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1
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Celebi Torabfam G, Porsuk MH. The Role of the Receptor Activator of Nuclear Factor Kappa-B Ligand/Osteoprotegerin Ratio in Vascular Diseases: A Therapeutic Approach. Angiology 2025; 76:309-322. [PMID: 38171493 DOI: 10.1177/00033197231226275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Cardiovascular and bone diseases contribute independently to mortality and global health. The exact mechanisms involved in the pathophysiology shared between bone and vascular diseases are not well defined. Endothelial cells and osteoblasts communicate during osteogenesis, thus establishing a connection between angiogenesis and osteogenesis. One shared mechanism may involve osteoprotegerin (OPG) and its ligand Receptor Activator of NF-κB Ligand (RANKL). The RANKL/OPG ratio is an important modulator for the skeletal, immunological, and vascular systems. OPG levels are elevated due to either osteogenic causes or inflammatory responses in the vasculature. The data obtained from clinical and in vitro studies support the role of the RANKL/OPG ratio as a potential marker for the progression of endothelial damage. Therefore, determining the therapeutic approaches for the targeting RANKL/OPG ratio and evaluating its usage as a biomarker in cardiovascular and bone pathophysiology are needed. By integrating the protective and disease-causing role of OPG with its ligand, this review outlines the role of the RANKL/OPG ratio at the molecular level. We also consider targeted therapeutic approaches.
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Affiliation(s)
- Gizem Celebi Torabfam
- Faculty of Engineering and Natural Sciences, Molecular Biology, Genetics, and Bioengineering Program, Sabanci University, Istanbul, Turkey
| | - Melis Hazal Porsuk
- Faculty of Engineering and Natural Sciences, Molecular Biology, Genetics, and Bioengineering Program, Sabanci University, Istanbul, Turkey
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2
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Valverde A, George A, Nares S, Naqvi AR. Emerging therapeutic strategies targeting bone signaling pathways in periodontitis. J Periodontal Res 2025; 60:101-120. [PMID: 39044454 PMCID: PMC11873684 DOI: 10.1111/jre.13326] [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: 01/29/2024] [Revised: 06/22/2024] [Accepted: 07/05/2024] [Indexed: 07/25/2024]
Abstract
Periodontitis is a multifactorial immune-mediated disease exacerbated by dysregulated alveolar bone homeostasis. Timely intervention is crucial for disease management to prevent tooth loss. To successfully manage periodontitis, it is imperative to understand the cellular and molecular mechanisms involved in its pathogenesis to develop novel treatment modalities. Non-surgical periodontal therapy (NSPT) such as subgingival instrumentation/debridement has been the underlying treatment strategy over the past decades. However, new NSPT approaches that target key signaling pathways regulating alveolar bone homeostasis have shown positive clinical outcomes. This narrative review aims to discuss endogenous bone homeostasis mechanisms impaired in periodontitis and highlight the clinical outcomes of preventive periodontal therapy to avoid invasive periodontal therapies. Although the anti-resorptive therapeutic adjuncts have demonstrated beneficial outcomes, adverse events have been reported. Diverse immunomodulatory therapies targeting the osteoblast/osteoclast (OB/OC) axis have shown promising outcomes in vivo. Future controlled randomized clinical trials (RCT) would help clinicians and patients in the selection of novel preventing therapies targeting key molecules to effectively treat or prevent periodontitis.
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Affiliation(s)
- Araceli Valverde
- Department of PeriodonticsCollege of Dentistry, University of Illinois ChicagoChicagoIllinoisUSA
| | - Anne George
- Department of Oral BiologyCollege of Dentistry, University of Illinois ChicagoChicagoIllinoisUSA
| | - Salvador Nares
- Department of PeriodonticsCollege of Dentistry, University of Illinois ChicagoChicagoIllinoisUSA
| | - Afsar R. Naqvi
- Department of PeriodonticsCollege of Dentistry, University of Illinois ChicagoChicagoIllinoisUSA
- Department of Microbiology and ImmunologyUniversity of Illinois ChicagoChicagoIllinoisUSA
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3
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Mitsis A, Khattab E, Christodoulou E, Myrianthopoulos K, Myrianthefs M, Tzikas S, Ziakas A, Fragakis N, Kassimis G. From Cells to Plaques: The Molecular Pathways of Coronary Artery Calcification and Disease. J Clin Med 2024; 13:6352. [PMID: 39518492 PMCID: PMC11545949 DOI: 10.3390/jcm13216352] [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: 09/22/2024] [Revised: 10/19/2024] [Accepted: 10/21/2024] [Indexed: 11/15/2024] Open
Abstract
Coronary artery calcification (CAC) is a hallmark of atherosclerosis and a critical factor in the development and progression of coronary artery disease (CAD). This review aims to address the complex pathophysiological mechanisms underlying CAC and its relationship with CAD. We examine the cellular and molecular processes that drive the formation of calcified plaques, highlighting the roles of inflammation, lipid accumulation, and smooth muscle cell proliferation. Additionally, we explore the genetic and environmental factors that contribute to the heterogeneity in CAC and CAD presentation among individuals. Understanding these intricate mechanisms is essential for developing targeted therapeutic strategies and improving diagnostic accuracy. By integrating current research findings, this review provides a comprehensive overview of the pathways linking CAC to CAD, offering insights into potential interventions to mitigate the burden of these interrelated conditions.
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Affiliation(s)
- Andreas Mitsis
- Cardiology Department, Nicosia General Hospital, State Health Services Organization, Nicosia 2029, Cyprus; (A.M.); (E.K.); (K.M.); (M.M.)
| | - Elina Khattab
- Cardiology Department, Nicosia General Hospital, State Health Services Organization, Nicosia 2029, Cyprus; (A.M.); (E.K.); (K.M.); (M.M.)
| | - Evi Christodoulou
- Cardiology Department, Limassol General Hospital, State Health Services Organization, Limassol 3304, Cyprus;
| | - Kimon Myrianthopoulos
- Cardiology Department, Nicosia General Hospital, State Health Services Organization, Nicosia 2029, Cyprus; (A.M.); (E.K.); (K.M.); (M.M.)
| | - Michael Myrianthefs
- Cardiology Department, Nicosia General Hospital, State Health Services Organization, Nicosia 2029, Cyprus; (A.M.); (E.K.); (K.M.); (M.M.)
| | - Stergios Tzikas
- Third Department of Cardiology, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece;
| | - Antonios Ziakas
- First Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece;
| | - Nikolaos Fragakis
- Second Department of Cardiology, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece;
| | - George Kassimis
- Second Department of Cardiology, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece;
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4
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Rusu ME, Bigman G, Ryan AS, Popa DS. Investigating the Effects and Mechanisms of Combined Vitamin D and K Supplementation in Postmenopausal Women: An Up-to-Date Comprehensive Review of Clinical Studies. Nutrients 2024; 16:2356. [PMID: 39064799 PMCID: PMC11279569 DOI: 10.3390/nu16142356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/11/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
Aging is a complex process and a significant risk factor for chronic diseases. Menopause, a component of aging in women, is associated with several important cardiometabolic conditions including metabolic syndrome, osteoporosis, and cardiovascular diseases. Menopausal women could benefit from preventative strategies that may decrease morbidity and mortality and improve their quality of life. Vitamins D and K are essential nutrients required for bone health, immune function, and reducing cardiovascular risks, yet their synergistic effect is less understood in aging women. This is the first comprehensive review to summarize the evidence found in randomized clinical trials of the beneficial effects of vitamin D and K co-treatment in postmenopausal women. In our literature search across key electronic databases such as Cochrane, PubMed, and Ovid, we identified 31 pertinent studies. Overall, significant findings indicate that the combined intake of vitamins D and K may positively affect cardiovascular and bone health in postmenopausal women, emphasizing the importance of maintaining a healthy diet rich in vegetables and fermented dairy products. Given the challenges in obtaining all necessary nutrients solely through the diet, vitamin D and K supplements are recommended for postmenopausal women to promote healthy aging and well-being.
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Affiliation(s)
- Marius Emil Rusu
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Galya Bigman
- Division of Gerontology, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Alice S. Ryan
- Baltimore Veterans Affairs Medical Center, Division of Gerontology, Geriatrics and Palliative Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
- Baltimore Geriatric Research, Education and Clinical Center, Veterans Affairs Maryland Health Care System, Baltimore, MD 21201, USA
| | - Daniela-Saveta Popa
- Department of Toxicology, Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
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5
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Wang T, Xiong K, He Y, Feng B, Guo L, Gu J, Zhang M, Wang H, Wu X. Chronic pancreatitis-associated metabolic bone diseases: epidemiology, mechanisms, and clinical advances. Am J Physiol Endocrinol Metab 2024; 326:E856-E868. [PMID: 38656128 DOI: 10.1152/ajpendo.00113.2024] [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: 03/19/2024] [Revised: 04/11/2024] [Accepted: 04/17/2024] [Indexed: 04/26/2024]
Abstract
Chronic pancreatitis (CP) is a progressive inflammatory disease with an increasing global prevalence. In recent years, a strong association between CP and metabolic bone diseases (MBDs), especially osteoporosis, has been identified, attracting significant attention in the research field. Epidemiological data suggest a rising trend in the incidence of MBDs among CP patients. Notably, recent studies have highlighted a profound interplay between CP and altered nutritional and immune profiles, offering insights into its linkage with MBDs. At the molecular level, CP introduces a series of biochemical disturbances that compromise bone homeostasis. One critical observation is the disrupted metabolism of vitamin D and vitamin K, both essential micronutrients for maintaining bone integrity, in CP patients. In this review, we provide physio-pathological perspectives on the development and mechanisms of CP-related MBDs. We also outline some of the latest therapeutic strategies for treating patients with CP-associated MBDs, including stem cell transplantation, monoclonal antibodies, and probiotic therapy. In summary, CP-associated MBDs represent a rising medical challenge, involving multiple tissues and organs, complex disease mechanisms, and diverse treatment approaches. More in-depth studies are required to understand the complex interplay between CP and MBDs to facilitate the development of more specific and effective therapeutic approaches.
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Affiliation(s)
- Tianlin Wang
- Department of Emergency, The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Ke Xiong
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yanli He
- Department of General Surgery, The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Binbin Feng
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - LinBin Guo
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jingliang Gu
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mengrui Zhang
- Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, California, United States
- Division of Immunology and Rheumatology, Stanford University, Stanford, California, United States
- Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States
| | - Hong Wang
- Department of General Surgery, The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiaohao Wu
- Division of Immunology and Rheumatology, Stanford University, Stanford, California, United States
- Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States
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6
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Fawzy El-Sayed KM, Cosgarea R, Sculean A, Doerfer C. Can vitamins improve periodontal wound healing/regeneration? Periodontol 2000 2024; 94:539-602. [PMID: 37592831 DOI: 10.1111/prd.12513] [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: 05/12/2023] [Revised: 07/13/2023] [Accepted: 07/19/2023] [Indexed: 08/19/2023]
Abstract
Periodontitis is a complex inflammatory disorder of the tooth supporting structures, associated with microbial dysbiosis, and linked to a number if systemic conditions. Untreated it can result in an irreversible damage to the periodontal structures and eventually teeth loss. Regeneration of the lost periodontium requires an orchestration of a number of biological events on cellular and molecular level. In this context, a set of vitamins have been advocated, relying their beneficial physiological effects, to endorse the biological regenerative events of the periodontium on cellular and molecular levels. The aim of the present article is to elaborate on the question whether or not vitamins improve wound healing/regeneration, summarizing the current evidence from in vitro, animal and clinical studies, thereby shedding light on the knowledge gap in this field and highlighting future research needs. Although the present review demonstrates the current heterogeneity in the available evidence and knowledge gaps, findings suggest that vitamins, especially A, B, E, and CoQ10, as well as vitamin combinations, could exert positive attributes on the periodontal outcomes in adjunct to surgical or nonsurgical periodontal therapy.
