedex, France
| | - Patricia Leroyer
- INSERM, Univ Rennes, INRAE, CHU Rennes, U 1241, Institut NuMeCan (Nutrition Metabolisms and Cancer), Rennes, France
| | - Chloé Latour
- IRSD, Univ Toulouse, INSERM, INRAE, ENVT, UPS, Toulouse, France
| | - Guillaume Mabilleau
- Univ Angers, Nantes Université, Oniris, Inserm, RMeS, REGOS, SFR ICAT, Angers, France
| | | | - Thibault Cavey
- INSERM, Univ Rennes, INRAE, CHU Rennes, U 1241, Institut NuMeCan (Nutrition Metabolisms and Cancer), Rennes, France
| | - Mathieu Horeau
- INSERM, Univ Rennes, INRAE, CHU Rennes, U 1241, Institut NuMeCan (Nutrition Metabolisms and Cancer), Rennes, France
- Laboratory "Movement Sport and Health Sciences" EA7470, University of Rennes/ENS Rennes, Rennes, France
| | - Frédéric Derbré
- Laboratory "Movement Sport and Health Sciences" EA7470, University of Rennes/ENS Rennes, Rennes, France
| | | | - Martine Ropert
- INSERM, Univ Rennes, INRAE, CHU Rennes, U 1241, Institut NuMeCan (Nutrition Metabolisms and Cancer), Rennes, France
- AEM2 Platform, Univ Rennes, University Hospital, Rennes, France
| | - Pascal Guggenbuhl
- INSERM, Univ Rennes, INRAE, CHU Rennes, U 1241, Institut NuMeCan (Nutrition Metabolisms and Cancer), Rennes, France
| | - Olivier Loréal
- INSERM, Univ Rennes, INRAE, CHU Rennes, U 1241, Institut NuMeCan (Nutrition Metabolisms and Cancer), Rennes, France
- AEM2 Platform, Univ Rennes, University Hospital, Rennes, France
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13
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Bao J, Yan Y, Zuo D, Zhuo Z, Sun T, Lin H, Han Z, Zhao Z, Yu H. Iron metabolism and ferroptosis in diabetic bone loss: from mechanism to therapy. Front Nutr 2023; 10:1178573. [PMID: 37215218 PMCID: PMC10196368 DOI: 10.3389/fnut.2023.1178573] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 04/07/2023] [Indexed: 05/24/2023] Open
Abstract
Osteoporosis, one of the most serious and common complications of diabetes, has affected the quality of life of a large number of people in recent years. Although there are many studies on the mechanism of diabetic osteoporosis, the information is still limited and there is no consensus. Recently, researchers have proven that osteoporosis induced by diabetes mellitus may be connected to an abnormal iron metabolism and ferroptosis inside cells under high glucose situations. However, there are no comprehensive reviews reported. Understanding these mechanisms has important implications for the development and treatment of diabetic osteoporosis. Therefore, this review elaborates on the changes in bones under high glucose conditions, the consequences of an elevated glucose microenvironment on the associated cells, the impact of high glucose conditions on the iron metabolism of the associated cells, and the signaling pathways of the cells that may contribute to diabetic bone loss in the presence of an abnormal iron metabolism. Lastly, we also elucidate and discuss the therapeutic targets of diabetic bone loss with relevant medications which provides some inspiration for its cure.
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Affiliation(s)
- Jiahao Bao
- Department of Oral & Cranio-maxillofacial Surgery, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China
| | - Yixuan Yan
- Guangdong Provincial Key Laboratory of Stomatology, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
| | - Daihui Zuo
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Zhiyong Zhuo
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Tianhao Sun
- Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, Guangdong Engineering Technology Research Center for Orthopaedic Trauma Repair, Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Hongli Lin
- School of Public Health, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China
| | - Zheshen Han
- School of Public Health, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China
| | - Zhiyang Zhao
- Department of Oral & Cranio-maxillofacial Surgery, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China
| | - Hongbo Yu
- Department of Oral & Cranio-maxillofacial Surgery, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China
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14
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Fighting age-related orthopedic diseases: focusing on ferroptosis. Bone Res 2023; 11:12. [PMID: 36854703 PMCID: PMC9975200 DOI: 10.1038/s41413-023-00247-y] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 01/03/2023] [Accepted: 01/11/2023] [Indexed: 03/02/2023] Open
Abstract
Ferroptosis, a unique type of cell death, is characterized by iron-dependent accumulation and lipid peroxidation. It is closely related to multiple biological processes, including iron metabolism, polyunsaturated fatty acid metabolism, and the biosynthesis of compounds with antioxidant activities, including glutathione. In the past 10 years, increasing evidence has indicated a potentially strong relationship between ferroptosis and the onset and progression of age-related orthopedic diseases, such as osteoporosis and osteoarthritis. Therefore, in-depth knowledge of the regulatory mechanisms of ferroptosis in age-related orthopedic diseases may help improve disease treatment and prevention. This review provides an overview of recent research on ferroptosis and its influences on bone and cartilage homeostasis. It begins with a brief overview of systemic iron metabolism and ferroptosis, particularly the potential mechanisms of ferroptosis. It presents a discussion on the role of ferroptosis in age-related orthopedic diseases, including promotion of bone loss and cartilage degradation and the inhibition of osteogenesis. Finally, it focuses on the future of targeting ferroptosis to treat age-related orthopedic diseases with the intention of inspiring further clinical research and the development of therapeutic strategies.
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15
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Regulatory Mechanism between Ferritin and Mitochondrial Reactive Oxygen Species in Spinal Ligament-Derived Cells from Ossification of Posterior Longitudinal Ligament Patient. Int J Mol Sci 2023; 24:ijms24032872. [PMID: 36769191 PMCID: PMC9917908 DOI: 10.3390/ijms24032872] [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: 01/05/2023] [Revised: 01/20/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Primary spinal ligament-derived cells (SLDCs) from cervical herniated nucleus pulposus tissue (control, Ctrl) and ossification of the posterior longitudinal ligament (OPLL) tissue of surgical patients were analyzed for pathogenesis elucidation. Here, we found that decreased levels of ferritin and increased levels of alkaline phosphatase (ALP), a bone formation marker, provoked osteogenesis in SLDCs in OPLL. SLDCs from the Ctrl and OPLL groups satisfied the definition of mesenchymal stem/stromal cells. RNA sequencing revealed that oxidative phosphorylation and the citric acid cycle pathway were upregulated in the OPLL group. SLDCs in the OPLL group showed increased mitochondrial mass, increased mitochondrial reactive oxygen species (ROS) production, decreased levels of ROS scavengers including ferritin. ROS and ferritin levels were upregulated and downregulated in a time-dependent manner, and both types of molecules repressed ALP. Osteogenesis was mitigated by apoferritin addition. We propose that enhancing ferritin levels might alleviate osteogenesis in OPLL.
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16
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Ciosek Ż, Kot K, Rotter I. Iron, Zinc, Copper, Cadmium, Mercury, and Bone Tissue. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:2197. [PMID: 36767564 PMCID: PMC9915283 DOI: 10.3390/ijerph20032197] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 01/13/2023] [Accepted: 01/24/2023] [Indexed: 06/18/2023]
Abstract
The paper presents the current understanding on the effects of five metals on bone tissue, namely iron, zinc, copper, cadmium, and mercury. Iron, zinc, and copper contribute significantly to human and animal metabolism when present in sufficient amounts, but their excess or shortage increases the risk of developing bone disorders. In contrast, cadmium and mercury serve no physiological purpose and their long-term accumulation damages the osteoarticular system. We discuss the methods of action and interactions between the discussed elements as well as the concentrations of each element in distinct bone structures.
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Affiliation(s)
- Żaneta Ciosek
- Chair and Department of Medical Rehabilitation and Clinical Physiotherapy, Pomeranian Medical University in Szczecin, Żołnierska 54, 70-210 Szczecin, Poland
| | - Karolina Kot
- Department of Biology and Medical Parasitology, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland
| | - Iwona Rotter
- Chair and Department of Medical Rehabilitation and Clinical Physiotherapy, Pomeranian Medical University in Szczecin, Żołnierska 54, 70-210 Szczecin, Poland
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17
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High-Altitude Hypoxia Exposure Induces Iron Overload and Ferroptosis in Adipose Tissue. Antioxidants (Basel) 2022; 11:antiox11122367. [PMID: 36552575 PMCID: PMC9774922 DOI: 10.3390/antiox11122367] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/25/2022] [Accepted: 11/27/2022] [Indexed: 12/05/2022] Open
Abstract
High altitude (HA) has become one of the most challenging environments featuring hypobaric hypoxia, which seriously threatens public health, hence its gradual attraction of public attention over the past decade. The purpose of this study is to investigate the effect of HA hypoxia on iron levels, redox state, inflammation, and ferroptosis in adipose tissue. Here, 40 mice were randomly divided into two groups: the sea-level group and HA hypoxia group (altitude of 5000 m, treatment for 4 weeks). Total iron contents, ferrous iron contents, ROS generation, lipid peroxidation, the oxidative enzyme system, proinflammatory factor secretion, and ferroptosis-related biomarkers were examined, respectively. According to the results, HA exposure increases total iron and ferrous iron levels in both WAT and BAT. Meanwhile, ROS release, MDA, 4-HNE elevation, GSH depletion, as well as the decrease in SOD, CAT, and GSH-Px activities further evidenced a phenotype of redox imbalance in adipose tissue during HA exposure. Additionally, the secretion of inflammatory factors was also significantly enhanced in HA mice. Moreover, the remarkably changed expression of ferroptosis-related markers suggested that HA exposure increased ferroptosis sensitivity in adipose tissue. Overall, this study reveals that HA exposure is capable of inducing adipose tissue redox imbalance, inflammatory response, and ferroptosis, driven in part by changes in iron overload, which is expected to provide novel preventive targets for HA-related illness.
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18
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Ma J, Wang A, Zhang H, Liu B, Geng Y, Xu Y, Zuo G, Jia P. Iron overload induced osteocytes apoptosis and led to bone loss in Hepcidin -/- mice through increasing sclerostin and RANKL/OPG. Bone 2022; 164:116511. [PMID: 35933095 DOI: 10.1016/j.bone.2022.116511] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/22/2022] [Accepted: 08/01/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Numerous studies have demonstrated that iron overload is a risk factor of osteoporosis. However, there has been no systematic and in-depth studies on the effect of iron overload on osteocytes and its role in iron overload-induced bone loss. Therefore, to address this problem, we carried out in vitro and in vivo studies using MLO-Y4 osteocyte-like cells and Hepcidin-/- mice as iron overload models. METHODS (1) MLO-Y4 cells were treated with ferric ammonium citrate (FAC). Intracellular reactive oxygen species (ROS) levels and apoptosis of MLO-Y4 cells were determined by flow cytometry. Western blotting was performed to evaluate the effect of FAC on the expression of sclerostin and RANKL/OPG. (2) The conditioned medium of MLO-Y4 cells after treatment with FAC was collected and used to treat pre-osteoblasts and monocytes. Alkaline phosphatase (ALP) staining and alizarin red (AR) staining were used to evaluate osteogenic differentiation capacity, and tartrate-resistant acid phosphatase (TRAP) staining was performed to demonstrate osteoclast differentiation capacity. (3) In vivo studies included a wild type mouse, Hepcidin-/- mice, Hepcidin-/- mice + deferoxamine (DFO), and Hepcidin-/- mice + N-actyl-l-cysteine (NAC) group. Micro-CT was performed to evaluate the bone mineral density (BMD), bone volume, and bone micro-architecture of the mice, and three bending tests were used to assess bone strength. Histological analysis was used to detect alterations in bone turnover. TUNEL staining and scanning electron microscopy (SEM) were performed to evaluate the apoptosis and morphology of osteocytes. Immunohistochemical staining and Western blotting were used to determine alterations in sclerostin and RANKL/OPG expression levels in mice. RESULTS (1) FAC increased intracellular ROS and apoptosis in MLO-Y4 cells, while FAC enhanced the expression of sclerostin and RANKL/OPG in MLO-Y4 cells. (2) Conditioned medium of MLO-Y4 cells inhibited the osteogenic capacity of osteoblasts while stimulating osteoclast differentiation. (3) By increasing oxidative stress, iron overload promotes the apoptosis of osteocytes and undermines the morphology of osteocytes in Hepcidin-/- mice, further increasing the expression levels of sclerostin and RANKL/OPG in osteocytes, which is considered to be the causative factor for reduced bone formation and enhanced bone resorption. DFO administration reduced iron levels, and NAC treatment decreased oxidative stress in Hepcidin-/- mice. Therefore, DFO or NAC treatment rescued the decrease in BMD, bone volume, and bone strength and attenuated the deterioration of bone architecture in Hepcidin-/- mice by attenuating the effect of iron overload on osteocytes. CONCLUSION Osteocyte apoptosis due to increased ROS and resultant sclerostin and RANKL/OPG expression alteration was the main reason for bone loss in Hepcidin-/- mice. Osteocytes are the main targets for the prevention and treatment of iron overload-induced osteoporosis.
