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Vitamin K and Vitamin K-Dependent Proteins in Homeostasis and Pathology
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Vitamin K and Vitamin K-Dependent Proteins in Homeostasis and Pathology

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (17 December 2021) | Viewed by 26510

Special Issue Editors

Dr. Dina Costa Simes

E-Mail Website
Guest Editor
Centre of Marine Sciences (CCMAR), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
Interests: vitamin-K-dependent proteins (VKDPs); Gla-rich protein (GRP); pathological calcification; chronic inflammatory diseases; clinical, therapeutic, and biomolecular aspects of Vitamin K and VKDPs
Special Issues, Collections and Topics in MDPI journals
Dr. Carla Viegas

E-Mail Website
Guest Editor
Centre of Marine Sciences (CCMAR), Campus de Gambelas, Universidade do Algarve, 8005-139 Faro, Portugal
Interests: Gla-rich protein (GRP); calcification-related chronic inflammatory diseases; cardiovascular calcification; pathological calcification–inflammation molecular crosstalk; VKDPs in inflammation; VKDPs biomarker and therapeutic potential; extracellular vesicles
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Vitamin K (VK) is a multifunctional micronutrient with protective roles in many chronic inflammatory and age-related diseases such as cardiovascular diseases, diabetes, chronic kidney disease (CKD), arthritis, neurodegenerative disorders, cancer, mobility disability and frailty, and more recently linked to COVID-19. This wide range of biological effects has been attributed mainly to its function as a co-factor for the γ-carboxylation of extra-hepatic vitamin-K-dependent proteins (VKDPs), but novel γ-carboxylation-independent roles have been suggested. Molecularly, extra-hepatic VKDPs are involved in many biological functions such as bone homeostasis, ectopic calcification, cell differentiation and proliferation, inflammation, and signal transduction. Importantly, VK deficiency or impaired functionality of extra-hepatic VKDPs have been associated to pathological states, including poor COVID-19 prognosis, while VK diet supplementation is reported to have health-beneficial effects without toxic/adverse effects. This Special Issue is dedicated to highlighting recent advances in the field of VKDPs and vitamin K biology, providing novel molecular insights into their functional role in health and disease, and therapeutic and nutraceutical application. We invite authors to submit reviews or original research articles on any of the above topics.

Assist. Prof. Dr. Dina Costa Simes
Dr. Carla Viegas
Guest Editors

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Keywords

  • vitamin K1
  • menaquinones (MKn)
  • inflammation
  • pathological calcification
  • coagulation
  • vitamin-K-dependent proteins (VKDPs)
  • Gla-rich protein (GRP)
  • matrix-Gla protein (MGP)
  • osteocalcin (OC)
  • growth arrest-specific protein 6 (Gas6)
  • protein S
  • vitamin K nutrition

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Published Papers (5 papers)

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Research

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18 pages, 2609 KiB  
Article
Nanoencapsulation of Gla-Rich Protein (GRP) as a Novel Approach to Target Inflammation
by Carla S. B. Viegas, Nuna Araújo, Joana Carreira, Jorge F. Pontes, Anjos L. Macedo, Maurícia Vinhas, Ana S. Moreira, Tiago Q. Faria, Ana Grenha, António A. de Matos, Leon Schurgers, Cees Vermeer and Dina C. Simes
Int. J. Mol. Sci. 2022, 23(9), 4813; https://doi.org/10.3390/ijms23094813 - 27 Apr 2022
Cited by 3 | Viewed by 2261
Abstract
Chronic inflammation is a major driver of chronic inflammatory diseases (CIDs), with a tremendous impact worldwide. Besides its function as a pathological calcification inhibitor, vitamin K-dependent protein Gla-rich protein (GRP) was shown to act as an anti-inflammatory agent independently of its gamma-carboxylation status. [...] Read more.
Chronic inflammation is a major driver of chronic inflammatory diseases (CIDs), with a tremendous impact worldwide. Besides its function as a pathological calcification inhibitor, vitamin K-dependent protein Gla-rich protein (GRP) was shown to act as an anti-inflammatory agent independently of its gamma-carboxylation status. Although GRP’s therapeutic potential has been highlighted, its low solubility at physiological pH still constitutes a major challenge for its biomedical application. In this work, we produced fluorescein-labeled chitosan-tripolyphosphate nanoparticles containing non-carboxylated GRP (ucGRP) (FCNG) via ionotropic gelation, increasing its bioavailability, stability, and anti-inflammatory potential. The results indicate the nanosized nature of FCNG with PDI and a zeta potential suitable for biomedical applications. FCNG’s anti-inflammatory activity was studied in macrophage-differentiated THP1 cells, and in primary vascular smooth muscle cells and chondrocytes, inflamed with LPS, TNFα and IL-1β, respectively. In all these in vitro human cell systems, FCNG treatments resulted in increased intra and extracellular GRP levels, and decreased pro-inflammatory responses of target cells, by decreasing pro-inflammatory cytokines and inflammation mediators. These results suggest the retained anti-inflammatory bioactivity of ucGRP in FCNG, strengthening the potential use of ucGRP as an anti-inflammatory agent with a wide spectrum of application, and opening up perspectives for its therapeutic application in CIDs. Full article
(This article belongs to the Special Issue Vitamin K and Vitamin K-Dependent Proteins in Homeostasis and Pathology)
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Review