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Affiliation(s)
- Karim M Fawzy El-Sayed
- Oral Medicine and Periodontology Department, Faculty of Oral and Dental Medicine, Cairo University, Giza, Egypt
- Clinic for Conservative Dentistry and Periodontology, School of Dental Medicine, Christian Albrechts University, Kiel, Germany
| | - Raluca Cosgarea
- Department of Periodontology, Operative and Preventive Dentistry, University of Bonn, Bonn, Germany
- Department of Periodontology and Peri-implant Diseases, Philips University Marburg, Marburg, Germany
- Clinic for Prosthetic Dentistry, University Iuliu-Hatieganu, Cluj-Napoca, Romania
| | - Anton Sculean
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Christof Doerfer
- Clinic for Conservative Dentistry and Periodontology, School of Dental Medicine, Christian Albrechts University, Kiel, Germany
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7
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Wang H, Ma Y. The Potential of Vitamin K as a Regulatory Factor of Bone Metabolism-A Review. Nutrients 2023; 15:4935. [PMID: 38068793 PMCID: PMC10708186 DOI: 10.3390/nu15234935] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 11/23/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Vitamin K (VK), a fat-soluble vitamin, is essential for the clotting of blood because of its role in the production of clotting factors in the liver. Moreover, researchers continue to explore the role of VK as an emerging novel bioactive molecule with the potential function of improving bone health. This review focuses on the effects of VK on bone health and related mechanisms, covering VK research history, homologous analogs, dietary sources, bioavailability, recommended intake, and deficiency. The information summarized here could contribute to the basic and clinical research on VK as a natural dietary additive and drug candidate for bone health. Future research is needed to extend the dietary VK database and explore the pharmacological safety of VK and factors affecting VK bioavailability to provide more support for the bone health benefits of VK through more clinical trials.
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Affiliation(s)
- Huakai Wang
- Department of Animal Nutrition and Feed Science, State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China;
- Institute of Animal Husbandry and Veterinary Medicine, Anhui Academy of Agricultural Sciences, Nongkenan Road No. 40, Hefei 230031, China
| | - Yongxi Ma
- Department of Animal Nutrition and Feed Science, State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China;
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8
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Olszewska-Czyz I, Firkova E. A Case Control Study Evaluating the Relationship between Vitamin K2 Serum Level and Periodontitis. Healthcare (Basel) 2023; 11:2937. [PMID: 37998429 PMCID: PMC10670967 DOI: 10.3390/healthcare11222937] [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: 09/15/2023] [Revised: 11/02/2023] [Accepted: 11/08/2023] [Indexed: 11/25/2023] Open
Abstract
BACKGROUND AND AIM Vitamin K2 (VK2) is an essential co-factor for bone metabolism. There is still very little data regarding possible VK2 relation to periodontitis. This study aimed to investigate any potential link between VK2 serum level and the severity of periodontitis in comparison to a control group of healthy individuals. The trial was performed on 100 patients among whom 50 were diagnosed with periodontitis. The patients underwent full clinical periodontal and radiological examination. The VK2 serum level was assessed using the ELISA kit (Gla-type osteocalcin EIA Kit, Takara, Kusatsu). Patients with periodontitis had mean serum levels of VK2 significantly lower (0.27 ± 0.06 nmol/L; p < 0.001) than the control group (0.43 ± 0.09 nmol/L; p < 0.001) regardless of the patient's age or sex. The VK2 serum level decreased with the severity of periodontitis with the lowest level in stage IV of the disease (0.19 ± 0.01 nmol/L; p < 0.001). Also, a significant drop was noticed between the grades of periodontitis. Individuals with localized forms of the disease had significantly lower VK2 levels (0.26 ± 0.006 nmol/L; p < 0.001) in comparison to subjects with generalized periodontitis (0.30 ± 0.01 nmol/L; p < 0.001). The VK2 serum levels were also associated with most of the clinical parameters such as bleeding on probing (-0.805, 95% CI: -0.894 to -0.654, p < 0.001), attachment loss (-0.752, 95% CI: -0.862 to -0.574, p < 0.001), and bone loss (-0.656, 95% CI: -0.801 to -0.439, p < 0.001). In the present study, the VK2 serum level was correlated to periodontitis, and its severity, complexity, extension, and grade. The range of VK2 was decreasing together with the worsening of all clinical parameters of periodontitis.
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Affiliation(s)
- Iwona Olszewska-Czyz
- Department of Periodontology, Prophylaxis and Oral Pathology, Medical Faculty, Jagiellonian University, 31155 Krakow, Poland
| | - Elena Firkova
- Department of Periodontology and Oral Diseases, Faculty of Dental Medicine, Medical University, 4002 Plovdiv, Bulgaria;
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9
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Hao J, Zhang B, Wang B, Zhang M, Fan W, Li W. Effects of dietary vitamin K3 supplementation on production performance, egg quality, vitamin K-dependent proteins, and antioxidant properties in breeding geese during the laying period. Poult Sci 2023; 102:102880. [PMID: 37419050 PMCID: PMC10344679 DOI: 10.1016/j.psj.2023.102880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 06/09/2023] [Accepted: 06/14/2023] [Indexed: 07/09/2023] Open
Abstract
The aim of this work was to investigate the effects of dietary vitamin K3 (VK3) supplementation on production performance, egg quality, vitamin K-dependent proteins, and antioxidant properties in breeding geese during the laying period. A total of one hundred twenty 82-wk-old Wulong geese with similar body weights were randomly divided into 6 groups with 4 replicates and 5 geese each (1 male and 4 female). The geese in the control group were fed a basal diet, and the geese in the treatment groups were fed diets supplemented with different levels of VK3 (2.5, 5.0, 7.5, 10.0, and 12.5 mg/kg) for 11 wk. Dietary VK3 supplementation linearly and quadratically increased feed intake, egg mass, egg weight, and egg production (P < 0.05). Increasing VK3 levels linearly and quadratically increased albumen height, shell thickness and Haugh unit of eggs (P < 0.05). VK3 reduced osteocalcin (OC) and uncarboxylated osteocalcin (ucOC) levels in the serum. Dietary VK3 addition linearly decreased serum malondialdehyde (MDA) levels (P < 0.01). There was linear and quadratic effect in the activity of serum total superoxide dismutase (T-SOD) (P < 0.01), and linear effect in serum total antioxidant capacity (T-AOC) (P < 0.01). In conclusion, dietary VK3 supplementation enhanced the production performance, egg quality, vitamin K-dependent proteins, and antioxidant properties in breeding geese during the laying period. The optimal dose of dietary VK3 supplementation was 10.0 mg/kg.
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Affiliation(s)
- Jianzhong Hao
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Beibei Zhang
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Baowei Wang
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Mingai Zhang
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Wenlei Fan
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Wenli Li
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China.
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10
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Ariano A, Posa F, Storlino G, Mori G. Molecules Inducing Dental Stem Cells Differentiation and Bone Regeneration: State of the Art. Int J Mol Sci 2023; 24:9897. [PMID: 37373044 DOI: 10.3390/ijms24129897] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/30/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
Teeth include mesenchymal stem cells (MSCs), which are multipotent cells that promote tooth growth and repair. Dental tissues, specifically the dental pulp and the dental bud, constitute a relevant source of multipotent stem cells, known as dental-derived stem cells (d-DSCs): dental pulp stem cells (DPSCs) and dental bud stem cells (DBSCs). Cell treatment with bone-associated factors and stimulation with small molecule compounds are, among the available methods, the ones who show excellent advantages promoting stem cell differentiation and osteogenesis. Recently, attention has been paid to studies on natural and non-natural compounds. Many fruits, vegetables, and some drugs contain molecules that can enhance MSC osteogenic differentiation and therefore bone formation. The purpose of this review is to examine research work over the past 10 years that has investigated two different types of MSCs from dental tissues that are attractive targets for bone tissue engineering: DPSCs and DBSCs. The reconstruction of bone defects, in fact, is still a challenge and therefore more research is needed; the articles reviewed are meant to identify compounds useful to stimulate d-DSC proliferation and osteogenic differentiation. We only consider the results of the research which is encouraging, assuming that the mentioned compounds are of some importance for bone regeneration.
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Affiliation(s)
- Anastasia Ariano
- Department of Clinical and Experimental Medicine, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy
| | - Francesca Posa
- Department of Clinical and Experimental Medicine, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy
| | - Giuseppina Storlino
- Department of Clinical and Experimental Medicine, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy
| | - Giorgio Mori
- Department of Clinical and Experimental Medicine, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy
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11
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Yan Q, Zhang T, O'Connor C, Barlow JW, Walsh J, Scalabrino G, Xu F, Sheridan H. The biological responses of vitamin K2: A comprehensive review. Food Sci Nutr 2023; 11:1634-1656. [PMID: 37051359 PMCID: PMC10084986 DOI: 10.1002/fsn3.3213] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 12/14/2022] [Accepted: 12/19/2022] [Indexed: 01/09/2023] Open
Abstract
Vitamin K1 (VitK1) and Vitamin K2 (VitK2), two important naturally occurring micronutrients in the VitK family, found, respectively, in green leafy plants and algae (VitK1) and animal and fermented foods (VitK2). The present review explores the multiple biological functions of VitK2 from recently published in vitro and in vivo studies, including promotion of osteogenesis, prevention of calcification, relief of menopausal symptoms, enhancement of mitochondrial energy release, hepato- and neuro-protective effects, and possible use in treatment of coronavirus disease. The mechanisms of action associated with these biological effects are also explored. Overall, the findings presented here suggest that VitK, especially VitK2, is an important nutrient family for the normal functioning of human health. It acts on almost all major body systems and directly or indirectly participates in and regulates hundreds of physiological or pathological processes. However, as biological and clinical data are still inconsistent and conflicting, more in-depth investigations are warranted to elucidate its potential as a therapeutic strategy to prevent and treat a range of disease conditions.
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Affiliation(s)
- Quanxiang Yan
- Institute of Science and TechnologyShenyang Open UniversityShenyangChina
| | - Tao Zhang
- School of Food Science & Environmental HealthTechnological University DublinDublin 7Ireland
- NatPro Centre, School of Pharmacy and Pharmaceutical SciencesTrinity College DublinDublin 2Ireland
| | - Christine O'Connor
- School of Food Science & Environmental HealthTechnological University DublinDublin 7Ireland
| | - James W. Barlow
- Department of ChemistryRCSI University of Medicine and Health SciencesDublin 2Ireland
| | - John Walsh
- NatPro Centre, School of Pharmacy and Pharmaceutical SciencesTrinity College DublinDublin 2Ireland
- School of Pharmacy and Pharmaceutical SciencesTrinity College DublinDublin 2Ireland
| | - Gaia Scalabrino
- NatPro Centre, School of Pharmacy and Pharmaceutical SciencesTrinity College DublinDublin 2Ireland
| | - Feng Xu
- The Centre of Vitamin K2 ResearchShenyang Pharmaceutical UniversityShenyangChina
| | - Helen Sheridan
- NatPro Centre, School of Pharmacy and Pharmaceutical SciencesTrinity College DublinDublin 2Ireland
- School of Pharmacy and Pharmaceutical SciencesTrinity College DublinDublin 2Ireland
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12
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Sojan JM, Licini C, Marcheggiani F, Carnevali O, Tiano L, Mattioli-Belmonte M, Maradonna F. Bacillus subtilis Modulated the Expression of Osteogenic Markers in a Human Osteoblast Cell Line. Cells 2023; 12:cells12030364. [PMID: 36766709 PMCID: PMC9913848 DOI: 10.3390/cells12030364] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 01/12/2023] [Accepted: 01/13/2023] [Indexed: 01/20/2023] Open
Abstract
Several in vivo trials have previously demonstrated the beneficial effects of the administration of various probiotic forms on bone health. In this study, we explored the potency of two probiotics, Bacillus subtilis and Lactococcus lactis, alone or in combination with vitamin D (VD), to modulate the transcription of genes involved in the ossification process in a human osteoblast cell line. Genes that mark the "osteoblast proliferation phase", such as RUNX2, TGFB1, and ALPL, "extracellular matrix (ECM) maturation", such as SPP1 and SPARC, as well as "ECM mineralization", such as BGN, BGLAP, and DCN, were all highly expressed in osteoblasts treated with B. subtilis extract. The observed increase in the transcription of the ALPL mRNA was further in agreement with its protein levels as observed by Western blot and immunofluorescence. Therefore, this higher transcription and translation of alkaline phosphatase in osteoblasts treated with the B. subtilis extract, indicated its substantial osteogenic impact on human osteoblasts. Although both the probiotic extracts showed no osteogenic synergy with VD, treatment with B. subtilis alone could increase the ECM mineralization, outperforming the effects of L. lactis and even VD. Furthermore, these results supported the validity of employing probiotic extracts rather than live cells to investigate the effects of probiotics in the in vitro systems.