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Affiliation(s)
- Jiawei Ma
- Second Affiliated Hospital of Soochow University, Orthopedic Department, China; Osteoporosis Research Institute of Soochow University, China
| | - Aifei Wang
- Second Affiliated Hospital of Soochow University, Orthopedic Department, China; Osteoporosis Research Institute of Soochow University, China
| | - Hui Zhang
- Second Affiliated Hospital of Soochow University, Orthopedic Department, China; Osteoporosis Research Institute of Soochow University, China
| | - Baoshan Liu
- Second Affiliated Hospital of Soochow University, Orthopedic Department, China; Osteoporosis Research Institute of Soochow University, China
| | - Yu Geng
- Second Affiliated Hospital of Soochow University, Orthopedic Department, China; Osteoporosis Research Institute of Soochow University, China
| | - Youjia Xu
- Second Affiliated Hospital of Soochow University, Orthopedic Department, China; Osteoporosis Research Institute of Soochow University, China
| | - Guilai Zuo
- Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Orthopedic Department, China.
| | - Peng Jia
- Second Affiliated Hospital of Soochow University, Orthopedic Department, China; Osteoporosis Research Institute of Soochow University, China.
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Kano T, Io H, Nakata J, Sasaki Y, Muto M, Shimizu Y, Fukao Y, Fukuzaki H, Maeda T, Hosoya R, Suzuki Y. Impact of Transferrin Saturation and Anemia on Radial Artery Calcification in Patients with End-Stage Kidney Disease. Nutrients 2022; 14:nu14204269. [PMID: 36296953 PMCID: PMC9606998 DOI: 10.3390/nu14204269] [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: 09/23/2022] [Revised: 10/10/2022] [Accepted: 10/11/2022] [Indexed: 11/17/2022] Open
Abstract
Background: Arterial calcification is an important factor in determining the prognosis of patients with chronic kidney disease (CKD). Few studies on aortic calcification have involved radial artery calcification (RAC). This study aimed to analyze risk factors for RAC in patients with end-stage kidney disease (ESKD) and investigate the relationship between subsequent cardiovascular events (CVE) and vascular access trouble (VAT). Methods: This cohort study included 64 consecutive patients with ESKD who initiated hemodialysis and underwent a procedure for the creation of a primary radiocephalic arteriovenous fistula (RCAVF). Small arterial specimens were obtained from patients during RCAVF surgery. Tissue samples were stained with von Kossa, and arterial microcalcification was evaluated. We analyzed the association between preexisting arterial microcalcifications, clinical characteristics, CVE, and VAT. Results: In the univariate analysis, RAC patients demonstrated high systolic blood pressure (sBP), low hemoglobin (Hb), and low transferrin saturation (TSAT) (<0.05, <0.05, and <0.05, respectively). In the multivariate analysis, Hb (HR−0.516 (0.278−0.959), p < 0.05), TSAT (HR−0.0012 (0.00000248−0.597), p < 0.05), and sBP (HR−1.037 (1.001−1.073), p < 0.05) were independent risk factors for RAC. The cumulative incidence rate of CVE/VAT was not associated with RAC for one year. Conclusion: RAC was associated with sBP, TSAT, and anemia; however, no association with CVE/VAT was observed.
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Affiliation(s)
- Toshiki Kano
- Department of Nephrology, Juntendo University Nerima Hospital, Tokyo 177-8521, Japan
| | - Hiroaki Io
- Department of Nephrology, Juntendo University Nerima Hospital, Tokyo 177-8521, Japan
- Correspondence: ; Tel.: +81-3-5923-3111
| | - Junichiro Nakata
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan
| | - Yu Sasaki
- Department of Nephrology, Juntendo University Nerima Hospital, Tokyo 177-8521, Japan
| | - Masahiro Muto
- Department of Nephrology, Juntendo University Nerima Hospital, Tokyo 177-8521, Japan
| | - Yuki Shimizu
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan
| | - Yusuke Fukao
- Department of Nephrology, Juntendo University Nerima Hospital, Tokyo 177-8521, Japan
| | - Haruna Fukuzaki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan
| | - Takuya Maeda
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan
| | - Reina Hosoya
- Department of Nephrology, Juntendo University Nerima Hospital, Tokyo 177-8521, Japan
| | - Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan
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Bell BI, Vercellino J, Brodin NP, Velten C, Nanduri LSY, Nagesh PK, Tanaka KE, Fang Y, Wang Y, Macedo R, English J, Schumacher MM, Duddempudi PK, Asp P, Koba W, Shajahan S, Liu L, Tomé WA, Yang WL, Kolesnick R, Guha C. Orthovoltage X-Rays Exhibit Increased Efficacy Compared with γ-Rays in Preclinical Irradiation. Cancer Res 2022; 82:2678-2691. [PMID: 35919990 PMCID: PMC9354647 DOI: 10.1158/0008-5472.can-22-0656] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/15/2022] [Accepted: 06/10/2022] [Indexed: 02/05/2023]
Abstract
Radionuclide irradiators (137Cs and 60Co) are commonly used in preclinical studies ranging from cancer therapy to stem cell biology. Amidst concerns of radiological terrorism, there are institutional initiatives to replace radionuclide sources with lower energy X-ray sources. As researchers transition, questions remain regarding whether the biological effects of γ-rays may be recapitulated with orthovoltage X-rays because different energies may induce divergent biological effects. We therefore sought to compare the effects of orthovoltage X-rays with 1-mm Cu or Thoraeus filtration and 137Cs γ-rays using mouse models of acute radiation syndrome. Following whole-body irradiation, 30-day overall survival was assessed, and the lethal dose to provoke 50% mortality within 30-days (LD50) was calculated by logistic regression. LD50 doses were 6.7 Gy, 7.4 Gy, and 8.1 Gy with 1-mm Cu-filtered X-rays, Thoraeus-filtered X-rays, and 137Cs γ-rays, respectively. Comparison of bone marrow, spleen, and intestinal tissue from mice irradiated with equivalent doses indicated that injury was most severe with 1-mm Cu-filtered X-rays, which resulted in the greatest reduction in bone marrow cellularity, hematopoietic stem and progenitor populations, intestinal crypts, and OLFM4+ intestinal stem cells. Thoraeus-filtered X-rays provoked an intermediate phenotype, with 137Cs showing the least damage. This study reveals a dichotomy between physical dose and biological effect as researchers transition to orthovoltage X-rays. With decreasing energy, there is increasing hematopoietic and intestinal injury, necessitating dose reduction to achieve comparable biological effects. SIGNIFICANCE Understanding the significance of physical dose delivered using energetically different methods of radiation treatment will aid the transition from radionuclide γ-irradiators to orthovoltage X-irradiators.
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Affiliation(s)
- Brett I. Bell
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Justin Vercellino
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - N. Patrik Brodin
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
| | - Christian Velten
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
| | | | - Prashanth K.B. Nagesh
- Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Kathryn E. Tanaka
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Yanan Fang
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Yanhua Wang
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Rodney Macedo
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
| | - Jeb English
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Michelle M. Schumacher
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | | | - Patrik Asp
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
| | - Wade Koba
- Department of Radiology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Shahin Shajahan
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
| | - Laibin Liu
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
| | - Wolfgang A. Tomé
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
- Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Weng-Lang Yang
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
| | - Richard Kolesnick
- Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Chandan Guha
- Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY, USA
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
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21
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Chang H, Zhang D, Xin Z, Zhang P, Ding W, Chang YZ. Influence of prazosin on systemic iron levels and the associated iron metabolic alterations in spontaneously hypertensive rats. Pharmacol Res Perspect 2022; 10:e00991. [PMID: 35892277 PMCID: PMC9326454 DOI: 10.1002/prp2.991] [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: 05/18/2022] [Revised: 06/30/2022] [Accepted: 07/05/2022] [Indexed: 12/23/2022] Open
Abstract
The relationship between cardiovascular diseases and iron disorders has gained increasing attention; however, the effects of hypotensive drugs on iron metabolic alterations in hypertension are not well understood. The purpose of this study was to investigate iron metabolic changes after prazosin treatment of spontaneously hypertensive rats (SHRs) and Wistar–Kyoto (WKY) rats. Our second objective was to examine the effects of hypertension and anti‐hypertensive drugs on bone formation and resorption. SHRs and WKY rats were randomized into either prazosin‐treated groups (WKY + PZ and SHR + PZ) or untreated groups (WKY and SHR). After 7 days of intragastric prazosin administration, the rats were sacrificed for analysis; blood samples and organs (the duodenum, liver, kidneys, spleen, and femur) were collected. Both WKY + PZ and SHR groups exhibited iron deficiency in the serum and liver. Prazosin increased the iron levels in the bone tissue of SHRs. Prazosin stimulated the expression of hepcidin mRNA in the liver of SHRs and inhibited the expression of this iron‐regulatory hormone in WKY rats. FPN1 expression in the duodenum was increased significantly in SHRs, however markedly decreased after prazosin treatment. The expression of TLR4 and Ctsk was enhanced in the bone tissue of SHRs, whereas CLC‐7 expression was inhibited. Both hypotension and hypertension can lead to iron deficiency. Treatment with prazosin restored iron homeostasis in SHRs. The inverse impacts of prazosin on hepatic hepcidin expression in SHRs versus WKY rats indicates differing iron regulatory mechanisms between hypertensive and normal animals. The osteoclast activity was found to be enhanced in SHRs. Further study is needed to address whether the changes in osteoblast and osteoclast activity in SHRs correlates with the effects on iron metabolism.