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19 pages, 2170 KiB  
Review
Vitamin K-Dependent Protein Activation: Normal Gamma-Glutamyl Carboxylation and Disruption in Disease
by Kathleen L. Berkner and Kurt W. Runge
Int. J. Mol. Sci. 2022, 23(10), 5759; https://doi.org/10.3390/ijms23105759 - 20 May 2022
Cited by 19 | Viewed by 6934
Abstract
Vitamin K-dependent (VKD) proteins undergo an unusual post-translational modification, which is the conversion of specific Glu residues to carboxylated Glu (Gla). Gla generation is required for the activation of VKD proteins, and occurs in the endoplasmic reticulum during their secretion to either the [...] Read more.
Vitamin K-dependent (VKD) proteins undergo an unusual post-translational modification, which is the conversion of specific Glu residues to carboxylated Glu (Gla). Gla generation is required for the activation of VKD proteins, and occurs in the endoplasmic reticulum during their secretion to either the cell surface or from the cell. The gamma-glutamyl carboxylase produces Gla using reduced vitamin K, which becomes oxygenated to vitamin K epoxide. Reduced vitamin K is then regenerated by a vitamin K oxidoreductase (VKORC1), and this interconversion of oxygenated and reduced vitamin K is referred to as the vitamin K cycle. Many of the VKD proteins support hemostasis, which is suppressed during therapy with warfarin that inhibits VKORC1 activity. VKD proteins also impact a broad range of physiologies beyond hemostasis, which includes regulation of calcification, apoptosis, complement, growth control, signal transduction and angiogenesis. The review covers the roles of VKD proteins, how they become activated, and how disruption of carboxylation can lead to disease. VKD proteins contain clusters of Gla residues that form a calcium-binding module important for activity, and carboxylase processivity allows the generation of multiple Glas. The review discusses how impaired carboxylase processivity results in the pseudoxanthoma elasticum-like disease. Full article
(This article belongs to the Special Issue Vitamin K and Vitamin K-Dependent Proteins in Homeostasis and Pathology)
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17 pages, 2011 KiB  
Review
The Molecular Basis of FIX Deficiency in Hemophilia B
by Guomin Shen, Meng Gao, Qing Cao and Weikai Li
Int. J. Mol. Sci. 2022, 23(5), 2762; https://doi.org/10.3390/ijms23052762 - 2 Mar 2022
Cited by 18 | Viewed by 8189
Abstract
Coagulation factor IX (FIX) is a vitamin K dependent protein and its deficiency causes hemophilia B, an X-linked recessive bleeding disorder. More than 1000 mutations in the F9 gene have been identified in hemophilia B patients. Here, we systematically summarize the structural and [...] Read more.
Coagulation factor IX (FIX) is a vitamin K dependent protein and its deficiency causes hemophilia B, an X-linked recessive bleeding disorder. More than 1000 mutations in the F9 gene have been identified in hemophilia B patients. Here, we systematically summarize the structural and functional characteristics of FIX and the pathogenic mechanisms of the mutations that have been identified to date. The mechanisms of FIX deficiency are diverse in these mutations. Deletions, insertions, duplications, and indels generally lead to severe hemophilia B. Those in the exon regions generate either frame shift or inframe mutations, and those in the introns usually cause aberrant splicing. Regarding point mutations, the bleeding phenotypes vary from severe to mild in hemophilia B patients. Generally speaking, point mutations in the F9 promoter region result in hemophilia B Leyden, and those in the introns cause aberrant splicing. Point mutations in the coding sequence can be missense, nonsense, or silent mutations. Nonsense mutations generate truncated FIX that usually loses function, causing severe hemophilia B. Silent mutations may lead to aberrant splicing or affect FIX translation. The mechanisms of missense mutation, however, have not been fully understood. They lead to FIX deficiency, often by affecting FIX’s translation, protein folding, protein stability, posttranslational modifications, activation to FIXa, or the ability to form functional Xase complex. Understanding the molecular mechanisms of FIX deficiency will provide significant insight for patient diagnosis and treatment. Full article