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Affiliation(s)
- Jerry Maria Sojan
- Department of Life and Environmental Sciences, Università Politecnica delle Marche, Via Brecce Bianche, 60131 Ancona, Italy
| | - Caterina Licini
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Via Tronto 10/a, 60126 Ancona, Italy
| | - Fabio Marcheggiani
- Department of Life and Environmental Sciences, Università Politecnica delle Marche, Via Brecce Bianche, 60131 Ancona, Italy
| | - Oliana Carnevali
- Department of Life and Environmental Sciences, Università Politecnica delle Marche, Via Brecce Bianche, 60131 Ancona, Italy
- Correspondence: (O.C.); (F.M.); Tel.: +39-0712204990 (O.C.)
| | - Luca Tiano
- Department of Life and Environmental Sciences, Università Politecnica delle Marche, Via Brecce Bianche, 60131 Ancona, Italy
| | - Monica Mattioli-Belmonte
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Via Tronto 10/a, 60126 Ancona, Italy
| | - Francesca Maradonna
- Department of Life and Environmental Sciences, Università Politecnica delle Marche, Via Brecce Bianche, 60131 Ancona, Italy
- Correspondence: (O.C.); (F.M.); Tel.: +39-0712204990 (O.C.)
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Alkaline Phosphatase: An Old Friend as Treatment Target for Cardiovascular and Mineral Bone Disorders in Chronic Kidney Disease. Nutrients 2022; 14:nu14102124. [PMID: 35631265 PMCID: PMC9144546 DOI: 10.3390/nu14102124] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/12/2022] [Accepted: 05/17/2022] [Indexed: 11/17/2022] Open
Abstract
Alkaline phosphatase (ALP) is an evolutionary conserved enzyme and widely used biomarker in clinical practice. Tissue-nonspecific alkaline phosphatase (TNALP) is one of four human isozymes that are expressed as distinct TNALP isoforms after posttranslational modifications, mainly in bone, liver, and kidney tissues. Beyond the well-known effects on bone mineralization, the bone ALP (BALP) isoforms (B/I, B1, B1x, and B2) are also involved in the pathogenesis of ectopic calcification. This narrative review summarizes the recent clinical investigations and mechanisms that link ALP and BALP to inflammation, metabolic syndrome, vascular calcification, endothelial dysfunction, fibrosis, cardiovascular disease, and mortality. The association between ALP, vitamin K, bone metabolism, and fracture risk in patients with chronic kidney disease (CKD) is also discussed. Recent advances in different pharmacological strategies are highlighted, with the potential to modulate the expression of ALP directly and indirectly in CKD–mineral and bone disorder (CKD-MBD), e.g., epigenetic modulation, phosphate binders, calcimimetics, vitamin D, and other anti-fracture treatments. We conclude that the significant evidence for ALP as a pathogenic factor and risk marker in CKD-MBD supports the inclusion of concrete treatment targets for ALP in clinical guidelines. While a target value below 120 U/L is associated with improved survival, further experimental and clinical research should explore interventional strategies with optimal risk–benefit profiles. The future holds great promise for novel drug therapies modulating ALP.
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14
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Ansari Z, Shah I, Bhurwal A, Mehta H, Uppal S, Srinivasan I, Reddymasu S, Chuang KY. Decreasing Rates of Fracture-Related Hospitalization With Primary Biliary Cholangitis: Insights From the Nationwide Inpatient Sample. Cureus 2022; 14:e25001. [PMID: 35719819 PMCID: PMC9191878 DOI: 10.7759/cureus.25001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/14/2022] [Indexed: 11/05/2022] Open
Abstract
Introduction Primary biliary cholangitis (PBC) is associated with an increased risk of developing fractures. Current guidelines recommend measures that can help prevent the development of fractures in these patients. The purpose of this study was to trend the rates of hospitalizations related to fractures and their burden on healthcare. Methods We performed a retrospective, cohort study of adults hospitalized in the United States with PBC between 2010 and 2014. Patients were identified using the Nationwide Inpatient Sample (NIS). Temporal analysis of PBC patients with a co-diagnosis of hip, vertebral, or wrist fractures (the study group) was performed with regards to the total number of inpatient admissions, inpatient mortality, length of stay, and total charges associated with hospitalization. Descriptive analyses were performed using the t-test for continuous data and the chi-square test for categorical data. Results During the five-year study period, there were 308,753 hospitalizations for PBC. There has been a downward trend (p=0.02) in fracture-related admissions among patients with PBC during this study period. Length of stay was higher in the PBC-fracture group (10.85 days vs 7.36 days; p<0.001). Total hospitalization charges were higher among the PBC-fracture patients when compared to the control group ($98,444 vs $72,964; p=0.004). Conclusion There has been a gradual reduction in the rate of fracture-related hospitalizations in patients with PBC. However, patients with PBC who have fractures have increased the utilization of health care resources as compared to their cohort admitted for reasons other than for a fracture.
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15
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Pugliese N, Arcari I, Aghemo A, Lania AG, Lleo A, Mazziotti G. Osteosarcopenia in autoimmune cholestatic liver diseases: Causes, management, and challenges. World J Gastroenterol 2022; 28:1430-1443. [PMID: 35582674 PMCID: PMC9048470 DOI: 10.3748/wjg.v28.i14.1430] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 12/05/2021] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis and primary sclerosing cholangitis (PSC) are the most common cholestatic liver diseases (CLD) in adults and are both characterized by an immune pathogenesis. While primary biliary cholangitis is a model autoimmune disease, with over 90% of patients presenting very specific autoantibodies against mitochondrial antigens, PSC is considered an immune mediated disease. Osteoporosis is the most common bone disease in CLD, resulting in frequent fractures and leading to significant morbidity. Further, sarcopenia is emerging as a frequent complication of chronic liver diseases with a significant prognostic impact and severe implications on the quality of life of patients. The mechanisms underlying osteoporosis and sarcopenia in CLD are still largely unknown and the association between these clinical conditions remains to be dissected. Although timely diagnosis, prevention, and management of osteosarcopenia are crucial to limit the consequences, there are no specific guidelines for management of osteoporosis and sarcopenia in patients with CLD. International guidelines recommend screening for bone disease at the time of diagnosis of CLD. However, the optimal monitoring strategies and treatments have not been defined yet and vary among centers. We herein aim to comprehensively outline the pathogenic mechanisms and clinical implications of osteosarcopenia in CLD, and to summarize expert recommendations for appropriate diagnostic and therapeutic approaches.
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Affiliation(s)
- Nicola Pugliese
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Ivan Arcari
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Alessio Aghemo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Andrea G Lania
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Endocrinology, Diabetology and Medical Andrology Unit, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
| | - Gherardo Mazziotti
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Endocrinology, Diabetology and Medical Andrology Unit, IRCCS Humanitas Research Hospital, Rozzano 20089, MI, Italy
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16
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New Therapeutics Targeting Arterial Media Calcification: Friend or Foe for Bone Mineralization? Metabolites 2022; 12:metabo12040327. [PMID: 35448514 PMCID: PMC9027727 DOI: 10.3390/metabo12040327] [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: 03/01/2022] [Revised: 03/31/2022] [Accepted: 04/03/2022] [Indexed: 01/27/2023] Open
Abstract
The presence of arterial media calcification, a highly complex and multifactorial disease, puts patients at high risk for developing serious cardiovascular consequences and mortality. Despite the numerous insights into the mechanisms underlying this pathological mineralization process, there is still a lack of effective treatment therapies interfering with the calcification process in the vessel wall. Current anti-calcifying therapeutics may induce detrimental side effects at the level of the bone, as arterial media calcification is regulated in a molecular and cellular similar way as physiological bone mineralization. This especially is a complication in patients with chronic kidney disease and diabetes, who are the prime targets of this pathology, as they already suffer from a disturbed mineral and bone metabolism. This review outlines recent treatment strategies tackling arterial calcification, underlining their potential to influence the bone mineralization process, including targeting vascular cell transdifferentiation, calcification inhibitors and stimulators, vascular smooth muscle cell (VSMC) death and oxidative stress: are they a friend or foe? Furthermore, this review highlights nutritional additives and a targeted, local approach as alternative strategies to combat arterial media calcification. Paving a way for the development of effective and more precise therapeutic approaches without inducing osseous side effects is crucial for this highly prevalent and mortal disease.
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17
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Ebeling PR, Nguyen HH, Aleksova J, Vincent AJ, Wong P, Milat F. Secondary Osteoporosis. Endocr Rev 2022; 43:240-313. [PMID: 34476488 DOI: 10.1210/endrev/bnab028] [Citation(s) in RCA: 139] [Impact Index Per Article: 46.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Indexed: 02/07/2023]
Abstract
Osteoporosis is a global public health problem, with fractures contributing to significant morbidity and mortality. Although postmenopausal osteoporosis is most common, up to 30% of postmenopausal women, > 50% of premenopausal women, and between 50% and 80% of men have secondary osteoporosis. Exclusion of secondary causes is important, as treatment of such patients often commences by treating the underlying condition. These are varied but often neglected, ranging from endocrine to chronic inflammatory and genetic conditions. General screening is recommended for all patients with osteoporosis, with advanced investigations reserved for premenopausal women and men aged < 50 years, for older patients in whom classical risk factors for osteoporosis are absent, and for all patients with the lowest bone mass (Z-score ≤ -2). The response of secondary osteoporosis to conventional anti-osteoporosis therapy may be inadequate if the underlying condition is unrecognized and untreated. Bone densitometry, using dual-energy x-ray absorptiometry, may underestimate fracture risk in some chronic diseases, including glucocorticoid-induced osteoporosis, type 2 diabetes, and obesity, and may overestimate fracture risk in others (eg, Turner syndrome). FRAX and trabecular bone score may provide additional information regarding fracture risk in secondary osteoporosis, but their use is limited to adults aged ≥ 40 years and ≥ 50 years, respectively. In addition, FRAX requires adjustment in some chronic conditions, such as glucocorticoid use, type 2 diabetes, and HIV. In most conditions, evidence for antiresorptive or anabolic therapy is limited to increases in bone mass. Current osteoporosis management guidelines also neglect secondary osteoporosis and these existing evidence gaps are discussed.
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Affiliation(s)
- Peter R Ebeling
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia
| | - Hanh H Nguyen
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Department of Endocrinology and Diabetes, Western Health, Victoria 3011, Australia
| | - Jasna Aleksova
- Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
| | - Amanda J Vincent
- Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Monash Centre for Health Research and Implementation, School of Public Health and Preventative Medicine, Monash University, Clayton, Victoria 3168, Australia
| | - Phillip Wong
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
| | - Frances Milat
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia.,Department of Endocrinology, Monash Health, Clayton, Victoria 3168, Australia.,Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
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18
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Fusaro M, Tondolo F, Gasperoni L, Tripepi G, Plebani M, Zaninotto M, Nickolas TL, Ketteler M, Aghi A, Politi C, La Manna G, Brandi ML, Ferrari S, Gallieni M, Mereu MC, Cianciolo G. The Role of Vitamin K in CKD-MBD. Curr Osteoporos Rep 2022; 20:65-77. [PMID: 35132525 PMCID: PMC8821802 DOI: 10.1007/s11914-022-00716-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/07/2021] [Indexed: 01/31/2023]
Abstract
PURPOSE OF REVIEW We describe the mechanism of action of vitamin K, and its implication in cardiovascular disease, bone fractures, and inflammation to underline its protective role, especially in chronic kidney disease (CKD). RECENT FINDINGS Vitamin K acts as a coenzyme of y-glutamyl carboxylase, transforming undercarboxylated in carboxylated vitamin K-dependent proteins. Furthermore, through the binding of the nuclear steroid and xenobiotic receptor, it activates the expression of genes that encode proteins involved in the maintenance of bone quality and bone remodeling. There are three main types of K vitamers: phylloquinone, menaquinones, and menadione. CKD patients, for several conditions typical of the disease, are characterized by lower levels of vitamin K than the general populations, with a resulting higher prevalence of bone fractures, vascular calcifications, and mortality. Therefore, the definition of vitamin K dosage is an important issue, potentially leading to reduced bone fractures and improved vascular calcifications in the general population and CKD patients.