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Affiliation(s)
- Hengrui Chang
- Department of Spinal Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China.,College of Life Science, Hebei Normal University, Shijiazhuang, Hebei, People's Republic of China
| | - Dong Zhang
- College of Life Science, Hebei Normal University, Shijiazhuang, Hebei, People's Republic of China
| | - Zhen Xin
- College of Life Science, Hebei Normal University, Shijiazhuang, Hebei, People's Republic of China
| | - Pengfei Zhang
- College of Life Science, Hebei Normal University, Shijiazhuang, Hebei, People's Republic of China
| | - Wenyuan Ding
- Department of Spinal Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
| | - Yan-Zhong Chang
- College of Life Science, Hebei Normal University, Shijiazhuang, Hebei, People's Republic of China
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22
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The Effect of Activated FXIII, a Transglutaminase, on Vascular Smooth Muscle Cells. Int J Mol Sci 2022; 23:ijms23105845. [PMID: 35628664 PMCID: PMC9144255 DOI: 10.3390/ijms23105845] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/18/2022] [Accepted: 05/20/2022] [Indexed: 02/06/2023] Open
Abstract
Plasma factor XIII (pFXIII) is a heterotetramer of FXIII-A and FXIII-B subunits. The cellular form (cFXIII), a dimer of FXIII-A, is present in a number of cell types. Activated FXIII (FXIIIa), a transglutaminase, plays an important role in clot stabilization, wound healing, angiogenesis and maintenance of pregnancy. It has a direct effect on vascular endothelial cells and fibroblasts, which have been implicated in the development of atherosclerotic plaques. Our aim was to explore the effect of FXIIIa on human aortic smooth muscle cells (HAoSMCs), another major cell type in the atherosclerotic plaque. Osteoblastic transformation induced by Pi and Ca2+ failed to elicit the expression of cFXIII in HAoSMCs. EZ4U, CCK-8 and CytoSelect Wound Healing assays were used to investigate cell proliferation and migration. The Sircol Collagen Assay Kit was used to monitor collagen secretion. Thrombospondin-1 (TSP-1) levels were measured by ELISA. Cell-associated TSP-1 was detected by the immunofluorescence technique. The TSP-1 mRNA level was estimated by RT-qPCR. Activated recombinant cFXIII (rFXIIIa) increased cell proliferation and collagen secretion. In parallel, a 67% decrease in TSP-1 concentration in the medium and a 2.5-fold increase in cells were observed. TSP-1 mRNA did not change significantly. These effects of FXIIIa might contribute to the pathogenesis of atherosclerotic plaques.
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23
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Machado SE, Spangler D, Black LM, Traylor AM, Balla J, Zarjou A. A Reproducible Mouse Model of Moderate CKD With Early Manifestations of Osteoblastic Transition of Cardiovascular System. Front Physiol 2022; 13:897179. [PMID: 35574469 PMCID: PMC9099146 DOI: 10.3389/fphys.2022.897179] [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: 03/15/2022] [Accepted: 04/13/2022] [Indexed: 12/02/2022] Open
Abstract
Chronic kidney disease (CKD) is a significant public health challenge with a substantial associated risk of mortality, morbidity, and health care expenditure. Culprits that lead to development and progression of CKD are multifaceted and heterogenous in nature. This notion underscores the need for diversification of animal models to investigate its pathophysiology, related complications, and to subsequently enable discovery of novel therapeutics. Importantly, animal models that could recapitulate complications of CKD in both genders are desperately needed. Cardiovascular disease is the most common cause of death in CKD patients that may be due in part to high prevalence of vascular calcification (VC). Using DBA/2 mice that are susceptible to development of VC, we sought to investigate the feasibility and reproducibility of a unilateral ischemia-reperfusion model followed by contralateral nephrectomy (UIRI/Nx) to induce CKD and its related complications in female and male mice. Our results demonstrate that irrespective of gender, mice faithfully displayed complications of moderate CKD following UIRI/Nx as evidenced by significant rise in serum creatinine, albuminuria, higher degree of collagen deposition, elevated expression of classic fibrotic markers, higher circulating levels of FGF-23, PTH and hepcidin. Moreover, we corroborate the osteoblastic transition of aortic smooth muscle cells and cardiomyocytes based on higher levels of osteoblastic markers namely, Cbfa-1, osteopontin, osteocalcin, and osterix. Our data confirms a viable, and consistent model of moderate CKD and its associated complications in both male and female mice. Furthermore, early evidence of osteoblastic transition of cardiovascular system in this model confirms its suitability for studying and implementing potential preventive and/or therapeutic approaches that are urgently needed in this field.
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Affiliation(s)
- Sarah E Machado
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Hungary
| | - Daryll Spangler
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Hungary
| | - Laurence M. Black
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Hungary
| | - Amie M. Traylor
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Hungary
| | - József Balla
- ELKH-UD Vascular Biology and Myocardial Pathophysiology Research Group, Division of Nephrology, Department of Medicine, Faculty of Medicine, Hungarian Academy of Sciences, University of Debrecen, Debrecen, Hungary
| | - Abolfazl Zarjou
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Hungary,*Correspondence: Abolfazl Zarjou,
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24
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Chowdhury A, Balogh E, Ababneh H, Tóth A, Jeney V. Activation of Nrf2/HO-1 Antioxidant Pathway by Heme Attenuates Calcification of Human Lens Epithelial Cells. Pharmaceuticals (Basel) 2022; 15:ph15050493. [PMID: 35631320 PMCID: PMC9145770 DOI: 10.3390/ph15050493] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/07/2022] [Accepted: 04/16/2022] [Indexed: 02/04/2023] Open
Abstract
Cataract, an opacification in the crystalline lens, is a leading cause of blindness. Deposition of hydroxyapatite occurs in a cataractous lens that could be the consequence of osteogenic differentiation of lens epithelial cells (LECs). Nuclear factor erythroid 2-related factor 2 (Nrf2) controls the transcription of a wide range of cytoprotective genes. Nrf2 upregulation attenuates cataract formation. Here we aimed to investigate the effect of Nrf2 system upregulation in LECs calcification. We induced osteogenic differentiation of human LECs (HuLECs) with increased phosphate and calcium-containing osteogenic medium (OM). OM-induced calcium and osteocalcin deposition in HuLECs. We used heme to activate Nrf2, which strongly upregulated the expression of Nrf2 and heme oxygenase-1 (HO-1). Heme-mediated Nrf2 activation was dependent on the production of reactive oxygens species. Heme inhibited Ca deposition, and the OM-induced increase of osteogenic markers, RUNX2, alkaline phosphatase, and OCN. Anti-calcification effect of heme was lost when the transcriptional activity of Nrf2 or the enzyme activity of HO-1 was blocked with pharmacological inhibitors. Among products of HO-1 catalyzed heme degradation iron mimicked the anti-calcification effect of heme. We concluded that heme-induced upregulation of the Nrf2/HO-1 system inhibits HuLECs calcification through the liberation of heme iron.
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Affiliation(s)
- Arpan Chowdhury
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.C.); (E.B.); (H.A.); (A.T.)
- Doctoral School of Molecular Cell and Immune Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Enikő Balogh
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.C.); (E.B.); (H.A.); (A.T.)
| | - Haneen Ababneh
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.C.); (E.B.); (H.A.); (A.T.)
- Doctoral School of Molecular Cell and Immune Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Andrea Tóth
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.C.); (E.B.); (H.A.); (A.T.)
- Doctoral School of Molecular Cell and Immune Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Viktória Jeney
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.C.); (E.B.); (H.A.); (A.T.)
- Correspondence:
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25
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Ren Y, Yang M, Wang X, Xu B, Xu Z, Su B. ELAV-like RNA binding protein 1 regulates osteogenesis in diabetic osteoporosis: Involvement of divalent metal transporter 1. Mol Cell Endocrinol 2022; 546:111559. [PMID: 35051552 DOI: 10.1016/j.mce.2022.111559] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 12/23/2021] [Accepted: 01/10/2022] [Indexed: 12/18/2022]
Abstract
Diabetic osteoporosis (DOP) is a complication of diabetes mellitus (DM) and occurs due to alterations in bone metabolism under hyperglycemic condition. ELAV-like RNA binding protein 1 (ELAVL1) is abnormally up-regulated in diabetes-related diseases. Bioinformatics prediction indicates that divalent metal transporter 1 (DMT1) is a potential target of ELAVL1. To explore the role of ELAVL1 and the involvement of ELAVL1/DMT1 axis in DOP, we established a mouse model of DM by administration of high-fat diet and intraperitoneal injection with streptozotocin (STZ). The expression of ELAVL1 and DMT1 was increased in the bone tissues of DM mice. Knockdown of ELAVL1 reduced iron level and oxidative stress, promoted osteogensis, and prevented bone mass loss, thus mitigating DOP in DM mice. In vitro, mouse pre-osteoblast MC3T3-E1 cells were treated with high glucose (25 mM) and ferric ammonium citrate (FAC, 200 μM). The inhibitory effects of ELAVL1 knockdown on iron accumulation and oxidative stress were evidenced in MC3T3-E1 cells. Knockdown of ELAVL1 enhanced osteoblast viability, differentiation and mineralization. Notably, the expression of DMT1 was positively correlated with that of ELAVL1 in vivo and in vitro. Overexpression of DMT1 abolished the effect of ELAVL1 knockdown on the behaviors of MC3T3-E1 cells, suggesting that ELAVL1 might function through regulating DMT1. In conclusion, knockdown of ELAVL1 likely alleviated DOP by inhibiting iron overload and oxidative stress and promoting osteogenesis, and DMT1 might be involved in this process. These findings provide insights into the pathogenesis of DOP and suggest a potential therapeutic target for DOP treatment.
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Affiliation(s)
- Yuanfei Ren
- Department of Orthopedics, The First Hospital of China Medical University, Shenyang, Liaoning, China; The First Department of Hand and Foot Surgery, Dalian Municipal Central Hospital, Dalian, Liaoning, China
| | - Maowei Yang
- Department of Orthopedics, The First Hospital of China Medical University, Shenyang, Liaoning, China.
| | - Xindong Wang
- Department of Orthopedics, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Buxuan Xu
- Department of Orthopedics, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zerong Xu
- Department of Orthopedics, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Bo Su
- Department of Orthopedics, The First Hospital of China Medical University, Shenyang, Liaoning, China
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26
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Yang K, Cao F, Xue Y, Tao L, Zhu Y. Three Classes of Antioxidant Defense Systems and the Development of Postmenopausal Osteoporosis. Front Physiol 2022; 13:840293. [PMID: 35309045 PMCID: PMC8927967 DOI: 10.3389/fphys.2022.840293] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 01/25/2022] [Indexed: 01/04/2023] Open
Abstract
Osteoporosis is a common bone imbalance disease that threatens the health of postmenopausal women. Estrogen deficiency accelerates the aging of women. Oxidative stress damage is regarded as the main pathogenesis of postmenopausal osteoporosis. The accumulation of reactive oxygen species in the bone microenvironment plays a role in osteoblast and osteoclast apoptosis. Improving the oxidative state is essential for the prevention and treatment of postmenopausal osteoporosis. There are three classes of antioxidant defense systems in the body to eliminate free radicals and peroxides including antioxidant substances, antioxidant enzymes, and repair enzymes. In our review, we demonstrated the mechanism of antioxidants and their effect on bone metabolism in detail. We concluded that glutathione/oxidized glutathione (GSH/GSSG) conversion involved the PI3K/Akt-Nrf2/HO-1 signaling pathway and that the antioxidant enzyme-mediated mitochondrial apoptosis pathway of osteoblasts was necessary for the development of postmenopausal osteoporosis. Since the current therapeutic effects of targeting bone cells are not significant, improving the systemic peroxidation state and then regulating bone homeostasis will be a new method for the treatment of postmenopausal osteoporosis.
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Affiliation(s)
- Keda Yang
- Department of Orthopedics, First Hospital of China Medical University, Shenyang, China
| | - Fangming Cao
- Department of Orthopedics, First Hospital of China Medical University, Shenyang, China
| | - Yuchuan Xue
- The First Department of Clinical Medicine, China Medical University, Shenyang, China
| | - Lin Tao
- Department of Orthopedics, First Hospital of China Medical University, Shenyang, China
- *Correspondence: Lin Tao,
| | - Yue Zhu
- Department of Orthopedics, First Hospital of China Medical University, Shenyang, China
- Yue Zhu,
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27
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Identification of Common Pathogenic Pathways Involved in Hemochromatosis Arthritis and Calcium Pyrophosphate Deposition Disease: a Review. Curr Rheumatol Rep 2022; 24:40-45. [PMID: 35143028 DOI: 10.1007/s11926-022-01054-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/03/2022] [Indexed: 12/15/2022]
Abstract
OBJECTIVES Arthritis is a common clinical manifestation of hereditary hemochromatosis (HH), and HH is one of a handful of conditions linked to calcium pyrophosphate deposition (CPPD) in joints. The connection between these two types of arthritis has not yet been fully elucidated. In light of new pathogenic pathways recently implicated in CPPD involving bone, we reviewed the literature on the etiology of hemochromatosis arthropathy (HHA) seeking shared pathogenic mechanisms. RESULTS Clinical observations reinforce striking similarities between HHA and CPPD even in the absence of CPP crystals. They share a similar joint distribution, low grade synovial inflammation, and generalized bone loss. Excess iron damages chondrocytes and bone cells in vitro. While direct effects of iron on cartilage are not consistently seen in animal models of HH, there is decreased osteoblast alkaline phosphatase activity, and increased osteoclastogenesis. These abnormalities are also seen in CPPD. Joint repair processes may also be impaired in both CPPD and HHA. CONCLUSIONS Possible shared pathogenic pathways relate more to bone and abnormal damage/repair mechanisms than direct damage to articular cartilage. While additional work is necessary to fully understand the pathogenesis of arthritis in HH and to firmly establish causal links with CPPD, this review provides some plausible hypotheses explaining the overlap of these two forms of arthritis.
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28
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Sanabria-de la Torre R, Martínez-Heredia L, González-Salvatierra S, Andújar-Vera F, Iglesias-Baena I, Villa-Suárez JM, Contreras-Bolívar V, Corbacho-Soto M, Martínez-Navajas G, Real PJ, García-Fontana C, Muñoz-Torres M, García-Fontana B. Characterization of Genetic Variants of Uncertain Significance for the ALPL Gene in Patients With Adult Hypophosphatasia. Front Endocrinol (Lausanne) 2022; 13:863940. [PMID: 35498405 PMCID: PMC9047899 DOI: 10.3389/fendo.2022.863940] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 03/14/2022] [Indexed: 11/29/2022] Open
Abstract
Hypophosphatasia (HPP) a rare disease caused by mutations in the ALPL gene encoding for the tissue-nonspecific alkaline phosphatase protein (TNSALP), has been identified as a potentially under-diagnosed condition worldwide which may have higher prevalence than currently established. This is largely due to the overlapping of its symptomatology with that of other more frequent pathologies. Although HPP is usually associated with deficient bone mineralization, the high genetic variability of ALPL results in high clinical heterogeneity, which makes it difficult to establish a specific HPP symptomatology. In the present study, three variants of ALPL gene with uncertain significance and no previously described (p.Del Glu23_Lys24, p.Pro292Leu and p.His379Asn) were identified in heterozygosis in patients diagnosed with HPP. These variants were characterized at phenotypic, functional and structural levels. All genetic variants showed significantly lower in vitro ALP activity than the wild-type (WT) genotype (p-value <0.001). Structurally, p.His379Asn variant resulted in the loss of two Zn2+ binding sites in the protein dimer which may greatly affect ALP activity. In summary, we identified three novel ALPL gene mutations associated with adult HPP. The correct identification and characterization of new variants and the subsequent study of their phenotype will allow the establishment of genotype-phenotype relationships that facilitate the management of the disease as well as making it possible to individualize treatment for each specific patient. This would allow the therapeutic approach to HPP to be personalized according to the unique genetic characteristics and clinical manifestations of each patient.
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Affiliation(s)
- Raquel Sanabria-de la Torre
- Department of Medicine, University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada, Granada, Spain
| | - Luis Martínez-Heredia
- Department of Medicine, University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada, Granada, Spain
| | - Sheila González-Salvatierra
- Department of Medicine, University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada, Granada, Spain
| | - Francisco Andújar-Vera
- Instituto de Investigación Biosanitaria de Granada, Granada, Spain
- Department of Computer Science and Artificial Intelligence, University of Granada, Granada, Spain
- Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI Institute), Granada, Spain
| | | | - Juan Miguel Villa-Suárez
- Instituto de Investigación Biosanitaria de Granada, Granada, Spain
- Clinical Analysis Unit, University Hospital Clínico San Cecilio, Granada, Spain
| | - Victoria Contreras-Bolívar
- Instituto de Investigación Biosanitaria de Granada, Granada, Spain
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, Granada, Spain
| | | | - Gonzalo Martínez-Navajas
- Gene Regulation, Stem Cells and Development Lab, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (GENYO), Granada, Spain
- Department of Biochemistry and Molecular Biology I, Faculty of Science, University of Granada, Granada, Spain
| | - Pedro J. Real
- Instituto de Investigación Biosanitaria de Granada, Granada, Spain
- Gene Regulation, Stem Cells and Development Lab, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (GENYO), Granada, Spain
- Department of Biochemistry and Molecular Biology I, Faculty of Science, University of Granada, Granada, Spain
| | - Cristina García-Fontana
- Instituto de Investigación Biosanitaria de Granada, Granada, Spain
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, Granada, Spain
- Biomedical Research Network in Fragility and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
- *Correspondence: Cristina García-Fontana, ; Manuel Muñoz-Torres,
| | - Manuel Muñoz-Torres
- Department of Medicine, University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada, Granada, Spain
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, Granada, Spain
- Biomedical Research Network in Fragility and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
- *Correspondence: Cristina García-Fontana, ; Manuel Muñoz-Torres,
| | - Beatriz García-Fontana
- Instituto de Investigación Biosanitaria de Granada, Granada, Spain
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, Granada, Spain
- Biomedical Research Network in Fragility and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
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29
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Guo Q, Li L, Hou S, Yuan Z, Li C, Zhang W, Zheng L, Li X. The Role of Iron in Cancer Progression. Front Oncol 2021; 11:778492. [PMID: 34858857 PMCID: PMC8631356 DOI: 10.3389/fonc.2021.778492] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 10/15/2021] [Indexed: 01/19/2023] Open
Abstract
Iron is an essential trace element for the human body, and its deficiency or excess can induce a variety of biological processes. Plenty of evidences have shown that iron metabolism is closely related to the occurrence and development of tumors. In addition, iron plays an important role in cell death, which is very important for the development of potential strategies for tumor treatment. Here, we reviewed the latest research about iron metabolism disorders in various types of tumors, the functions and properties of iron in ferroptosis and ferritinophagy, and new opportunities for iron-based on treatment methods for tumors, providing more information regarding the prevention and treatment of tumors.
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Affiliation(s)
- Qianqian Guo
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Liwen Li
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Shanshan Hou
- Department of Pharmacy, Zhejiang Pharmaceutical College, Ningbo, China
| | - Ziqiao Yuan
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Chenhui Li
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Wenzhou Zhang
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiaoman Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
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30
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Sun K, Guo Z, Hou L, Xu J, Du T, Xu T, Guo F. Iron homeostasis in arthropathies: From pathogenesis to therapeutic potential. Ageing Res Rev 2021; 72:101481. [PMID: 34606985 DOI: 10.1016/j.arr.2021.101481] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 08/25/2021] [Accepted: 09/29/2021] [Indexed: 02/08/2023]
Abstract
Iron is an essential element for proper functioning of cells within mammalian organ systems; in particular, iron homeostasis is critical for joint health. Excess iron can induce oxidative stress damage, associated with the pathogenesis of iron-storage and ageing-related diseases. Therefore, iron levels in body tissues and cells must be tightly regulated. In the past decades, excess iron content within joints has been found in some patients with joint diseases including hemophilic arthropathy, hemochromatosis arthropathy, and osteoarthritis (OA). Currently, increased evidence has shown that iron accumulation is closely associated with multiple pathological changes of these arthropathies. This review summarizes system-level and intracellular regulation of iron homeostasis, and emphasizes the role of iron in synovial alterations, cartilage degeneration, and subchondral bone of several arthropathies. Of note, we discuss the potential link between iron homeostasis and OA pathogenesis. Finally, we discuss the therapeutic potential of maintaining iron homeostasis in these arthropathies.
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Valanezhad A, Odatsu T, Abe S, Watanabe I. Bone Formation Ability and Cell Viability Enhancement of MC3T3-E1 Cells by Ferrostatin-1 a Ferroptosis Inhibitor of Cancer Cells. Int J Mol Sci 2021; 22:ijms222212259. [PMID: 34830144 PMCID: PMC8620900 DOI: 10.3390/ijms222212259] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 11/09/2021] [Accepted: 11/10/2021] [Indexed: 01/31/2023] Open
Abstract
Recently, ferroptosis has gained scientists’ attention as an iron-related regulated necrosis. However, not many reports have investigated the effect of ferroptosis on bone. Therefore, with the present study, we assessed the effect of ferroptosis inhibition using ferrostatin-1 on the MC3T3-E1 pre-osteoblast cell. Cell images, cell viability, alkaline phosphatase activity test, alizarin red staining, and RUNX2 gene expression using real-time PCR were applied to investigate the effects of ferrostatin and erastin on MC3T3-E1 osteoblast cells. Erastin was used as a well-known ferroptosis inducer reagent. Erastin with different concentrations ranging from 0 to 50 µmol/L was used for inducing cell death. The 25 µmol/L erastin led to controllable partial cell death on osteoblast cells. Ferrostatin-1 with 0 to 40 µmol/L was used for cell doping and cell death inhibition effect. Ferrostatin-1 also displayed a recovery effect on the samples, which had already received the partially artificial cell death by erastin. Cell differentiation, alizarin red staining, and RUNX2 gene expression confirmed the promotion of the bone formation ability effect of ferrostatin-1 on osteoblast cells. The objective of this study was to assess ferrostatin-1’s effect on the MC3T3-E1 osteoblast cell line based on its ferroptosis inhibitory property.
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Affiliation(s)
- Alireza Valanezhad
- Department of Dental and Biomedical Materials Science, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan; (S.A.); (I.W.)
- Correspondence: (A.V.); (T.O.)
| | - Tetsurou Odatsu
- Department of Applied Prosthodontics, Institute of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan
- Correspondence: (A.V.); (T.O.)
| | - Shigeaki Abe
- Department of Dental and Biomedical Materials Science, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan; (S.A.); (I.W.)
| | - Ikuya Watanabe
- Department of Dental and Biomedical Materials Science, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan; (S.A.); (I.W.)
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Md Yusop AH, Ulum MF, Al Sakkaf A, Hartanto D, Nur H. Insight into the bioabsorption of Fe-based materials and their current developments in bone applications. Biotechnol J 2021; 16:e2100255. [PMID: 34520117 DOI: 10.1002/biot.202100255] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 09/09/2021] [Accepted: 09/11/2021] [Indexed: 11/10/2022]
Abstract
Iron (Fe) and Fe-based materials have been vigorously explored in orthopedic applications in the past decade mainly owing to their promising mechanical properties including high yield strength, elastic modulus and ductility. Nevertheless, their corrosion products and low corrosion kinetics are the major concerns that need to be improved further despite their appealing mechanical strengths. The current studies on porous Fe-based scaffolds show an improved corrosion rate but the in vitro biocompatibility is still problematic in general. Unlike the Mg implants, the biodegradation and bioabsorption of Fe-based implants are still not well described. This vague issue could implicate the development of Fe-based materials as potential medical implants as they have not reached the clinical trial stage yet. Thus, there is a need to understand in-depth the Fe corrosion behavior and its bioabsorption mechanism to facilitate the material design of Fe-based scaffolds and further improve its biocompatibility. This manuscript provides an important insight into the basic bioabsorption of the multi-ranged Fe-based corrosion products with a review of the latest progress on the corrosion & in vitro biocompatibility of porous Fe-based scaffolds together with the remaining challenges and the perspective on the future direction.