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Affiliation(s)
- Maria Fusaro
- National Research Council (CNR), Institute of Clinical Physiology (IFC), Via G. Moruzzi 1, 56124, Pisa, Italy.
- Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy.
| | - Francesco Tondolo
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS - Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Lorenzo Gasperoni
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS - Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Giovanni Tripepi
- CNR-IFC, Clinical Epidemiology of Renal Diseases and Hypertension, Ospedali Riuniti, Reggio Calabria, Italy
| | - Mario Plebani
- Laboratory Medicine Unit, Department of Medicine, University of Padua, Padua, Italy
| | - Martina Zaninotto
- Laboratory Medicine Unit, Department of Medicine, University of Padua, Padua, Italy
| | - Thomas L Nickolas
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York City, NY, USA
| | - Markus Ketteler
- Department of General Internal Medicine and Nephrology, Robert-Bosch-Krankenhaus, Stuttgart, Germany
| | - Andrea Aghi
- Department of Medicine, Clinica Medica 1, University of Padua, Padua, Italy
| | - Cristina Politi
- CNR-IFC, Clinical Epidemiology of Renal Diseases and Hypertension, Ospedali Riuniti, Reggio Calabria, Italy
| | - Gaetano La Manna
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS - Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Maria Luisa Brandi
- Department of Surgery and Translational Medicine, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy
| | - Serge Ferrari
- Service des Maladies Osseuses, Département de Médecine, HUG, Genève, Switzerland
| | - Maurizio Gallieni
- Department of Biomedical and Clinical Sciences 'Luigi Sacco', Università di Milano, 20157, Milano, Italy
| | | | - Giuseppe Cianciolo
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS - Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Bologna, Italy
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19
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Menaquinone 4 Reduces Bone Loss in Ovariectomized Mice through Dual Regulation of Bone Remodeling. Nutrients 2021; 13:nu13082570. [PMID: 34444729 PMCID: PMC8398915 DOI: 10.3390/nu13082570] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/22/2021] [Accepted: 07/26/2021] [Indexed: 11/17/2022] Open
Abstract
Epidemiologic studies showed that higher vitamin K (VK) consumption correlates with a reduced risk of osteoporosis, yet the dispute remains about whether VK is effective in improving bone mineral density (BMD). We sought to discover the anti-osteoporotic effect of menaquinone-4 (MK-4) and evaluate the expression of critical genes related to bone formation and bone resorption pathways in the body. Fifty female C57BL/6 mice (aged 13 weeks) were randomly arranged to a sham-operated group (SHAM, treated with corn oil) and four ovariectomized groups that were administered corn oil (OVX group), estradiol valerate (EV, 2 mg/kg body weight as the positive control), low or high doses of VK (LVK and HVK; 20 and 40 mg MK-4/kg body weight, respectively) by gavage every other day for 12 weeks. Body and uterine weight, serum biochemical indicators, bone microarchitecture, hematoxylin-eosin (HE) staining, and the mRNA expression of critical genes related to bone formation and bone resorption pathways were assessed. Either dose of MK-4 supplementation increased the alkaline phosphatase (ALP), decreased the undercarboxylated osteocalcin (ucOC) and tartrate-resistant acid phosphatase (TRACP, p < 0.05) levels, and presented higher BMD, percent bone volume (BV/TV), trabecular thickness (Tb.Th), and lower trabecular separation (Tb.Sp) and structure model index (SMI, p < 0.05) compared with the OVX group. Additionally, both doses of MK4 increased the mRNA expression of Runx2 and Bmp2 (p < 0.05), whereas the doses down-regulated Pu.1 and Nfatc1 (p < 0.05) mRNA expression, the high dose decreased Osx and Tgfb (p < 0.05) mRNA expression, and the low dose decreased Mitd and Akt1 (p < 0.05) mRNA expression. These data show the dual regulatory effects of MK-4 on bone remodeling in ovariectomized mice: the promotion of bone anabolic activity and inhibition of osteoclast differentiation, which provides a novel idea for treating osteoporosis.
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20
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Iwamoto D, Masaki C, Shibata Y, Watanabe C, Nodai T, Munemasa T, Mukaibo T, Kondo Y, Hosokawa R. Microstructural and mechanical recovery of bone in ovariectomized rats: The effects of menaquinone-7. J Mech Behav Biomed Mater 2021; 120:104571. [PMID: 34029943 DOI: 10.1016/j.jmbbm.2021.104571] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/28/2021] [Accepted: 05/02/2021] [Indexed: 10/21/2022]
Abstract
The loss of bone quantity and quality in postmenopausal female patients can be a problem for dental treatment. A sufficient intake of nutrients such as calcium, magnesium, and vitamins D and K is likely correlated with the mechanical properties of bone. In particular, vitamin K2, also called menaquinone (MK), inhibits bone loss in postmenopausal women. Here we demonstrate the microstructural and mechanical properties of bone recovery in ovariectomized (OVX) rats during MK-7 administration. Bilateral ovariectomy and a sham operation were performed on 14-week-old female SPF Wistar rats. MK-4 and -7 were orally administered at 30 mg/kg daily for 12 weeks. The femur was used for the 3-point bending test and microstructural analysis of the cancellous bone by micro-CT, and the mandibular cortical bone for the evaluation of mechanical properties on a nanoscale. Micro-computed tomography revealed irregular trabecular architecture, hollow marrow cavities, and sparse trabecular bone in the femurs of the OVX group. Trabecular bone structure analysis showed that the MK-7 group had greater bone volume per tissue volume (BV/TV) and a higher trabecular number than the OVX group. The bulk-scale 3-point bending test did not allow the mechanical properties between OVX and OVX/MK7 groups to be discerned, yet at the smallest level, the elastic-plastic transition point of the nanoindentation stress-strain curve of the mandibular cortical bone was higher in the MK-7 group than in the OVX group. These findings suggest that MK-7 enables bone microstructural and mechanical recovery in the OVX model.
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Affiliation(s)
- Daisei Iwamoto
- Division of Oral Reconstruction and Rehabilitation, Kyushu Dental University, Japan
| | - Chihiro Masaki
- Division of Oral Reconstruction and Rehabilitation, Kyushu Dental University, Japan.
| | - Yo Shibata
- Department of Conservative Dentistry, Division of Biomaterials and Engineering, Showa University School of Dentistry, Japan
| | - Chie Watanabe
- Department of Conservative Dentistry, Division of Biomaterials and Engineering, Showa University School of Dentistry, Japan
| | - Tomotaka Nodai
- Division of Oral Reconstruction and Rehabilitation, Kyushu Dental University, Japan
| | - Takashi Munemasa
- Division of Oral Reconstruction and Rehabilitation, Kyushu Dental University, Japan
| | - Taro Mukaibo
- Division of Oral Reconstruction and Rehabilitation, Kyushu Dental University, Japan
| | - Yusuke Kondo
- Division of Oral Reconstruction and Rehabilitation, Kyushu Dental University, Japan
| | - Ryuji Hosokawa
- Division of Oral Reconstruction and Rehabilitation, Kyushu Dental University, Japan
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21
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The Dual Role of Vitamin K2 in "Bone-Vascular Crosstalk": Opposite Effects on Bone Loss and Vascular Calcification. Nutrients 2021; 13:nu13041222. [PMID: 33917175 PMCID: PMC8067793 DOI: 10.3390/nu13041222] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 03/30/2021] [Accepted: 04/04/2021] [Indexed: 12/13/2022] Open
Abstract
Osteoporosis (OP) and vascular calcification (VC) represent relevant health problems that frequently coexist in the elderly population. Traditionally, they have been considered independent processes, and mainly age-related. However, an increasing number of studies have reported their possible direct correlation, commonly defined as “bone-vascular crosstalk”. Vitamin K2 (VitK2), a family of several natural isoforms also known as menaquinones (MK), has recently received particular attention for its role in maintaining calcium homeostasis. In particular, VitK2 deficiency seems to be responsible of the so-called “calcium paradox” phenomenon, characterized by low calcium deposition in the bone and its accumulation in the vessel wall. Since these events may have important clinical consequences, and the role of VitK2 in bone-vascular crosstalk has only partially been explained, this review focuses on its effects on the bone and vascular system by providing a more recent literature update. Overall, the findings reported here propose the VitK2 family as natural bioactive molecules that could be able to play an important role in the prevention of bone loss and vascular calcification, thus encouraging further in-depth studies to achieve its use as a dietary food supplement.
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22
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Yang YJ, Kim DJ. An Overview of the Molecular Mechanisms Contributing to Musculoskeletal Disorders in Chronic Liver Disease: Osteoporosis, Sarcopenia, and Osteoporotic Sarcopenia. Int J Mol Sci 2021; 22:ijms22052604. [PMID: 33807573 PMCID: PMC7961345 DOI: 10.3390/ijms22052604] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/28/2021] [Accepted: 03/02/2021] [Indexed: 02/07/2023] Open
Abstract
The prevalence of osteoporosis and sarcopenia is significantly higher in patients with liver disease than in those without liver disease and osteoporosis and sarcopenia negatively influence morbidity and mortality in liver disease, yet these musculoskeletal disorders are frequently overlooked in clinical practice for patients with chronic liver disease. The objective of this review is to provide a comprehensive understanding of the molecular mechanisms of musculoskeletal disorders accompanying the pathogenesis of liver disease. The increased bone resorption through the receptor activator of nuclear factor kappa (RANK)-RANK ligand (RANKL)-osteoprotegerin (OPG) system and upregulation of inflammatory cytokines and decreased bone formation through increased bilirubin and sclerostin and lower insulin-like growth factor-1 are important mechanisms for osteoporosis in patients with liver disease. Sarcopenia is associated with insulin resistance and obesity in non-alcoholic fatty liver disease, whereas hyperammonemia, low amount of branched chain amino acids, and hypogonadism contributes to sarcopenia in liver cirrhosis. The bidirectional crosstalk between muscle and bone through myostatin, irisin, β-aminoisobutyric acid (BAIBA), osteocalcin, as well as the activation of the RANK and the Wnt/β-catenin pathways are associated with osteosarcopenia. The increased understandings for these musculoskeletal disorders would be contributes to the development of effective therapies targeting the pathophysiological mechanism involved.
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Affiliation(s)
- Young Joo Yang
- Department of Internal Medicine, Hallym University College of Medicine, Gangwon-do, Chuncheon 24252, Korea;
- Institute for Liver and Digestive Diseases, Hallym University, Gangwon-do, Chuncheon 24253, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Gangwon-do, Chuncheon 24252, Korea;
- Institute for Liver and Digestive Diseases, Hallym University, Gangwon-do, Chuncheon 24253, Korea
- Correspondence:
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23
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Ziemińska M, Sieklucka B, Pawlak K. Vitamin K and D Supplementation and Bone Health in Chronic Kidney Disease-Apart or Together? Nutrients 2021; 13:809. [PMID: 33804453 PMCID: PMC7999920 DOI: 10.3390/nu13030809] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/15/2021] [Accepted: 02/24/2021] [Indexed: 12/16/2022] Open
Abstract
Vitamin K (VK) and vitamin D (VD) deficiency/insufficiency is a common feature of chronic kidney disease (CKD), leading to impaired bone quality and a higher risk of fractures. CKD patients, with disturbances in VK and VD metabolism, do not have sufficient levels of these vitamins for maintaining normal bone formation and mineralization. So far, there has been no consensus on what serum VK and VD levels can be considered sufficient in this particular population. Moreover, there are no clear guidelines how supplementation of these vitamins should be carried out in the course of CKD. Based on the existing results of preclinical studies and clinical evidence, this review intends to discuss the effect of VK and VD on bone remodeling in CKD. Although the mechanisms of action and the effects of these vitamins on bone are distinct, we try to find evidence for synergy between them in relation to bone metabolism, to answer the question of whether combined supplementation of VK and VD will be more beneficial for bone health in the CKD population than administering each of these vitamins separately.