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Affiliation(s)
- Abdul Hakim Md Yusop
- Center for Sustainable Nanomaterials, Ibnu Sina Institute for Scientific and Industrial Research, Universiti Teknologi Malaysia, Skudai, Johor, Malaysia
| | | | - Ahmed Al Sakkaf
- School of Mechanical Engineering, Universiti Teknologi Malaysia, Skudai, Johor, Malaysia
| | - Djoko Hartanto
- Department of Chemistry, Institut Teknologi Sepuluh Nopember, Surabaya, Indonesia
| | - Hadi Nur
- Center for Sustainable Nanomaterials, Ibnu Sina Institute for Scientific and Industrial Research, Universiti Teknologi Malaysia, Skudai, Johor, Malaysia.,Center of Advanced Materials for Renewable Energy (CAMRY), Universiti Negeri Malang, Malang, Indonesia
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Liu LL, Liu GW, Liu H, Zhao K, Xu YJ. Iron accumulation deteriorated bone loss in estrogen-deficient rats. J Orthop Surg Res 2021; 16:525. [PMID: 34429140 PMCID: PMC8383398 DOI: 10.1186/s13018-021-02663-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 08/11/2021] [Indexed: 12/15/2022] Open
Abstract
Background Postmenopausal osteoporosis is characterized by an imbalance of bone resorption exceeding bone formation, resulting in a net loss of bone mass. Whether a menopause-related excess of iron contributes to the development of postmenopausal osteoporosis has remained unresolved due to a lack of an appropriate animal model. This study aimed to explore the effects of iron accumulation in bone mass in estrogen-deficient rats. Methods In the present study, ovariectomy (OVX) was performed in female rats and the changes of iron metabolism and some related modulated genes were detected. Ferric ammonium citrate (FAC) was used as a donor of iron for OVX rats. Moreover, micro-CT was performed to assess the bone microarchitecture in sham group, OVX, and FAC groups. Histological detection of iron in liver was assessed by Perl’s staining. The expressions of β-CTX and osteocalcin were assessed by ELISA. Results It was found that serum iron decreased after OVX. It was found that the expressions of Hepcidin in liver and Fpn, DMT-1 in duodenum significantly decreased at transcriptional level in OVX group than sham group. However, no difference existed in the expression of DMT-1. Then, ferric ammonium citrate (FAC) was used as a donor of iron for OVX rats. The FAC group manifested significant iron accumulation by increased serum iron and hepatic iron content. In addition, FAC treatment accelerated bone loss and decreased BMD and biomechanics in OVX rats. Moreover, bone biomarker β-CTX rather than osteocalcin increased significantly in FAC groups than OVX group. Conclusions In conclusion, no iron accumulation occurred in OVX rats. Furthermore, iron accumulation could further deteriorate osteopenia through enhanced bone resorption.
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Affiliation(s)
- Lu-Lin Liu
- Department of Orthopedics, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, China.,Department of Orthopedics, Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, China
| | - Gong-Wen Liu
- Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, 215009, Jiangsu, China
| | - Hui Liu
- Department of Orthopedics, Ganxian District Traditional Chinese Medicine Hospital of Ganzhou City, Ganzhou, 341100, Jiangxi, China
| | - Kai Zhao
- Department of Orthopedics, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, China
| | - You-Jia Xu
- Department of Orthopedics, Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, China.
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Vinchi F. Non-Transferrin-Bound Iron in the Spotlight: Novel Mechanistic Insights into the Vasculotoxic and Atherosclerotic Effect of Iron. Antioxid Redox Signal 2021; 35:387-414. [PMID: 33554718 PMCID: PMC8328045 DOI: 10.1089/ars.2020.8167] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 01/06/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022]
Abstract
Significance: While atherosclerosis is an almost inevitable consequence of aging, food preferences, lack of exercise, and other aspects of the lifestyle in many countries, the identification of new risk factors is of increasing importance to tackle a disease, which has become a major health burden for billions of people. Iron has long been suspected to promote the development of atherosclerosis, but data have been conflicting, and the contribution of iron is still debated controversially. Recent Advances: Several experimental and clinical studies have been recently published about this longstanding controversial problem, highlighting the critical need to unravel the complexity behind this topic. Critical Issues: The aim of the current review is to provide an overview of the current knowledge about the proatherosclerotic impact of iron, and discuss the emerging role of non-transferrin-bound iron (NTBI) as driver of vasculotoxicity and atherosclerosis. Finally, I will provide detailed mechanistic insights on the cellular processes and molecular pathways underlying iron-exacerbated atherosclerosis. Overall, this review highlights a complex framework where NTBI acts at multiple levels in atherosclerosis by altering the serum and vascular microenvironment in a proatherogenic and proinflammatory manner, affecting the functionality and survival of vascular cells, promoting foam cell formation and inducing angiogenesis, calcification, and plaque destabilization. Future Directions: The use of additional iron markers (e.g., NTBI) may help adequately predict predisposition to cardiovascular disease. Clinical studies are needed in the aging population to address the atherogenic role of iron fluctuations within physiological limits and the therapeutic value of iron restriction approaches. Antioxid. Redox Signal. 35, 387-414.
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Affiliation(s)
- Francesca Vinchi
- Iron Research Program, Lindsley F. Kimball Research Institute (LFKRI), New York Blood Center (NYBC), New York, New York, USA
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Cornell University, New York, New York, USA
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Shi L, Lin CL, Su CH, Lin KC, Leong KH, Wang YTT, Kuo CF, Tsai SY. The Risk of Developing Osteoporosis in Hemolytic Anemia-What Aggravates the Bone Loss? J Clin Med 2021; 10:jcm10153364. [PMID: 34362147 PMCID: PMC8348015 DOI: 10.3390/jcm10153364] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 01/05/2023] Open
Abstract
Hemolytic anemia (HA) renders erythropoietic stress on the bone marrow and has been linked to osteoporosis. In this nationwide retrospective cohort study, we examined this correlation by utilizing the Taiwan National Health Insurance Research Database (NHIRD). We identified two cohorts, matching population with and without HA in a 1:4 ratio. A total of 2242 HA patients and 8968 non-HA patients were enrolled. Patients with HA had a significantly higher cumulative incidence (log-rank test p = 0.0073), higher incidence density (5.11 vs. 3.76 per 1000 persons-years), and a 1.31-fold risk of developing osteoporosis than non-HA patients (aHR = 1.31, 95% C.I. 1.04-1.63, p = 0.01). After adjusting for age, sex, and comorbidities, patients with factors including female (aHR = 2.57, 95% C.I. 2.05-3.22, p < 0.001), age > 65 (aHR = 9.25, 95% C.I. 7.46-11.50, p < 0.001), diagnosis of cholelithiasis (aHR = 1.76, 95% C.I. 1.20-2.58, p = 0.003) and peptic ulcer disease (aHR = 1.87, 95% C.I. 1.52-2.29, p < 0.001) had significantly higher risk of osteoporosis. We propose that this correlation may be related to increased hematopoietic stress, increased consumption of nitric oxide (NO) by hemolysis, and the inhibitory effects of iron supplements on osteogenesis through the receptor activator of nuclear factor κB ligand (RANKL)/Osteoprotegerin pathway and the Runt-related transcription factor 2 (RUNX2) factor. Our findings suggest that patients with hemolytic anemia are at a higher risk of developing osteoporosis, and it would be in the patient's best interest for physicians to be aware of this potential complication and offer preventative measures.
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Affiliation(s)
- Leiyu Shi
- Department of Health Policy and Management, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA;
| | - Cheng-Li Lin
- College of Medicine, China Medical University, Taichung City 404, Taiwan;
| | - Ching-Huang Su
- Department of Laboratory Medicine, Mackay Memorial Hospital, Taipei City 104, Taiwan; (C.-H.S.); (K.-C.L.); (K.-H.L.); (Y.-T.T.W.)
| | - Keng-Chian Lin
- Department of Laboratory Medicine, Mackay Memorial Hospital, Taipei City 104, Taiwan; (C.-H.S.); (K.-C.L.); (K.-H.L.); (Y.-T.T.W.)
| | - Kam-Hang Leong
- Department of Laboratory Medicine, Mackay Memorial Hospital, Taipei City 104, Taiwan; (C.-H.S.); (K.-C.L.); (K.-H.L.); (Y.-T.T.W.)
| | - Yu-Ting Tina Wang
- Department of Laboratory Medicine, Mackay Memorial Hospital, Taipei City 104, Taiwan; (C.-H.S.); (K.-C.L.); (K.-H.L.); (Y.-T.T.W.)
| | - Chien-Feng Kuo
- Division of Infectious Diseases, Department of Internal Medicine, Mackay Memorial Hospital, Taipei City 104, Taiwan;
- Department of Medicine, Mackay Medical College, New Taipei City 25245, Taiwan
- Department of Cosmetic Applications and Management, MacKay Junior College of Medicine, Nursing and Management, New Taipei City 25245, Taiwan
| | - Shin-Yi Tsai
- Department of Health Policy and Management, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA;
- Department of Laboratory Medicine, Mackay Memorial Hospital, Taipei City 104, Taiwan; (C.-H.S.); (K.-C.L.); (K.-H.L.); (Y.-T.T.W.)
- Department of Medicine, Mackay Medical College, New Taipei City 25245, Taiwan
- Graduate Institute of Long-Term Care, Mackay Medical College, New Taipei City 25245, Taiwan
- Graduate Institute of Biomedical Sciences, Mackay Medical College, New Taipei City 25245, Taiwan
- Correspondence: ; Tel.: +886-975-835-797 or +886-915-309-666
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Donato M, Faggin E, Cinetto F, Felice C, Lupo MG, Ferri N, Rattazzi M. The Emerging Role of Nutraceuticals in Cardiovascular Calcification: Evidence from Preclinical and Clinical Studies. Nutrients 2021; 13:nu13082603. [PMID: 34444763 PMCID: PMC8401694 DOI: 10.3390/nu13082603] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/22/2021] [Accepted: 07/27/2021] [Indexed: 02/03/2023] Open
Abstract
Cardiovascular calcification is the ectopic deposition of calcium-phosphate crystals within the arterial wall and the aortic valve leaflets. This pathological process leads to increased vascular stiffness, reduced arterial elasticity, and aortic valve stenosis, increasing the risk of cardiovascular diseases. Although cardiovascular calcification is an increasing health care burden, to date no medical therapies have been approved for treating or preventing it. Considering the current lack of therapeutic strategies and the increasing prevalence of cardiovascular calcification, the investigation of some nutraceuticals to prevent this pathological condition has become prevalent in recent years. Recent preclinical and clinical studies evaluated the potential anti-calcific role of nutraceuticals (including magnesium, zinc, iron, vitamin K, and phytate) in the progression of vascular calcification, providing evidence for their dietary supplementation, especially in high-risk populations. The present review summarizes the current knowledge and latest advances for nutraceuticals with the most relevant preclinical and clinical data, including magnesium, zinc, iron, vitamin K, and phytate. Their supplementation might be recommended as a cost-effective strategy to avoid nutritional deficiency and to prevent or treat cardiovascular calcification. However, the optimal dose of nutraceuticals has not been identified and large interventional trials are warranted to support their protective effects on cardiovascular disease.
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Affiliation(s)
- Maristella Donato
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35122 Padua, Italy; (M.D.); (M.G.L.); (N.F.)
| | - Elisabetta Faggin
- Department of Medicine—DIMED, University of Padova, 35122 Padua, Italy; (E.F.); (F.C.); (C.F.)
| | - Francesco Cinetto
- Department of Medicine—DIMED, University of Padova, 35122 Padua, Italy; (E.F.); (F.C.); (C.F.)
- Medicina Generale I^, Ca’ Foncello Hospital, 31100 Treviso, Italy
| | - Carla Felice
- Department of Medicine—DIMED, University of Padova, 35122 Padua, Italy; (E.F.); (F.C.); (C.F.)
- Medicina Generale I^, Ca’ Foncello Hospital, 31100 Treviso, Italy
| | - Maria Giovanna Lupo
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35122 Padua, Italy; (M.D.); (M.G.L.); (N.F.)
| | - Nicola Ferri
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35122 Padua, Italy; (M.D.); (M.G.L.); (N.F.)
| | - Marcello Rattazzi
- Department of Medicine—DIMED, University of Padova, 35122 Padua, Italy; (E.F.); (F.C.); (C.F.)