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Affiliation(s)
- Marta Ziemińska
- Department of Monitored Pharmacotherapy, Medical University of Bialystok, 15-222 Bialystok, Poland;
| | - Beata Sieklucka
- Department of Pharmacodynamics, Medical University of Bialystok, 15-222 Bialystok, Poland;
| | - Krystyna Pawlak
- Department of Monitored Pharmacotherapy, Medical University of Bialystok, 15-222 Bialystok, Poland;
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24
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AlHajri L, Ayoub A, Ahmed H, AlMulla M. Effect of Vitamin K2 Alone or in Combination on Various Bone Turnover Markers Amongst Postmenopausal Females. J Bone Metab 2021; 28:11-26. [PMID: 33730780 PMCID: PMC7973400 DOI: 10.11005/jbm.2021.28.1.11] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 01/28/2021] [Indexed: 11/27/2022] Open
Abstract
Background Osteoporosis is common in postmenopausal women. Some studies have demonstrated the usefulness of vitamin K through the action of bone-specific proteins and osteoblast and osteoclast activities. However, no systematic review had explored this aspect in postmenopausal women. Hence, this systematic review aimed to explore the effect of vitamin K2 alone or in combination with other agents (vitamin D3 or calcium) on various bone turnover markers (BTMs) and bone mineral density (BMD) in postmenopausal women. Methods MEDLINE, ScienceDirect, PubMed, and Google Scholar were searched to identify relevant studies using specific inclusion criteria. Data extraction and quality assessment were carried out using standardized tests, and the results were narratively synthesized and presented in the form of tables. Results Vitamin K2 was beneficial in inducing an improvement or preventing deterioration, as evidenced by the BMD and osteocalcin (OC), undercarboxylated OC (ucOC), carboxylated OC (cOC), and γ-carboxylated OC levels. However, its effect was not conclusive when procollagen type 1 N-terminal propeptide, carboxyterminal propeptide of type I procollagen, C-terminal telopeptide of type I collagen, bone alkaline phosphatase, deoxypyridinoline, and N-terminal telopeptide levels (NTX) and ucOC:cOC or cOC:ucOC, and NTX:creatinine ratios were examined. Conclusions Vitamin K2 supplementation combined with vitamin D and calcium was found to be advantageous. However, vitamin K2 supplementation cannot replace the existing treatment options. In addition, vitamin K2 should be used with caution, considering its interactions with food and other drugs.
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Affiliation(s)
- Lamia AlHajri
- Department of Health Sciences and Pharmacy, Higher Colleges of Technology, Dubai, United Arab Emirates.,Department of Health Research, Lancaster University, Lancaster, UK
| | - Amna Ayoub
- United Arab Emirates University, Al Ain, United Arab Emirates
| | - Hessa Ahmed
- Department of Health Sciences and Pharmacy, Higher Colleges of Technology, Dubai, United Arab Emirates
| | - Marwa AlMulla
- Department of Health Sciences and Pharmacy, Higher Colleges of Technology, Dubai, United Arab Emirates
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Cui Q, Li N, Nie F, Yang F, Li H, Zhang J. Vitamin K2 promotes the osteogenic differentiation of periodontal ligament stem cells via the Wnt/β-catenin signaling pathway. Arch Oral Biol 2021; 124:105057. [PMID: 33517171 DOI: 10.1016/j.archoralbio.2021.105057] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/30/2020] [Accepted: 01/05/2021] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Vitamin K2 (MK-4, menaquinone 4) plays an important role in osteoprotection. The present study aimed to examine the effect of MK-4 on the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) in vitro and probed the potential signaling pathway. DESIGN PDLSCs were isolated from extracted premolars by tissue block culture method and were identified by flow cytometry. Cell Counting Kit-8 (CCK-8) and colony formation assays were used to determine the effect of MK-4 on the proliferation of PDLSCs. Alkaline phosphatase (ALP) activity was analyzed quantitatively, and extracellular matrix mineralization was examined by Alizarin Red S staining. The mRNA and protein expression levels of ALP, Runx Family Transcription Factor 2 (Runx2), osteocalcin (OCN), and Sp7 Transcription Factor (SP7; Osterix) were measured by qRT-PCR and Western blot. In addition, after adding the inhibitor XAV-939, Western blot was used to assess the correlation with the Wnt/β-catenin signaling pathway. The above results were obtained by observing at least three fields randomly, and each experiment was repeated at least three times. RESULTS This study found that 10-5 M MK-4 significantly promoted the osteogenic differentiation of PDLSCs. Gene and protein expression levels of ALP, Runx2, OCN, and Osterix were all upregulated compared with control. Remarkably, after blocking the Wnt/β-catenin signaling pathway with XAV-939, the effect of MK-4 was apparently reversed. CONCLUSION These results demonstrate that MK-4 can promote the osteogenic differentiation of PDLSCs, which is likely related to the activation of the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Qun Cui
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No. 44-1 Wenhua Road West, 250012, Jinan, Shandong, China.
| | - Na Li
- Stomatology Department of The First Affiliated Hospital of Shandong First Medical University, No. 16766, Jingshi Road, 250012, Jinan, Shandong, China.
| | - Fujiao Nie
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No. 44-1 Wenhua Road West, 250012, Jinan, Shandong, China.
| | - Fan Yang
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No. 44-1 Wenhua Road West, 250012, Jinan, Shandong, China.
| | - Hongkun Li
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No. 44-1 Wenhua Road West, 250012, Jinan, Shandong, China.
| | - Jun Zhang
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No. 44-1 Wenhua Road West, 250012, Jinan, Shandong, China.
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Elshaikh AO, Shah L, Joy Mathew C, Lee R, Jose MT, Cancarevic I. Influence of Vitamin K on Bone Mineral Density and Osteoporosis. Cureus 2020; 12:e10816. [PMID: 33173624 PMCID: PMC7645307 DOI: 10.7759/cureus.10816] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Vitamin K (VK) has an established biological function in blood coagulation and hemostasis and maintains general health and bone wellbeing. VK supplements have been promoted to treat and prevent many diseases, particularly for decreasing fracture risk in osteoporosis, a chronic condition described by weak bone tissue, and a high fracture risk following minor trauma. It affects older people from different races and ethnicity, mainly postmenopausal women. Many kinds of research emphasize the role of VK in improving bone health and preventing osteoporotic bone fracture, but the findings are mostly inconclusive. In this literature review, PubMed and Google Scholar databases were used as the primary sources to select the relevant studies and review the association between VK and bone health and also, to explore the impact of VK supplementation in osteoporosis management. A majority of studies reported that VK has an essential role in promoting bone health. Although some studies revealed that VK might increase bone mineral density and reduce fracture risk in people with osteoporosis, VK supplements' potential benefits were not sufficiently supported. Thus, more clinical studies are needed to determine the positive effects of VK supplementation in osteoporosis prevention and treatment.
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Affiliation(s)
- Abeer O Elshaikh
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Lisa Shah
- Family and Community Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | | | - Robert Lee
- Surgery, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Merin Tresa Jose
- Family Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Ivan Cancarevic
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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Schröder M, Riksen EA, He J, Skallerud BH, Møller ME, Lian AM, Syversen U, Reseland JE. Vitamin K2 Modulates Vitamin D-Induced Mechanical Properties of Human 3D Bone Spheroids In Vitro. JBMR Plus 2020; 4:e10394. [PMID: 32995695 PMCID: PMC7507351 DOI: 10.1002/jbm4.10394] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 07/06/2020] [Accepted: 07/08/2020] [Indexed: 12/11/2022] Open
Abstract
Rotational culture promotes primary human osteoblasts (hOBs) to form three-dimensional (3D) multicellular spheroids with bone tissue-like structure without any scaffolding material. Cell-based bone models enable us to investigate the effect of different agents on the mechanical strength of bone. Given that low dietary intake of both vitamin D and K is negatively associated with fracture risk, we aimed to assess the effect of these vitamins in this system. Osteospheres of hOBs were generated with menaquinone-4 (MK-4; 10μM) and 25-hydroxyvitamin D3 [25(OH)D3; 0.01μM], alone and in combination, or without vitamins. The mechanical properties were tested by nanoindentation using a flat-punch compression method, and the mineralized extracellular bone matrix was characterized by microscopy. The in vitro response of hOBs to MK-4 and 25(OH)D3 was further evaluated in two-dimensional (2D) cultures and in the 3D bone constructs applying gene expression analysis and multiplex immunoassays. Mechanical testing revealed that 25(OH)D3 induced a stiffer and MK-4 a softer or more flexible osteosphere compared with control. Combined vitamin conditions induced the same flexibility as MK-4 alone. Enhanced levels of periostin (p < 0.001) and altered distribution of collagen type I (COL-1) were found in osteospheres supplemented with MK-4. In contrast, 25(OH)D3 reduced COL-1, both at the mRNA and protein levels, increased alkaline phosphatase, and stimulated mineral deposition in the osteospheres. With the two vitamins in combination, enhanced gene expression of periostin and COL-1 was seen, as well as extended osteoid formation into the central region and increased mineral deposition all over the area. Moreover, we observed enhanced levels of osteocalcin in 2D and osteopontin in 3D cultures exposed to 25(OH)D3 alone and combined with MK-4. In conclusion, the two vitamins seem to affect bone mechanical properties differently: vitamin D enhancing stiffness and K2 conveying flexibility to bone. These effects may translate to increased fracture resistance in vivo. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Maria Schröder
- Department of Biomaterials University of Oslo Oslo Norway
| | | | - Jianying He
- Department of Structural Engineering, Faculty of Engineering Norwegian University of Science and Technology (NTNU) Trondheim Norway
| | - Bjørn Helge Skallerud
- Department of Structural Engineering, Faculty of Engineering Norwegian University of Science and Technology (NTNU) Trondheim Norway
| | | | - Aina-Mari Lian
- Oral Research Laboratory, Institute for Clinical Dentistry University of Oslo Oslo Norway
| | - Unni Syversen
- Oral Research Laboratory, Institute for Clinical Dentistry University of Oslo Oslo Norway.,Department of Clinical and Molecular Medicine NTNU Trondheim Norway.,Department of Endocrinology, Clinic of Medicine, St. Olavs Hospital Trondheim University Hospital Trondheim Norway
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The effect of aeration and mixing in developing a dairy-based functional food rich in menaquinone-7. Bioprocess Biosyst Eng 2020; 43:1773-1780. [PMID: 32377942 DOI: 10.1007/s00449-020-02366-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 04/24/2020] [Indexed: 12/17/2022]
Abstract
Vitamin menaquinone-7 (MK-7) supplementation improves bone health and reduces the incidence of osteoporosis. Despite the recent developments in MK-7 fermentation using Bacillus subtilis natto, low fermentation yields, as well as complicated downstream processing steps, are still the main reasons for the expensive final product. To overcome these issues, developing a fermented dairy-based product rich in MK-7 by avoiding costly downstream steps and optimising the fermentation operating conditions to enhance the MK-7 concentration would be an alternative approach. The present study, therefore, aims to evaluate the role of agitation and aeration as the key operating conditions on MK-7 production by Bacillus subtilis natto using a milk media. The agitation and aeration rates of 525 RPM and 5 VVM were found to be the optimum levels leading to the production of 3.54 mg/L of MK-7. Further, the sensory evaluation was performed to compare the sensory properties of the freeze-dried fermented samples with non-fermented milk samples. The results illustrated that the fermented samples had a significant saltiness with intense aroma resulting in the less acceptability of them by the panellists.