- Medicina Generale I^, Ca’ Foncello Hospital, 31100 Treviso, Italy
- Correspondence: ; Tel.: +39-04-9821-1867 or +39-04-2232-2207
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Nováková S, Danchenko M, Okajčeková T, Baranovičová E, Kováč A, Grendár M, Beke G, Pálešová J, Strnádel J, Janíčková M, Halašová E, Škovierová H. Comparative Proteomic and Metabolomic Analysis of Human Osteoblasts, Differentiated from Dental Pulp Stem Cells, Hinted Crucial Signaling Pathways Promoting Osteogenesis. Int J Mol Sci 2021; 22:ijms22157908. [PMID: 34360674 PMCID: PMC8347416 DOI: 10.3390/ijms22157908] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/18/2021] [Accepted: 07/20/2021] [Indexed: 12/11/2022] Open
Abstract
Population aging has been a global trend for the last decades, which increases the pressure to develop new cell-based or drug-based therapies, including those that may cure bone diseases. To understand molecular processes that underlie bone development and turnover, we followed osteogenic differentiation of human dental pulp stem cells (DPSCs) using a specific induction medium. The differentiation process imitating in vivo osteogenesis is triggered by various signaling pathways and is associated with massive proteome and metabolome changes. Proteome was profiled by ultrahigh-performance liquid chromatography and comprehensively quantified by ion mobility-enhanced mass spectrometry. From 2667 reproducibly quantified and identified proteins, 432 were differentially abundant by strict statistic criteria. Metabolome profiling was carried out by nuclear magnetic resonance. From 27 detected metabolites, 8 were differentially accumulated. KEGG and MetaboAnalyst hinted metabolic pathways that may be involved in the osteogenic process. Enrichment analysis of differentially abundant proteins highlighted PPAR, FoxO, JAK-STAT, IL-17 signaling pathways, biosynthesis of thyroid hormones and steroids, mineral absorption, and fatty acid metabolism as processes with prominent impact on osteoinduction. In parallel, metabolomic data showed that aminoacyl-tRNA biosynthesis, as well as specific amino acids, likely promote osteodifferentiation. Targeted immunoassays validated and complemented omic results. Our data underlined the complexity of the osteogenic mechanism. Finally, we proposed promising targets for future validation in patient samples, a step toward the treatment of bone defects.
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Affiliation(s)
- Slavomíra Nováková
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava (JFM CU), Malá Hora 4C, 036 01 Martin, Slovakia; (T.O.); (E.B.); (M.G.); (J.P.); (J.S.); (E.H.)
- Correspondence: (S.N.); (H.Š.); Tel.: +421-43-2633-904 (S.N.); +421-43-2633-904 (H.Š.)
| | - Maksym Danchenko
- Plant Science and Biodiversity Center, Slovak Academy of Sciences, Dúbravská cesta 9, 845 23 Bratislava, Slovakia;
| | - Terézia Okajčeková
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava (JFM CU), Malá Hora 4C, 036 01 Martin, Slovakia; (T.O.); (E.B.); (M.G.); (J.P.); (J.S.); (E.H.)
| | - Eva Baranovičová
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava (JFM CU), Malá Hora 4C, 036 01 Martin, Slovakia; (T.O.); (E.B.); (M.G.); (J.P.); (J.S.); (E.H.)
| | - Andrej Kováč
- Institute of Neuroimmunology, Slovak Academy of Sciences, Dúbravská cesta 9, 845 10 Bratislava, Slovakia;
| | - Marián Grendár
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava (JFM CU), Malá Hora 4C, 036 01 Martin, Slovakia; (T.O.); (E.B.); (M.G.); (J.P.); (J.S.); (E.H.)
| | - Gábor Beke
- Institute of Molecular Biology, Slovak Academy of Sciences, Dúbravská cesta 21, 845 51 Bratislava, Slovakia;
| | - Janka Pálešová
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava (JFM CU), Malá Hora 4C, 036 01 Martin, Slovakia; (T.O.); (E.B.); (M.G.); (J.P.); (J.S.); (E.H.)
| | - Ján Strnádel
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava (JFM CU), Malá Hora 4C, 036 01 Martin, Slovakia; (T.O.); (E.B.); (M.G.); (J.P.); (J.S.); (E.H.)
| | - Mária Janíčková
- Department of Stomatology and Maxillofacial Surgery, University Hospital in Martin and JFM CU, Kollárova 2, 036 01 Martin, Slovakia;
| | - Erika Halašová
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava (JFM CU), Malá Hora 4C, 036 01 Martin, Slovakia; (T.O.); (E.B.); (M.G.); (J.P.); (J.S.); (E.H.)
- Department of Medical Biology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava (JFM CU), Malá Hora 4C, 036 01 Martin, Slovakia
| | - Henrieta Škovierová
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava (JFM CU), Malá Hora 4C, 036 01 Martin, Slovakia; (T.O.); (E.B.); (M.G.); (J.P.); (J.S.); (E.H.)
- Correspondence: (S.N.); (H.Š.); Tel.: +421-43-2633-904 (S.N.); +421-43-2633-904 (H.Š.)
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Ledesma-Colunga MG, Weidner H, Vujic Spasic M, Hofbauer LC, Baschant U, Rauner M. Shaping the bone through iron and iron-related proteins. Semin Hematol 2021; 58:188-200. [PMID: 34389111 DOI: 10.1053/j.seminhematol.2021.06.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/18/2021] [Accepted: 06/08/2021] [Indexed: 01/04/2023]
Abstract
Well-controlled iron levels are indispensable for health. Iron deficiency is the most common cause of anemia, whereas iron overload, either hereditary or secondary due to disorders of ineffective erythropoiesis, causes widespread organ failure. Bone is particularly sensitive to fluctuations in systemic iron levels as both iron deficiency and overload are associated with low bone mineral density and fragility. Recent studies have shown that not only iron itself, but also iron-regulatory proteins that are mutated in hereditary hemochromatosis can control bone mass. This review will summarize the current knowledge on the effects of iron on bone homeostasis and bone cell activities, and on the role of proteins that regulate iron homeostasis, i.e. hemochromatosis proteins and proteins of the bone morphogenetic protein pathway, on bone remodeling. As disorders of iron homeostasis are closely linked to bone fragility, deeper insights into common regulatory mechanisms may provide new opportunities to concurrently treat disorders affecting iron homeostasis and bone.
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Affiliation(s)
- Maria G Ledesma-Colunga
- Divisions of Endocrinology and Molecular Bone Biology, Department of Medicine III & University Center for Healty Aging, Technische Universität Dresden, Dresden, Germany
| | - Heike Weidner
- Divisions of Endocrinology and Molecular Bone Biology, Department of Medicine III & University Center for Healty Aging, Technische Universität Dresden, Dresden, Germany
| | - Maja Vujic Spasic
- Institute of Comparative Molecular Endocrinology, Ulm University, Ulm, Germany
| | - Lorenz C Hofbauer
- Divisions of Endocrinology and Molecular Bone Biology, Department of Medicine III & University Center for Healty Aging, Technische Universität Dresden, Dresden, Germany
| | - Ulrike Baschant
- Divisions of Endocrinology and Molecular Bone Biology, Department of Medicine III & University Center for Healty Aging, Technische Universität Dresden, Dresden, Germany
| | - Martina Rauner
- Divisions of Endocrinology and Molecular Bone Biology, Department of Medicine III & University Center for Healty Aging, Technische Universität Dresden, Dresden, Germany.
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Wu H, Yu M, Xiao C, Zhang Q, Xiao X. Clinical characteristics of endocrinopathies in Chinese patients with hereditary haemochromatosis. Diabetes Metab Res Rev 2021; 37:e3448. [PMID: 33738915 DOI: 10.1002/dmrr.3448] [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: 07/09/2020] [Revised: 12/22/2020] [Accepted: 02/07/2021] [Indexed: 11/09/2022]
Abstract
AIMS Hereditary haemochromatosis (HH) is a genetic disorder characterised by systemic iron overload and can lead to end-organ failure. However, very few data on this disorder, especially those on endocrine gland involvement in Chinese populations, are currently available. This study aimed to analyse the clinical features of endocrinopathies in patients with HH to generate concern among endocrinologists and improve the management of this disorder. MATERIALS AND METHODS Chinese patients with HH-related endocrine dysfunction were enrolled at Peking Union Medical College Hospital from January 2010 to December 2018. All clinical data were analysed and summarised. RESULTS A total of six patients were enrolled in this study, comprising five men and one woman; the average age was 36.5 ± 13.3 years. Mean serum ferritin concentration was 4508.8 ± 1074.3 ng/ml, and median transferrin saturation was 97.9% (96.6%-110.0%). Endocrine gland involvement associated with HH included the pancreas (5/6 patients), the adenohypophysis (5/6 patients) and the bones (1/6 patients); secondary endocrinopathies consisted of diabetes mellitus, hypogonadism, adrenal insufficiency and osteoporosis. Based on phlebotomy and iron chelation therapy, five patients were treated with exogenous insulin preparations, and three patients were treated with exogenous sex hormone replacement therapy. The clinical symptoms of five patients improved, although one patient died of hepatic encephalopathy and multiple organ failure. CONCLUSIONS HH can cause multiple endocrinopathies. The possibility of HH should be carefully considered in patients with endocrine gland dysfunctions and concomitant elevated serum ferritin levels. Endocrine gland function should also be assessed and followed up in patients with a clear diagnosis of HH.
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Affiliation(s)
- Han Wu
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Miao Yu
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Cheng Xiao
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Qian Zhang
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xinhua Xiao
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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Jiang S, Wang M, He J. A review of biomimetic scaffolds for bone regeneration: Toward a cell-free strategy. Bioeng Transl Med 2021; 6:e10206. [PMID: 34027093 PMCID: PMC8126827 DOI: 10.1002/btm2.10206] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 11/05/2020] [Accepted: 11/12/2020] [Indexed: 12/20/2022] Open
Abstract
In clinical terms, bone grafting currently involves the application of autogenous, allogeneic, or xenogeneic bone grafts, as well as natural or artificially synthesized materials, such as polymers, bioceramics, and other composites. Many of these are associated with limitations. The ideal scaffold for bone tissue engineering should provide mechanical support while promoting osteogenesis, osteoconduction, and even osteoinduction. There are various structural complications and engineering difficulties to be considered. Here, we describe the biomimetic possibilities of the modification of natural or synthetic materials through physical and chemical design to facilitate bone tissue repair. This review summarizes recent progresses in the strategies for constructing biomimetic scaffolds, including ion-functionalized scaffolds, decellularized extracellular matrix scaffolds, and micro- and nano-scale biomimetic scaffold structures, as well as reactive scaffolds induced by physical factors, and other acellular scaffolds. The fabrication techniques for these scaffolds, along with current strategies in clinical bone repair, are described. The developments in each category are discussed in terms of the connection between the scaffold materials and tissue repair, as well as the interactions with endogenous cells. As the advances in bone tissue engineering move toward application in the clinical setting, the demonstration of the therapeutic efficacy of these novel scaffold designs is critical.
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Affiliation(s)
- Sijing Jiang
- Department of Plastic SurgeryFirst Affiliated Hospital of Anhui Medical University, Anhui Medical UniversityHefeiChina
| | - Mohan Wang
- Stomatologic Hospital & College, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui ProvinceHefeiChina
| | - Jiacai He
- Stomatologic Hospital & College, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui ProvinceHefeiChina
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Musculoskeletal complications associated with pathological iron toxicity and its molecular mechanisms. Biochem Soc Trans 2021; 49:747-759. [PMID: 33929529 DOI: 10.1042/bst20200672] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 04/12/2021] [Accepted: 04/13/2021] [Indexed: 12/25/2022]
Abstract
Iron is fundamental for several biological functions, but when in excess can lead to the development of toxic events. Some tissues and cells are more susceptible than others, but systemic iron levels can be controlled by treating patients with iron-chelating molecules and phlebotomy. An early diagnostic can be decisive to limit the progression of musculoskeletal complications like osteoarthritis and osteoporosis because of iron toxicity. In iron-related osteoarthritis, aggravation can be associated to a few events that can contribute to joints articular cartilage exposure to high iron concentrations, which can promote articular degeneration with very little chance of tissue regeneration. In contrast, bone metabolism is much more dynamic than cartilage, but progressive iron accumulation and ageing can be decisive factors for bone health. The iron overload associated with hereditary diseases like hemochromatosis, hemophilias, thalassemias and other hereditary anaemias increase the negative impact of iron toxicity in joints and bone, as well as in life quality, even when iron levels can be controlled. The molecular mechanisms by which iron can compromise cartilage and bone have been illusive and only in the last 20 years studies have started to shed some light into the molecular mechanisms associated with iron toxicity. Ferroptosis and the regulation of intracellular iron levels is instrumental in the balance between detoxification and induced cell death. In addition, these complications are accompanied with multiple susceptibility factors that can aggravate iron toxicity and should be identified. Therefore, understanding tissues microenvironment and cell communication is fundamental to contextualize iron toxicity.
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Hypophosphatasia: A Unique Disorder of Bone Mineralization. Int J Mol Sci 2021; 22:ijms22094303. [PMID: 33919113 PMCID: PMC8122659 DOI: 10.3390/ijms22094303] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/18/2021] [Accepted: 04/19/2021] [Indexed: 12/25/2022] Open
Abstract
Hypophosphatasia (HPP) is a rare genetic disease characterized by a decrease in the activity of tissue non-specific alkaline phosphatase (TNSALP). TNSALP is encoded by the ALPL gene, which is abundantly expressed in the skeleton, liver, kidney, and developing teeth. HPP exhibits high clinical variability largely due to the high allelic heterogeneity of the ALPL gene. HPP is characterized by multisystemic complications, although the most common clinical manifestations are those that occur in the skeleton, muscles, and teeth. These complications are mainly due to the accumulation of inorganic pyrophosphate (PPi) and pyridoxal-5′-phosphate (PLP). It has been observed that the prevalence of mild forms of the disease is more than 40 times the prevalence of severe forms. Patients with HPP present at least one mutation in the ALPL gene. However, it is known that there are other causes that lead to decreased alkaline phosphatase (ALP) levels without mutations in the ALPL gene. Although the phenotype can be correlated with the genotype in HPP, the prediction of the phenotype from the genotype cannot be made with complete certainty. The availability of a specific enzyme replacement therapy for HPP undoubtedly represents an advance in therapeutic strategy, especially in severe forms of the disease in pediatric patients.
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Balogh E, Chowdhury A, Ababneh H, Csiki DM, Tóth A, Jeney V. Heme-Mediated Activation of the Nrf2/HO-1 Axis Attenuates Calcification of Valve Interstitial Cells. Biomedicines 2021; 9:biomedicines9040427. [PMID: 33920891 PMCID: PMC8071288 DOI: 10.3390/biomedicines9040427] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/06/2021] [Accepted: 04/13/2021] [Indexed: 12/24/2022] Open
Abstract
Calcific aortic valve stenosis (CAVS) is a heart disease characterized by the progressive fibro-calcific remodeling of the aortic valves, an actively regulated process with the involvement of the reactive oxygen species-mediated differentiation of valvular interstitial cells (VICs) into osteoblast-like cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of a variety of antioxidant genes, and plays a protective role in valve calcification. Heme oxygenase-1 (HO-1), an Nrf2-target gene, is upregulated in human calcified aortic valves. Therefore, we investigated the effect of Nrf2/HO-1 axis in VIC calcification. We induced osteogenic differentiation of human VICs with elevated phosphate and calcium-containing osteogenic medium (OM) in the presence of heme. Heme inhibited Ca deposition and OM-induced increase in alkaline phosphatase and osteocalcin (OCN) expression. Heme induced Nrf2 and HO-1 expression in VICs. Heme lost its anti-calcification potential when we blocked transcriptional activity Nrf2 or enzyme activity of HO-1. The heme catabolism products bilirubin, carbon monoxide, and iron, and also ferritin inhibited OM-induced Ca deposition and OCN expression in VICs. This study suggests that heme-mediated activation of the Nrf2/HO-1 pathway inhibits the calcification of VICs. The anti-calcification effect of heme is attributed to the end products of HO-1-catalyzed heme degradation and ferritin.
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Affiliation(s)
- Enikő Balogh
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (E.B.); (A.C.); (H.A.); (D.M.C.); (A.T.)
| | - Arpan Chowdhury
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (E.B.); (A.C.); (H.A.); (D.M.C.); (A.T.)
- Doctoral School of Molecular Cell and Immune Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Haneen Ababneh
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (E.B.); (A.C.); (H.A.); (D.M.C.); (A.T.)
- Doctoral School of Molecular Cell and Immune Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Dávid Máté Csiki
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (E.B.); (A.C.); (H.A.); (D.M.C.); (A.T.)
- Doctoral School of Molecular Cell and Immune Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Andrea Tóth
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (E.B.); (A.C.); (H.A.); (D.M.C.); (A.T.)
- Doctoral School of Molecular Cell and Immune Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Viktória Jeney
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (E.B.); (A.C.); (H.A.); (D.M.C.); (A.T.)
- Correspondence:
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Mehta KJ. Role of iron and iron-related proteins in mesenchymal stem cells: Cellular and clinical aspects. J Cell Physiol 2021; 236:7266-7289. [PMID: 33821487 DOI: 10.1002/jcp.30383] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 03/17/2021] [Accepted: 03/19/2021] [Indexed: 12/14/2022]
Abstract
Mesenchymal stem cells (MSCs) are located in various tissues where these cells show niche-dependent multilineage differentiation and secrete immunomodulatory molecules to support numerous physiological processes. Due to their regenerative and reparative properties, MSCs are extremely valuable for cell-based therapy in tackling several pathological conditions including COVID-19. Iron is essential for MSC processes but iron-loading, which is common in several chronic conditions, hinders normal MSC functionality. This not only aggravates disease pathology but can also affect allogeneic and autologous MSC therapy. Thus, understanding MSCs from an iron perspective is of clinical significance. Accordingly, this review highlights the roles of iron and iron-related proteins in MSC physiology. It describes the contribution of iron and endogenous iron-related effectors like hepcidin, ferroportin, transferrin receptor, lactoferrin, lipocalin-2, bone morphogenetic proteins and hypoxia inducible factors in MSC biology. It summarises the excess-iron-induced alterations in MSC components, processes and discusses signalling pathways involving ROS, PI3K/AKT, MAPK, p53, AMPK/MFF/DRP1 and Wnt. Additionally, it evaluates the endogenous and exogenous saviours of MSCs against iron-toxicity. Lastly, it elaborates on the involvement of MSCs in the pathology of clinical conditions of iron-excess, namely, hereditary hemochromatosis, diabetes, β-thalassaemia and myelodysplastic syndromes. This unique review integrates the distinct fields of iron regulation and MSC physiology. Through an iron-perspective, it describes both mechanistic and clinical aspects of MSCs and proposes an iron-linked MSC-contribution to physiology, pathology and therapeutics. It advances the understanding of MSC biology and may aid in identifying signalling pathways, molecular targets and compounds for formulating adjunctive iron-based therapies for excess-iron conditions, and thereby inform regenerative medicine.
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Affiliation(s)
- Kosha J Mehta
- Faculty of Life Sciences and Medicine, Centre for Education, King's College London, London, UK
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Ramírez-Salazar EG, Almeraya EV, López-Perez TV, Patiño N, Salmeron J, Velázquez-Cruz R. MicroRNA-548-3p overexpression inhibits proliferation, migration and invasion in osteoblast-like cells by targeting STAT1 and MAFB. J Biochem 2021; 168:203-211. [PMID: 32196088 DOI: 10.1093/jb/mvaa033] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 03/16/2020] [Indexed: 02/06/2023] Open
Abstract
Osteoporosis is the most common bone disease and a public health issue with increasing prevalence in Mexico. This disease is caused by an imbalance in the bone remodelling process mediated by osteoclast and osteoblast. MicroRNAs have emerged as key players during the differentiation of both types of cells specialized involved in bone metabolism. We found high expression levels of miR-548x-3p in circulating monocytes derived from postmenopausal osteoporotic women. This study aimed to analyse the functional characterization of miR-548x-3p roles in the bone remodelling process. We validated by RT-qPCR, the elevated levels of miR-548x-3p in circulating monocytes derived from osteoporosis women. Through bioinformatics analysis, we identify MAFB and STAT1 as potential target genes for miR-548x-3p. Both genes showed low levels of expression in circulating monocytes derived from osteoporotic women. In addition, we demonstrated the binding of miR-548x-3p to the 3'-UTR of both mRNAs. MiR-548x-3p was overexpressed in osteoblasts-like cell lines decreasing the levels of MAFB and STAT1 mRNA and protein. We found that miR-548x-3p overexpression inhibits the proliferation, migration and invasion of the cell lines evaluated. Our results identified, by the first time, the potential role of miR-548x-3p as a modulator of the bone remodelling process by regulating the expression of MAFB and STAT1.
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Affiliation(s)
- Eric G Ramírez-Salazar
- Consejo Nacional de Ciencia y Tecnología (CONACYT), Laboratorio de Genómica del Metabolismo Óseo, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico
| | - Erika V Almeraya
- Laboratorio de Genómica del Metabolismo Óseo, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
| | - Tania V López-Perez
- Laboratorio de Genómica del Metabolismo Óseo, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
| | - Nelly Patiño
- Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico
| | - Jorge Salmeron
- Centro de Investigación en Políticas, Población y Salud de la Facultad de Medicina-UNAM, Mexico City 04510, Mexico
| | - Rafael Velázquez-Cruz
- Laboratorio de Genómica del Metabolismo Óseo, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
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Wijarnpreecha K, Aby ES, Panjawatanan P, Kroner PT, Harnois DM, Palmer WC, Ungprasert P. Hereditary hemochromatosis and risk of joint replacement surgery: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2021; 33:96-101. [PMID: 32118852 DOI: 10.1097/meg.0000000000001704] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND/OBJECTIVES Arthritis is a known manifestation of hereditary hemochromatosis. However, whether patients with hereditary hemochromatosis have an increased risk of having joint replacement surgery compared to the general population is still unknown. This meta-analysis was conducted to better characterize this risk. METHODS A comprehensive literature review was conducted utilizing the MEDLINE and EMBASE databases through September 2019 to identify all cohort studies that compared prevalence or incidence of joint replacement surgery (hip, ankle, or knee) between patients with hereditary hemochromatosis and individuals without hereditary hemochromatosis. Effect estimates from each study were extracted and combined together using the random-effect, generic inverse variance method of DerSimonian and Laird. RESULTS A total of five studies with 1 293 407 participants fulfilled the eligibility criteria and were included in the meta-analysis. Overall, the risk of having joint replacement surgery was significantly increased in patients with hereditary hemochromatosis compared to individuals without hereditary hemochromatosis with the pooled relative risk (RR) of 3.32 [95% confidence interval (CI), 1.60-6.86; I 88%]. Analysis by joint found a significantly increased risk of having hip and ankle replacement surgery among patients with hereditary hemochromatosis compared with the pooled RR of 2.62 (95% CI, 2.09-3.30; I 47%) and 8.94 (95% CI, 3.85-20.78; I 14%), respectively. The risk of having knee replacement surgery was also increased but was not statistically significant (pooled RR 1.57, 95% CI, 0.83-2.98; I 66%). CONCLUSIONS A significantly increased risk of needed joint replacement surgery among patients with hereditary hemochromatosis compared to patients without hereditary hemochromatosis was demonstrated in this study. Further studies are required to determine whether this association is causal.