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Zhang Y, Liu Z, Duan L, Ji Y, Yang S, Zhang Y, Li H, Wang Y, Wang P, Chen J, Li Y. Effect of Low-Dose Vitamin K2 Supplementation on Bone Mineral Density in Middle-Aged and Elderly Chinese: A Randomized Controlled Study. Calcif Tissue Int 2020; 106:476-485. [PMID: 32060566 DOI: 10.1007/s00223-020-00669-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 02/03/2020] [Indexed: 10/25/2022]
Abstract
Previous studies indicated a positive effect of vitamin K2 (VK2) supplementation on bone turnover biomarkers and bone mineral density (BMD), but the doses varied, and few studies have focused on the difference between VK2 supplementation alone and in combination with calcium and vitamin D3. The aim of this study was to explore a low and effective dose of VK2 for improving BMD, and to examine whether the co-supplementation of VK2, calcium and vitamin D3 would bring greater effects. In this trial, a total of 311 community-dwelling men and postmenopausal women aged 50 and 75 years were randomly assigned to four groups, receiving placebo, 50 µg/day, 90 µg/day or co-supplementation with calcium (500 mg/day) and vitamin D3 (10 µg/day) for 1 year. At the endpoint, the bone loss of femoral neck was significantly lower in postmenopausal women in the two 90 µg groups (treatment × time, p = 0.006) compared with placebo, but no effects in men. Serum biomarkers cOC/ucOC ratio increased in the intervention groups (treatment × time, p < 0.001). VK2 supplementation in dose of 90 µg/day performed a significant effect on reducing bone loss in postmenopausal women, but in combination with calcium and vitamin D3 brought no additional effects.Trial registration This trial was registered at http://www.chictr.org.cn as chiCTR1800019240.
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Affiliation(s)
- Yingfeng Zhang
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, 150086, People's Republic of China
| | - Zhipeng Liu
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, 150086, People's Republic of China
| | - Lili Duan
- Vitamin K2 Research Center, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110015, People's Republic of China
| | - Yeyu Ji
- Vitamin K2 Research Center, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110015, People's Republic of China
| | - Sen Yang
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, 150086, People's Republic of China
| | - Yuan Zhang
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, 150086, People's Republic of China
| | - Hongyin Li
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, 150086, People's Republic of China
| | - Yu Wang
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, 150086, People's Republic of China
| | - Peng Wang
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, 150086, People's Republic of China
| | - Jiepeng Chen
- Vitamin K2 Research Center, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110015, People's Republic of China.
| | - Ying Li
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, 150086, People's Republic of China.
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Danford CJ, Ezaz G, Trivedi HD, Tapper EB, Bonder A. The Pharmacologic Management of Osteoporosis in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis. J Clin Densitom 2020; 23:223-236. [PMID: 31146965 DOI: 10.1016/j.jocd.2019.05.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 05/06/2019] [Accepted: 05/07/2019] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Osteoporosis is a common complication of primary biliary cholangitis (PBC) yet evidence for effective therapy is lacking. We sought to review all randomized controlled trials evaluating pharmacotherapy against placebo or no intervention for treatment of osteoporosis in PBC. METHODOLOGY A comprehensive database search was conducted from inception through 29 March 2017. The primary outcome was incidence of fractures; secondary outcomes were change in bone mineral density (BMD) and adverse events. We assessed studies for risk of bias, graded quality of evidence, and used meta-analysis to obtain overall effect by pooling studies of the same drug class. RESULTS We identified 11 randomized controlled trials evaluating bisphosphonates (3), hormone replacement therapy (2), ursodeoxycholic acid (1), obeticholic acid (1), cyclosporin A (1), vitamin K (1), calcitriol (1), and sodium fluoride (1). No intervention significantly reduced fractures compared to control. Although significant improvement in BMD was seen in one study with alendronate, a third-generation bisphosphonate, no significant improvement was seen on pooled analysis of all bisphosphonates including first-generation bisphosphonates (standard mean difference 0.41, p = 0.68). On pooled analysis, hormone replacement therapy modestly improved lumbar BMD (standard mean difference 0.69, p = 0.02), but with significantly increased adverse events (odds ratio 8.82, p = 0.01). CONCLUSIONS There is a lack of high-quality evidence supporting the efficacy of any treatment of osteoporosis in PBC. This may be explained by lack of power in the included studies. However, our current understanding of PBC-related osteoporosis indicates that it results from decreased bone formation, which may explain the attenuated effect of traditional antiresorptive agents. Future studies should investigate newer anabolic bone agents.
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Affiliation(s)
- Christopher J Danford
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Ghideon Ezaz
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Hirsh D Trivedi
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Elliot B Tapper
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| | - Alan Bonder
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
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Danford CJ, Trivedi HD, Bonder A. Bone Health in Patients With Liver Diseases. J Clin Densitom 2020; 23:212-222. [PMID: 30744928 DOI: 10.1016/j.jocd.2019.01.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 01/15/2019] [Accepted: 01/15/2019] [Indexed: 12/19/2022]
Abstract
Osteoporosis is the most common bone disease in chronic liver disease (CLD) resulting in frequent fractures and leading to significant morbidity in this population. In addition to patients with cirrhosis and chronic cholestasis, patients with CLD from other etiologies may be affected in the absence of cirrhosis. The mechanism of osteoporosis in CLD varies according to etiology, but in cirrhosis and cholestatic liver disease it is driven primarily by decreased bone formation, which differs from the increased bone resorption seen in postmenopausal osteoporosis. Direct toxic effects from iron and alcohol play a role in hemochromatosis and alcoholic liver disease, respectively. Chronic inflammation also has been proposed to mediate bone disease in viral hepatitis and nonalcoholic fatty liver disease. Treatment trials specific to osteoporosis in CLD are small, confined to primary biliary cholangitis and post-transplant patients, and have not consistently demonstrated a benefit in this population. As it stands, prevention of osteoporosis in CLD relies on the mitigation of risk factors such as smoking and alcohol use, treatment of underlying hypogonadism, and encouraging a healthy diet and weight-bearing exercise. The primary medical intervention for the treatment of osteoporosis in CLD remains bisphosphonates though a benefit in terms of fracture reduction has never been shown. This review outlines what is known regarding the pathogenesis of bone disease in CLD and summarizes current and emerging therapies.
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Affiliation(s)
- Christopher J Danford
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA USA
| | - Hirsh D Trivedi
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA USA
| | - Alan Bonder
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA USA.
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Berg J, Seyedsadjadi N, Grant R. Increased Consumption of Plant Foods Is Associated with Increased Bone Mineral Density. J Nutr Health Aging 2020; 24:388-397. [PMID: 32242206 DOI: 10.1007/s12603-020-1339-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES To determine the relationship between plant food consumption and bone mineral density (BMD) in a healthy population when age, gender, BMI and physical activity are accounted for. DESIGN Cross-sectional study. SETTING Participants were recruited from the Sydney Adventist hospital and the University of New South Wales, Sydney, Australia. PARTICIPANTS 33 males and 40 females (total n=73) participated in this study. The mean age was 56.1 ± 8.5 years. All participants were non-diabetic and in general good health. MEASUREMENTS A principle component analysis (PCA) was performed on 12 month self-report food intake data, gathered using the Cancer Council Victoria Dietary Questionnaire for Epidemiological Studies Version 2. Dual-energy X-ray absorptiometry was used to measure total BMD. Fasting plasma total protein, calcium and 25-Hydroxy Vitamin D levels were analysed by the Sydney Adventist Hospital pathology laboratory. Anthropometric measures were obtained using a standardized protocol. Self-reported physical activity levels were assessed using the International Physical Activity Questionnaire. RESULTS The PCA revealed three principle components. These were termed 'Meat Based', 'Junk Food' and 'Plant Based.' After controlling for age, gender, physical activity and BMI, the Plant Based component correlated positively with BMD (p=0.054, R2=0.439) and T-score (p=0.053, R2=0.221). Using a similar model no association between the Meat Based component and BMD or T-score was found. However, when the Plant Based component was included the Meat Based component correlated positively with BMD (p=0.046, R2=0.474) and T-score (p=0.046, R2=0.279). There was no significant association between the Junk Food component and BMD or T-score. People in the third Plant (927 ± 339 vs 751 ± 255 g/day, p=0.025) and Meat Based (921 ± 270 vs 676 ± 241 g/day, p=0.002) tertile had higher calcium intakes than those in the first. People in the second Plant Based tertile had higher plasma Vitamin D levels than those in the first (63.5 ± 16.8 vs. 52.3 ± 22.1 nmol/L, p=0.053) while those in the third Junk Food tertile had lower levels than those in the first (52.4 ± 18.5 vs. 65.4 ± 19.8 nmol/L, p=0.027). No association between Plant Based tertiles and protein intake was observed, however those in the third Meat Based (99.7 ± 25.1 vs. 50.9 ± 13.8 g/day, p=0.000) and Junk Food (87.4 ± 30.7 vs. 56.6 ± 22.2 g/day, p=0.000) tertile had higher protein intake compared to those in the first tertile. CONCLUSION In a healthy middle aged population with normal BMD, an increase in plant food consumption, either alone or in combination with a diet containing meat, is associated with improved bone mineralisation markers. This positive relationship is most likely due to the extensive range of micronutrients and phytochemicals packaged within plants.
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Affiliation(s)
- J Berg
- Ross Grant, The University of Sydney Adventist Hospital Clinical School, 185 Fox Valley Rd, Wahroonga, NSW Australia, Phone: +61 2 9487 9602,
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A comparatively study of menaquinone-7 isolated from Cheonggukjang with vitamin K 1 and menaquinone-4 on osteoblastic cells differentiation and mineralization. Food Chem Toxicol 2019; 131:110540. [PMID: 31173816 DOI: 10.1016/j.fct.2019.05.048] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 05/13/2019] [Accepted: 05/27/2019] [Indexed: 12/25/2022]
Abstract
The effect of menaquinone-7 isolated from cheonggukjang was comparatively investigated with vitamin K1 and menaquinone-4 on cell differentiation and mineralization of the osteoblastic cell line MC3T3-E1. Results indicated that all vitamin K species significantly increased MC3T3-E1 cell proliferation, cellular alkaline phosphatase activity, osteocalcin synthesis, and calcium deposition in a dose-dependent manner. Menaquinone-4 and menaquinone-7 had more potent effects on calcium deposition than vitamin K1, and their effects were only partly reduced by warfarin (γ-carboxylation inhibitor) treatment, while warfarin abolished the induction activity of vitamin K1 on calcification. This suggests that vitamin K1 and K2 (menaquinone-4 & menaquinone-7) may have different mechanisms in stimulating osteoblast mineralization. In addition, the mRNA expression ratio of osteoprotegerin and the receptor activator of nuclear factor-kB ligand was also dramatically increased by treatment with vitamin K1 (62%), menaquinone-4 (247%), and menaquinone-7 (329%), suggesting that vitamin K may suppress the formation of osteoclast by up-regulating the ratio of osteoprotegerin/receptor activator of nuclear factor-kB ligand in osteoblasts. These results provide compelling evidence that vitamin K1, menaquinone-4, and menaquinone-7 all can promote bone health, which might be associated with elevations in the osteoprotegerin/receptor activator of nuclear factor-kB ligand ratio.
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Combined treatment with vitamin K2 and PTH enhanced bone formation in ovariectomized rats and increased differentiation of osteoblast in vitro. Chem Biol Interact 2019; 300:101-110. [PMID: 30639440 DOI: 10.1016/j.cbi.2019.01.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 12/22/2018] [Accepted: 01/09/2019] [Indexed: 02/06/2023]
Abstract
Osteoporosis is accompanied by insufficient osteogenic capacity. Several lines of evidence suggested that solutions to enhance osteoblastogenesis were important strategies for osteoporotic bone defect repair. This study investigated the effect of combined treatment with vitamin K2 and PTH on bone formation in calvarial bone defect in osteoporotic rats and its influence on osteoblast in vitro. Bilateral ovariectomy was used in SPF Sprague Dawley rats to generate an osteoporosis model. Subsequently, a calvarial defect model was established and all osteoporotic rats were randomly assigned to the following groups: control, VK (vitamin K2, 30 mg/kg everyday), PTH (recombinant human PTH (1-34), 60 μg/kg, three times a week) or VK + PTH (vitamin K2, 30 mg/kg everyday plus PTH, 60 μg/kg three times a week) for 8 weeks. In vitro, bone marrow-derived stem cells (BMSCs) were cultured and treated with vitamin K2, PTH or vitamin K2+PTH. ALP staining and western blot were performed to observe the influence of combined treatment on BMSCs. Bone formation within calvarial defect were assessed by serum γ-carboxylated osteocalcin (Gla-OC), micro-CT, histological and immunofluorescent labeling. In this study, combined treatment of PTH and vitamin K2 showed positive effects on preventing bone loss in femurs in OVX rats. Combined treatment increased serum Gla-OC and promoted bone formation in osteoporotic calvarial bone defects. Immunohistochemistry showed that OCN and RUNX2 were more highly expressed in the VK + PTH group than in the control groups. In vitro studies results suggested that combined treatment with PTH and vitamin K2 increased expression of ALP, BMP2 and RUNX2 in BMSCs. Our data suggested that the combination of vitamin K2 and PTH increased differentiation of osteoblast and had a synergistic effect on bone formation in osteoporotic calvarial bone defect.
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Danford CJ, Trivedi HD, Papamichael K, Tapper EB, Bonder A. Osteoporosis in primary biliary cholangitis. World J Gastroenterol 2018; 24:3513-3520. [PMID: 30131657 PMCID: PMC6102495 DOI: 10.3748/wjg.v24.i31.3513] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 07/11/2018] [Accepted: 07/21/2018] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease with multiple debilitating complications. Osteoporosis is a common complication of PBC resulting in frequent fractures and leading to significant morbidity in this population, yet evidence for effective therapy is lacking. We sought to summarize our current understanding of the pathophysiology of osteoporosis in PBC, as well as current and emerging therapies in order to guide future research directions. A complete search with a comprehensive literature review was performed with studies from PubMed, EMBASE, Web of Science, Cochrane database, and the Countway Library. Osteoporosis in PBC is driven primarily by decreased bone formation, which differs from the increased bone resorption seen in postmenopausal osteoporosis. Despite this fundamental difference, current treatment recommendations are based primarily on experience with postmenopausal osteoporosis. Trials specific to PBC-related osteoporosis are small and have not consistently demonstrated a benefit in this population. As it stands, prevention of osteoporosis in PBC relies on the mitigation of risk factors such as smoking and alcohol use, as well as encouraging a healthy diet and weight-bearing exercise. The primary medical intervention for the treatment of osteoporosis in PBC remains bisphosphonates though a benefit in terms of fracture reduction has never been shown. This review outlines what is known regarding the pathogenesis of bone disease in PBC and summarizes current and emerging therapies.
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Affiliation(s)
- Christopher J Danford
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, Unites States
| | - Hirsh D Trivedi
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, Unites States
| | - Konstantinos Papamichael
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, Unites States
| | - Elliot B Tapper
- Department of Hepatology, University of Michigan, Ann Arbor, MI 48109, Unites States
| | - Alan Bonder
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, Unites States
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Vitamin K and Bone Metabolism: A Review of the Latest Evidence in Preclinical Studies. BIOMED RESEARCH INTERNATIONAL 2018; 2018:4629383. [PMID: 30050932 PMCID: PMC6040265 DOI: 10.1155/2018/4629383] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 05/27/2018] [Indexed: 01/09/2023]
Abstract
Bone is a metabolically active tissue that renews itself throughout one's life. Cytokines along with several hormonal, nutritional, and growth factors are involved in tightly regulated bone remodeling. Accordingly, vitamin K as a multifunctional vitamin has been recently deemed appreciable as a topic of research as it plays a pivotal role in maintenance of the bone strength, and it has been proved to have a positive impact on the bone metabolism. Vitamin K exerts its anabolic effect on the bone turnover in different ways such as promoting osteoblast differentiation, upregulating transcription of specific genes in osteoblasts, and activating the bone-associated vitamin k dependent proteins which play critical roles in extracellular bone matrix mineralization. There is also credible evidence to support the effects of vitamin k2 on differentiation of other mesenchymal stem cells into osteoblast. The main objective of the present paper is to comprehensively outline the preclinical studies on the properties of vitamin K and its effects on the bone metabolism. The evidence could shed light on further clinical studies to improve osteogenesis in bone graft surgeries.
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Vitamin K: Redox-modulation, prevention of mitochondrial dysfunction and anticancer effect. Redox Biol 2018; 16:352-358. [PMID: 29597144 PMCID: PMC5953218 DOI: 10.1016/j.redox.2018.03.013] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 03/15/2018] [Accepted: 03/17/2018] [Indexed: 12/21/2022] Open
Abstract
This review is directed to the redox-modulating properties and anticancer effect of vitamin K. The concept is focused on two aspects: (i) redox-cycle of vitamin K and its effect on the calcium homeostasis, “oncogenic” and “onco-suppressive” reactive oxygen species and the specific induction of oxidative stress in cancer; (ii) vitamin K plus C as a powerful redox-system, which forms a bypass between mitochondrial complexes II and III and thus prevents mitochondrial dysfunction, restores oxidative phosphorylation and aerobic glycolysis, modulates the redox-state of endogenous redox-pairs, eliminates the hypoxic environment of cancer cells and induces cell death. The analyzed data suggest that vitamin C&K can sensitize cancer cells to conventional chemotherapy, which allows achievement of a lower effective dose of the drug and minimizing the harmful side-effects. The review is intended for a wide audience of readers - from students to specialists in the field.
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Myneni VD, Mezey E. Immunomodulatory effect of vitamin K2: Implications for bone health. Oral Dis 2018; 24:67-71. [PMID: 29480629 PMCID: PMC5831512 DOI: 10.1111/odi.12759] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 08/18/2017] [Accepted: 08/18/2017] [Indexed: 11/30/2022]
Abstract
OBJECTIVE In women with postmenopausal osteoporosis, vitamin K2 appears to decrease the incidence of hip, vertebral, and non-vertebral fractures. Women with postmenopausal osteoporosis have more circulating activated T cells compared with healthy postmenopausal and premenopausal women, but the effects of vitamin K2 on T cells have not been studied. In this study, we have looked at T-cell suppression by vitamin K2. MATERIALS AND METHODS Peripheral blood mononuclear cells (PBMCs) from three healthy donors were used. The PBMCs were stimulated with the mitogens phytohemagglutinin and concanavalin A, and T-cell proliferation was analyzed using flow cytometry based on carboxyfluorescein succinimidyl ester (CSFE) dye dilution. RESULTS Vitamin K2 (60 and 100 μM) inhibited T-cell proliferation. Vitamin K1 at the same concentrations did not inhibit T-cell proliferation. CONCLUSION Vitamin K2 has immunomodulatory activities.
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Affiliation(s)
- Vamsee D. Myneni
- Adult Stem Cell Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Eva Mezey
- Adult Stem Cell Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD 20892, USA
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Villa JKD, Diaz MAN, Pizziolo VR, Martino HSD. Effect of vitamin K in bone metabolism and vascular calcification: A review of mechanisms of action and evidences. Crit Rev Food Sci Nutr 2018; 57:3959-3970. [PMID: 27437760 DOI: 10.1080/10408398.2016.1211616] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Osteoporosis is a public health concern associated with an increased risk of bone fractures and vascular calcification. Vitamin K presents unique benefits on these issues, although understudied. The two main forms of vitamin K are phylloquinone (vitamin K1) and menaquinone (vitamin K2). In this study, it was especially investigated the action of vitamin K2 in bones and vessels. Vitamin K2 has shown to stimulate bone formation by promoting osteoblast differentiation and carboxylation of osteocalcin, and increasing alkaline phosphatase, insulin-like growth factor-1, growth differentiation factor-15, and stanniocalcin 2 levels. Furthermore, vitamin K2 reduces the pro-apoptotic proteins Fas and Bax in osteoblasts, and decreases osteoclast differentiation by increasing osteoprotegerin and reducing the receptor activator of nuclear factor kappa-B ligand. In blood vessels, vitamin K2 reduces the formation of hydroxyapatite, through the carboxylation of matrix Gla protein and Gla rich protein, inhibits the apoptosis of vascular smooth muscle cells, by increasing growth arrest-specific gene 6, and reduces the transdifferentiation of vascular smooth muscle cells to osteoblasts. The commonly used dosage of vitamin K2 in human studies is 45 mg/day and its application can be an interesting strategy in benefitting bone and vascular health, especially to osteoporotic post-menopausal women.
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Affiliation(s)
- Julia Khéde Dourado Villa
- a Departamento de Bioquímica e Biologia Molecular , Universidade Federal de Viçosa , Minas Gerais , Brazil
| | - Marisa Alves Nogueira Diaz
- a Departamento de Bioquímica e Biologia Molecular , Universidade Federal de Viçosa , Minas Gerais , Brazil
| | - Virgínia Ramos Pizziolo
- a Departamento de Bioquímica e Biologia Molecular , Universidade Federal de Viçosa , Minas Gerais , Brazil
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Myneni VD, Mezey E. Regulation of bone remodeling by vitamin K2. Oral Dis 2017; 23:1021-1028. [PMID: 27976475 PMCID: PMC5471136 DOI: 10.1111/odi.12624] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 12/02/2016] [Indexed: 11/27/2022]
Abstract
All living tissues require essential nutrients such as amino acids, fatty acids, carbohydrates, minerals, vitamins, and water. The skeleton requires nutrients for development, maintaining bone mass and density. If the skeletal nutritional requirements are not met, the consequences can be quite severe. In recent years, there has been growing interest in promotion of bone health and inhibition of vascular calcification by vitamin K2. This vitamin regulates bone remodeling, an important process necessary to maintain adult bone. Bone remodeling involves removal of old or damaged bone by osteoclasts and its replacement by new bone formed by osteoblasts. The remodeling process is tightly regulated, when the balance between bone resorption and bone formation shifts to a net bone loss results in the development of osteoporosis in both men and women. In this review, we focus on our current understanding of the effects of vitamin K2 on bone cells and its role in prevention and treatment of osteoporosis.
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Affiliation(s)
- Vamsee D. Myneni
- Adult Stem Cell Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Eva Mezey
- Adult Stem Cell Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD 20892, USA
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Hussein AG, Mohamed RH, Shalaby SM, Abd El Motteleb DM. Vitamin K 2 alleviates type 2 diabetes in rats by induction of osteocalcin gene expression. Nutrition 2017; 47:33-38. [PMID: 29429532 DOI: 10.1016/j.nut.2017.09.016] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 08/23/2017] [Accepted: 09/30/2017] [Indexed: 11/15/2022]
Abstract
OBJECTIVES The biological mechanisms behind the association between vitamin K (Vit K) and glucose metabolism are uncertain. We aimed to analyze the expression of insulin 1 (Ins 1), insulin 2 (Ins 2) and cyclin D2, the expression of adiponectin and UCP-1 . In addition, we aimed to estimate the doses of Vit K2 able to affect various aspects of glucose and energy metabolism in type 2 diabetes. METHODS Thirty adult male rats were allocated equally into five groups: control group, diabetes mellitus group, and groups 3, 4, and 5, which received Vit K2 at three daily dose levels (10, 15, and 30 mg/kg, respectively) for 8 wk. At the end of the study, blood samples were collected to quantify total osteocalcin, fasting plasma glucose, fasting insulin, and relevant variables. The expression of OC, Ins 1, Ins 2, cyclin D2, adiponectin, UCP-1 genes was analyzed by real-time polymerase chain reaction. RESULTS After administration of Vit K2, a dose-dependent decrease in fasting plasma glucose, hemoglobin A1c and homeostatic model assessment method insulin resistance, and a dose-dependent increase in fasting insulin and homeostatic model assessment method β cell function levels, when compared with diabetes mellitus rats, were detected. There was significant upregulation of OC, Ins 1, Ins 2, or cyclin D2 gene expression in the three treated groups in a dose-dependent manner when compared with the diabetic rats. However, expression of adiponectin and UCP-1 were significantly increased at the highest dose (30 mg/kg daily) only. CONCLUSIONS Vit K2 administration could improve glycemic status in type 2 diabetic rats by induction of OC gene expression. Osteocalcin could increase β-cell proliferation, energy expenditure, and adiponectin expression. Different concentrations of Vit K2 were required to affect glucose metabolism and insulin sensitivity.