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Affiliation(s)
- Karn Wijarnpreecha
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida
| | - Elizabeth S Aby
- Division of Gastroenterology and Hepatology, University of Minnesota, Minneapolis, Minnesota
| | | | - Paul T Kroner
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida
| | - Denise M Harnois
- Division of Transplant Surgery, Mayo Clinic, Jacksonville, Florida, USA
| | - William C Palmer
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida
| | - Patompong Ungprasert
- Clinical Epidemiology Unit, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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Mabrouk M, Taha SK, Abdel Hamid MA, Kenawy SH, Hassan EA, El-Bassyouni GT. Radiological evaluations of low cost wollastonite nano-ceramics graft doped with iron oxide in the treatment of induced defects in canine mandible. J Biomed Mater Res B Appl Biomater 2020; 109:1029-1044. [PMID: 33289320 DOI: 10.1002/jbm.b.34767] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 10/27/2020] [Accepted: 11/17/2020] [Indexed: 02/01/2023]
Abstract
Wollastonite with/without maghemite [(Fe2O3), 0, 3 and 10 wt%] was prepared by facile wet precipitation method. Effect of Fe2O3 presence in the obtained nano-ceramics on physical structure, morphology, size and the mechanical features was evaluated using X-ray diffraction, transmission electron microscope, and universal testing machine. Moreover, the in vitro biomineralization was examined using simulated body fluid (SBF) by means of scanning electron microscope/energy dispersive X-ray, Fourier transform infrared, and inductively coupled plasma. An in vivo study was conducted on 24 adult male mongrel dogs to test the biosafety of fabricated samples in the reconstruction of experimentally induced mandibular bone defects. Bone density was measured through cone beam computed tomography analysis conducted at 1 and 3 months following surgery. Wollastonite was the main phase in all the prepared samples however little maghemite was developed in Fe-containing samples. No remarkable changes were recognized for physical structure of obtained microcrystalline structures, however, a decrease in particle size was noted in the existence of Fe2O3 (10-15 nm) when compared to the pure wollastonite (30-50 nm). Mechanical features were dependent on the included Fe2O3 concentration within the wollastonite ceramic matrix. The degree of biomineralization of the samples immersed in SBF was elevated with the increase in Fe2O3 percentage. Clinically, the reconstruction of bone defects was uneventful without any adverse toxic effect. Bone density was significantly increased at 1 and 3 months (p < .001) in grafted defects compared to control ones. Increasing the doping concentrations of iron oxide was associated with significant increase (p < .001) of bone density in all induced defects. Due to the impressive healing effect of current fabricated nano-ceramics, they are recommended to be utilized as low cost bone graft alternatives.
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Affiliation(s)
- Mostafa Mabrouk
- Refractories, Ceramics and Building Materials Department, National Research Centre, Dokki, Giza, Egypt
| | - Said K Taha
- OMF surgeon researcher in Surgery and Oral Medicine Dept., Oral and Dental Researches Division, National Research Centre, Dokki, Giza, Egypt
| | - Mohamed A Abdel Hamid
- Department of Surgery, Anaesthesiology, and Radiology- Faculty of Veterinary Medicine, Cairo University- Giza, Egypt
| | - Sayed H Kenawy
- Refractories, Ceramics and Building Materials Department, National Research Centre, Dokki, Giza, Egypt
- Chemistry Department, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
| | - Elham A Hassan
- Department of Surgery, Anaesthesiology, and Radiology- Faculty of Veterinary Medicine, Cairo University- Giza, Egypt
| | - Gehan T El-Bassyouni
- Refractories, Ceramics and Building Materials Department, National Research Centre, Dokki, Giza, Egypt
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Abstract
INTRODUCTION Iron overload, a state with excessive iron storage in the body, is a common complication in thalassemia patients which leads to multiple organ dysfunctions including the bone. Iron overload-induced bone disease is one of the most common and severe complications of thalassemia including osteoporosis. Currently, osteoporosis is still frequently found in thalassemia even with widely available iron chelation therapy. STUDY SELECTION Relevant publications published before December 2019 in PubMed database were reviewed. Both pre-clinical studies and clinical trials were obtained using iron overload, thalassemia, osteoporosis, osteoblast, and osteoclast as keywords. RESULTS Increased ROS production is a hallmark of iron overload-induced impaired bone remodeling. At the cellular level, oxidative stress affects bone remodeling by both osteoblast inhibition and osteoclast activation via many signaling pathways. In thalassemia patients, it has been shown that bone resorption was increased while bone formation was concurrently reduced. CONCLUSION In this review, reports on the cellular mechanisms of iron overload-associated bone remodeling are comprehensively summarized and presented to provide current understanding this pathological condition. Moreover, current treatments and potential interventions for attenuating bone remodeling in iron overload are also summarized to pave ways for the future discoveries of novel agents that alleviate this condition.
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Liu LL, Cao ZH, He CL, Zhong YC, Liu WY, Zhang P, Yang F, Xu YJ. Ferric Ion Induction of Triggering Receptor Expressed in Myeloid Cells-2 Expression and PI3K/Akt Signaling Pathway in Preosteoclast Cells to Promote Osteoclast Differentiation. Orthop Surg 2020; 12:1304-1312. [PMID: 32729185 PMCID: PMC7454152 DOI: 10.1111/os.12750] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 05/24/2020] [Accepted: 06/18/2020] [Indexed: 12/16/2022] Open
Abstract
Objective Iron plays a significant role in multiple biological processes. The purpose of this study was to measure whether iron mediated osteoclast differentiation through regulation of triggering receptor expressed in myeloid cells‐2 (Trem‐2) expression and the PI3K/Akt signaling pathway. Methods The effects of six different concentrations of ferric ammonium citrate (FAC) (100, 80, 40, 20, 10 and 0 μmol/L) on RAW 264.7 cells proliferation were assessed by Cell Counting Kit‐8 (CCK‐8) gassay. Tartrate resistant acid phosphatase (TRAP) assay was performed to detect the effects of FAC on osteoclast formation. The expression of osteoclast differentiation‐related (TRAP, NFATc‐1, and c‐Fos) and Trem‐2 mRNA and proteins was analyzed by reverse transcription‐polymerase chain reaction and western blot, respectively. Si‐Trem‐2 was constructed and transfected to RAW264.7 to measure the effects of Trem‐2 on FAC‐mediated osteoclast formation. TRAP assay and osteoclast differentiation‐related gene analyses were further performed to identify the role of Trem‐2 in osteoclastogenesis. The Search Tool for the Retrieval of Interacting Genes (STRING) was used to explore the target genes of Trem‐2. Trem‐2‐related gene ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were used for further in‐depth analysis. PI3K/Akt pathway‐related proteins were detected by immunofluorescence and western blot. Results In groups with FAC concentration of 10 (102.5 ± 3.1), 20 (100.5 ± 1.5), and 40 μmol/L (98.7 ± 3.1), compared with the control group (100.1 ± 2.2), cell viability was not significantly different from the control (P > 0.05). When the concentration of FAC exceeded 80 μmol/L, cell viability was significantly decreased (87.5 ± 2.8 vs 100.1 ± 2.2, P < 0.05). FAC promotes Trem‐2 expression and osteoclast differentiation in a dose‐response manner (P < 0.05). The number of osteoclast‐like cells was found to be reduced following transfection with the siRNA of Trem‐2 (42 ± 3 vs 30 ± 5, P < 0.05). We observed that most of Trem‐2 target genes are primarily involved in response to organic substance, regulation of reactive oxygen species metabolic process, and regulation of protein phosphorylation. The STRING database revealed that Trem‐2 directly target two gene nodes (Pik3ca and Pik3r1), which are key transcriptional cofactors of the PI3K/Akt signaling pathway. KEGG pathways include the “PI3K‐Akt signaling pathway,” the “thyroid hormone signaling pathway”, “prostate cancer,” the “longevity regulating pathway,” and “insulin resistance.” Expression of p‐PI3K and p‐Akt protein, measured by immunofluorescence and western blotting, was markedly increased in the FAC groups. Trem‐2 siRNA caused partial reduction of these two proteins (p‐PI3K and p‐Akt) compared to the FAC alone group. Conclusion The FAC promoted osteoclast differentiation through the Trem‐2‐mediated PI3K/Akt signaling pathway. However, its regulation osteoclastogenesis should be verified through further in vivo studies.
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Affiliation(s)
- Lu-Lin Liu
- Department of Orthopaedics, The Second Affiliated Hospital of Soochow University, Suzhou, China.,Department of Orthopaedics, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Zi-Hou Cao
- Department of Orthopaedics, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Chun-Lei He
- Department of Orthopaedics, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Yan-Chun Zhong
- Department of Orthopaedics, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Wu-Yang Liu
- Department of Orthopaedics, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Peng Zhang
- Department of Orthopaedics, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Fan Yang
- Osteoporosis Institute of Soochow University, Suzhou, China
| | - You-Jia Xu
- Department of Orthopaedics, The Second Affiliated Hospital of Soochow University, Suzhou, China.,Osteoporosis Institute of Soochow University, Suzhou, China
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Jandl NM, Rolvien T, Schmidt T, Mussawy H, Nielsen P, Oheim R, Amling M, Barvencik F. Impaired Bone Microarchitecture in Patients with Hereditary Hemochromatosis and Skeletal Complications. Calcif Tissue Int 2020; 106:465-475. [PMID: 31989186 DOI: 10.1007/s00223-020-00658-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 01/08/2020] [Indexed: 02/06/2023]
Abstract
Hereditary hemochromatosis (HHC) is characterized by excessive intestinal iron absorption resulting in a pathological increase of iron levels. Parenchyma damage may be a consequence of iron deposition in affected organs (e.g., liver, pancreas, gonads) as well as bones and joints, leading to osteoporosis with increased fracture risk and arthropathy. Up to date, it is not known whether HHC can also be considered as a risk factor for osteonecrosis. Likewise, the underlying skeletal changes are unknown regarding, e.g., microstructural properties of bone. We aimed to study the spectrum of skeletal complications in HHC and the possible underlying microarchitectural changes. Therefore, we retrospectively analyzed all patients with HHC (n = 10) presenting in our outpatient clinic for bone diseases. In addition to dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT) was performed and bone turnover markers, 25-OH-D3, ferritin and transferrin saturation were measured. Cortical volumetric bone mineral density (Ct.BMD) and cortical thickness (Ct.Th) were reduced, whereas trabecular microstructure (Tb.Th) and volumetric bone mineral density (Tb.BMD) were preserved compared to age- and gender-adjusted reference values from the literature. Interestingly, the occurrence of bone complications was age dependent; while younger patients presented with osteonecroses or transient bone marrow edema, patients older than 65 years presented with fractures. Our study provides first insights into altered bone microarchitecture in HHC and sheds new light on the occurrence of osteonecrosis. If available, HR-pQCT is a useful complement to fracture risk assessment and to determine microstructural deterioration and volumetric bone mineralization deficits.
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Affiliation(s)
- Nico Maximilian Jandl
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestrasse 59, 22529, Hamburg, Germany.
- Department of Orthopedics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Tim Rolvien
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestrasse 59, 22529, Hamburg, Germany
- Department of Orthopedics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tobias Schmidt
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestrasse 59, 22529, Hamburg, Germany
| | - Haider Mussawy
- Department of Orthopedics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Peter Nielsen
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ralf Oheim
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestrasse 59, 22529, Hamburg, Germany
| | - Michael Amling
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestrasse 59, 22529, Hamburg, Germany
| | - Florian Barvencik
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestrasse 59, 22529, Hamburg, Germany
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