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Affiliation(s)
- Atef G Hussein
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Randa H Mohamed
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
| | - Sally M Shalaby
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Abstract
The association between dietary vitamin K intake and the risk of fractures is controversial. Therefore we perform a meta-analysis of cohort or nested case-control studies to investigate the relationship between dietary vitamin K intake and the risk of fractures. A comprehensive search of PubMed and EMBASE (to July 11, 2016) was performed to identify cohort or nested case-control studies providing quantitative estimates between dietary vitamin K intake and the risk of fractures. Summary relative risk (RRs) with corresponding 95% confidence intervals (CIs) were pooled by using a random-effects model. Four cohort studies and one nested case-control study, with a total of 1114 fractures cases and 80,982 participants, were included in our meta-analysis. Vitamin K intake in all included studies refers exclusively to the intake of phylloquinone (vitamin K1), which is the predominant form of vitamin K in foods. We observed a statistically significant inverse association between dietary vitamin K intake and risk of fractures (highest vs. the lowest intake, RR = 0.78, 95% CI: 0.56-0.99; I = 59.2%, P for heterogeneity = .04). Dose-response analysis indicated that the pooled RR of fracture for an increase of 50 μg dietary vitamin K intake per day was 0.97 (95% CI: 0.95-0.99) without heterogeneity among studies (I = 25.9%, P for heterogeneity = .25). When stratified by follow-up duration, the RR of fracture for dietary vitamin K intake was 0.76 (95% CI: 0.58-0.93) in studies with more than 10 years of follow-up. Our study suggests that higher dietary vitamin K intake may moderately decrease the risk of fractures.
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Affiliation(s)
- Guangliang Hao
- Department of Traumatic Orthopedic Surgery, General Hospital of Jinan Military Command
| | - Bei Zhang
- Department of Gynaecology and Obstetrics, First People's Hospital of Jinan, Jinan, China
| | - Mingyong Gu
- Department of Traumatic Orthopedic Surgery, General Hospital of Jinan Military Command
| | - Chen Chen
- Department of Traumatic Orthopedic Surgery, General Hospital of Jinan Military Command
| | - Qiang Zhang
- Department of Traumatic Orthopedic Surgery, General Hospital of Jinan Military Command
| | - Guichun Zhang
- Department of Traumatic Orthopedic Surgery, General Hospital of Jinan Military Command
| | - Xuecheng Cao
- Department of Traumatic Orthopedic Surgery, General Hospital of Jinan Military Command
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Zhang Y, Weng S, Yin J, Ding H, Zhang C, Gao Y. Vitamin K2 promotes mesenchymal stem cell differentiation by inhibiting miR‑133a expression. Mol Med Rep 2017; 15:2473-2480. [PMID: 28447758 PMCID: PMC5428867 DOI: 10.3892/mmr.2017.6308] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 01/13/2017] [Indexed: 12/24/2022] Open
Abstract
Vitamin K2 has been demonstrated to promote the osteogenic differentiation of mesenchymal stem cells; however, the mechanisms underlying this effect remain unclear. As microRNA (miR)-133a has been identified as a negative regulator of osteogenic differentiation, the present study hypothesized that vitamin K2 promoted osteogenesis by inhibiting miR-133a. Using human bone marrow stromal cells (hBMSCs) overexpressing miR-133a, or a control, the expression levels of osteogenesis-associated proteins, including runt-related transcription factor 2, alkaline phosphatase and osteocalcin, were analyzed. miR-133a significantly suppressed the osteogenic differentiation of hBMSCs. To determine the effect of vitamin K2 on miR-133a expression and osteogenesis, hBMSCs were treated with vitamin K2. Vitamin K2 inhibited miR-133a expression, which was accompanied by enhanced osteogenic differentiation. Furthermore, the expression levels of vitamin K epoxide reductase complex subunit 1, the key protein in γ-carboxylation, were downregulated by miR-133a overexpression and upregulated by vitamin K2 treatment, indicating a positive feedback on γ-carboxylation. The results of the present study suggested that vitamin K2 targets miR-133a to regulate osteogenesis.
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Affiliation(s)
- Yuelei Zhang
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Shiyang Weng
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Junhui Yin
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Hao Ding
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Changqing Zhang
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Youshui Gao
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
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Zhang YL, Yin JH, Ding H, Zhang W, Zhang CQ, Gao YS. Protective effect of VK2 on glucocorticoid-treated MC3T3-E1 cells. Int J Mol Med 2016; 39:160-166. [PMID: 27909721 PMCID: PMC5179185 DOI: 10.3892/ijmm.2016.2817] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 11/24/2016] [Indexed: 12/31/2022] Open
Abstract
Glucocorticoids (GCs) contribute to the increased incidence of secondary osteoporosis and osteonecrosis, and medications for the prevention and treatment of these complications have been investigated for many years. Vitamin K2 (VK2) has been proven to promote bone formation both in vitro and in vivo. In this study, we examined the effects of VK2 on dexamethasone (DEX)-treated MC3T3-E1 osteoblastic cells. We observed that VK2 promoted the proliferation and enhanced the survival of dexamethasone-treated MC3T3-E1 cells. In addition, VK2 upregulated the expression levels of osteogenic marker proteins, such as Runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP) and osteocalcin, which were significantly inhibited by dexamethasone. On the whole, our findings indicate that VK2 has the potential to antagonize the effects of GCs on MC3T3-E1 cells, and may thus prove to be a promising agent for the prevention and treatment of GC-induced osteoporosis and osteonecrosis.
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Affiliation(s)
- Yue-Lei Zhang
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Jun-Hui Yin
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Hao Ding
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Wei Zhang
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Chang-Qing Zhang
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - You-Shui Gao
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
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Menaquinone-4 (vitamin K 2 ) up-regulates expression of human intestinal alkaline phosphatase in Caco-2 cells. Nutr Res 2016; 36:1269-1276. [DOI: 10.1016/j.nutres.2016.10.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 10/03/2016] [Accepted: 10/10/2016] [Indexed: 11/23/2022]
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Diagnosis and Management of Cirrhosis-Related Osteoporosis. BIOMED RESEARCH INTERNATIONAL 2016; 2016:1423462. [PMID: 27840821 PMCID: PMC5093239 DOI: 10.1155/2016/1423462] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Accepted: 10/03/2016] [Indexed: 12/20/2022]
Abstract
Management of cirrhosis complications has greatly improved, increasing survival and quality of life of the patients. Despite that, some of these complications are still overlooked and scarcely treated, particularly those that are not related to the liver. This is the case of osteoporosis, the only cirrhosis complication that is not solved after liver transplantation, because bone loss often increases after immunosuppressant therapy. In this review, the definitions of bone conditions in cirrhotic patients are analyzed, focusing on the more common ones and on those that have the largest impact on this population. Risk factors, physiopathology, diagnosis, screening strategies, and treatment of osteoporosis in cirrhotic patients are discussed, presenting the more striking data on this issue. Therapies used for particular conditions, such as primary biliary cirrhosis and liver transplantation, are also presented.
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Wu WJ, Kim MS, Ahn BY. The inhibitory effect of vitamin K on RANKL-induced osteoclast differentiation and bone resorption. Food Funct 2016; 6:3351-8. [PMID: 26267519 DOI: 10.1039/c5fo00544b] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
To further understand the correlation between vitamin K and bone metabolism, the effects of vitamins K1, menaquinone-4 (MK-4), and menaquinone-7 (MK-7) on RANKL-induced osteoclast differentiation and bone resorption were comparatively investigated. Vitamin K2 groups (MK-4 and MK-7) were found to significantly inhibit RANKL-medicated osteoclast cell formation of bone marrow macrophages (BMMs) in a dose-dependent manner, without any evidence of cytotoxicity. The mRNA expression of specific osteoclast differentiation markers, such as c-Fos, NFATc1, OSCAR, and TRAP, as well as NFATc1 protein expression and TRAP activity in RANKL-treated BMMs were inhibited by vitamin K2, although MK-4 exhibited a significantly greater efficiency compared to MK-7. In contrast, the same dose of vitamin K1 had no inhibitory effect on RANKL-induced osteoclast cell formation, but increased the expression of major osteoclastogenic genes. Interestingly, vitamins K1, MK-4 and MK-7 all strongly inhibited osteoclastic bone resorption (p < 0.01) in a dose dependent manner. These results suggest that vitamins K1, MK-4 and MK-7 have anti-osteoporotic properties, while their regulation effects on osteoclastogenesis are somewhat different.
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Affiliation(s)
- Wei-Jie Wu
- Institute of food science, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang 310021, PR China
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Abstract
Primary biliary cirrhosis (PBC) is a liver-specific autoimmune disease that primarily affects women (female-to-male ratio, 10:1) between 40 and 60 years of age. Metabolic bone disease is a common complication of PBC, affecting 14% to 52% of patients, depending on the duration and severity of liver disease. The osteoporosis seen in PBC seems mainly due to low bone formation, although increased bone resorption may contribute. Treatment of osteoporosis consists primarily of antiresorptive agents. Additional large prospective, long-term studies in patients with PBC are needed to determine efficacy in improving bone density as well as reducing fracture risk.
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Affiliation(s)
- Lisa M Glass
- Gastroenterology Section, Department of Internal Medicine, VA Ann Arbor Health Care System, University of Michigan Health System, 2215 Fuller Road, Ann Arbor, MI 48105, USA
| | - Grace Li-Chun Su
- Gastroenterology Section, Specialty Care and Access, VA Ann Arbor Health Care System, University of Michigan Medical School, 2215 Fuller Road, Ann Arbor, MI 48105, USA.
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49
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Zhang YL, Yin JH, Ding H, Zhang W, Zhang CQ, Gao YS. Vitamin K2 Prevents Glucocorticoid-induced Osteonecrosis of the Femoral Head in Rats. Int J Biol Sci 2016; 12:347-58. [PMID: 27019620 PMCID: PMC4807155 DOI: 10.7150/ijbs.13269] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 11/21/2015] [Indexed: 12/03/2022] Open
Abstract
Glucocorticoid medication is one of the most common causes of atraumatic osteonecrosis of the femoral head (ONFH), and vitamin K2 (VK2) has been shown to play an important and beneficial role in bone metabolism. In this study, we hypothesized that VK2 could decrease the incidence of glucocorticoid-induced ONFH in a rat model. Using in vitro studies, we investigated how bone marrow-derived stem cells in the presence of methylprednisolone proliferate and differentiate, specifically examining osteogenic-related proteins, including Runx2, alkaline phosphatase and osteocalcin. Using in vivo studies, we established glucocorticoid-induced ONFH in rats and investigated the preventive effect of VK2. We employed micro-CT scanning, angiography of the femoral head, and histological and immunohistochemical analyses, which demonstrated that VK2 yielded beneficial effects for subchondral bone trabecula. In conclusion, VK2 is an effective antagonist for glucocorticoid on osteogenic progenitors. The underlying mechanisms include acceleration of BMSC propagation and promotion of bone formation-associated protein expression, which combine and contribute to the prevention of glucocorticoid-induced ONFH in rats.
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Affiliation(s)
- Yue-Lei Zhang
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jun-Hui Yin
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Hao Ding
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Wei Zhang
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Chang-Qing Zhang
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - You-Shui Gao
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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50
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Shikano K, Kaneko K, Kawazoe M, Kaburaki M, Hasunuma T, Kawai S. Efficacy of Vitamin K2 for Glucocorticoid-induced Osteoporosis in Patients with Systemic Autoimmune Diseases. Intern Med 2016; 55:1997-2003. [PMID: 27477405 DOI: 10.2169/internalmedicine.55.6230] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Objective Vitamin K2 (menatetrenone) is an effective treatment for patients with postmenopausal osteoporosis. We herein performed a subanalysis of patients with systemic autoimmune diseases undergoing glucocorticoid therapy in our previous prospective study. Methods Sixty patients were categorized into a group with vitamin K2 treatment (n=20, Group A) and a group without vitamin K2 treatment (n=40, Group B). All patients were treated with bisphosphonates. Results Serum levels of osteocalcin and undercarboxylated osteocalcin decreased significantly after the start of glucocorticoid therapy in both groups, while the serum osteocalcin level was significantly higher in Group A than Group B during the third (p=0.0250) and fourth weeks (p=0.0155). The serum level of the N-terminal peptide of type I procollagen, a bone formation marker, decreased during glucocorticoid therapy, but was significantly higher in Group A than Group B during the fourth week (p=0.0400). The bone mineral density and fracture rate showed no significant differences between the two groups. Conclusion Although vitamin K2 improves bone turnover markers in patients with osteoporosis on glucocorticoid therapy, it has no significant effect on the bone mineral density and fracture rate after 1.5 years of treatment.
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Affiliation(s)
- Kotaro Shikano
- Division of Rheumatology, Department of Internal Medicine, School of Medicine, Faculty of Medicine, Toho University, Japan
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