(This article belongs to the Special Issue Vitamin K and Vitamin K-Dependent Proteins in Homeostasis and Pathology)
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14 pages, 743 KiB  
Review
The Role of GRP and MGP in the Development of Non-Hemorrhagic VKCFD1 Phenotypes
by Suvoshree Ghosh, Johannes Oldenburg and Katrin J. Czogalla-Nitsche
Int. J. Mol. Sci. 2022, 23(2), 798; https://doi.org/10.3390/ijms23020798 - 12 Jan 2022
Cited by 3 | Viewed by 2395
Abstract
Vitamin K dependent coagulation factor deficiency type 1 (VKCFD1) is a rare hereditary bleeding disorder caused by mutations in γ-Glutamyl carboxylase (GGCX) gene. The GGCX enzyme catalyzes the γ-carboxylation of 15 different vitamin K dependent (VKD) proteins, which have function in [...] Read more.
Vitamin K dependent coagulation factor deficiency type 1 (VKCFD1) is a rare hereditary bleeding disorder caused by mutations in γ-Glutamyl carboxylase (GGCX) gene. The GGCX enzyme catalyzes the γ-carboxylation of 15 different vitamin K dependent (VKD) proteins, which have function in blood coagulation, calcification, and cell signaling. Therefore, in addition to bleedings, some VKCFD1 patients develop diverse non-hemorrhagic phenotypes such as skin hyper-laxity, skeletal dysmorphologies, and/or cardiac defects. Recent studies showed that GGCX mutations differentially effect γ-carboxylation of VKD proteins, where clotting factors are sufficiently γ-carboxylated, but not certain non-hemostatic VKD proteins. This could be one reason for the development of diverse phenotypes. The major manifestation of non-hemorrhagic phenotypes in VKCFD1 patients are mineralization defects. Therefore, the mechanism of regulation of calcification by specific VKD proteins as matrix Gla protein (MGP) and Gla-rich protein (GRP) in physiological and pathological conditions is of high interest. This will also help to understand the patho-mechanism of VKCFD1 phenotypes and to deduce new treatment strategies. In the present review article, we have summarized the recent findings on the function of GRP and MGP and how these proteins influence the development of non-hemorrhagic phenotypes in VKCFD1 patients. Full article
(This article belongs to the Special Issue Vitamin K and Vitamin K-Dependent Proteins in Homeostasis and Pathology)
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16 pages, 1469 KiB  
Review
Vitamin K-Dependent Proteins in Skeletal Development and Disease
by Michael Stock and Georg Schett
Int. J. Mol. Sci. 2021, 22(17), 9328; https://doi.org/10.3390/ijms22179328 - 28 Aug 2021
Cited by 26 | Viewed by 5109
Abstract
Vitamin K and Vitamin K-dependent proteins (VKDPs) are best known for their pivotal role in blood coagulation. Of the 14 VKPDs identified in humans to date, 6 play also important roles in skeletal biology and disease. Thus, osteocalcin, also termed bone Gla-protein, is [...] Read more.
Vitamin K and Vitamin K-dependent proteins (VKDPs) are best known for their pivotal role in blood coagulation. Of the 14 VKPDs identified in humans to date, 6 play also important roles in skeletal biology and disease. Thus, osteocalcin, also termed bone Gla-protein, is the most abundant non-collagenous protein in bone. Matrix Gla protein and Ucma/GRP on the other hand are highly abundant in cartilage. Furthermore, periostin, protein S, and growth arrest specific 6 protein (GAS 6) are expressed in skeletal tissues. The roles for these VKDPs are diverse but include the control of calcification and turnover of bone and cartilage. Vitamin K plays an important role in osteoporosis and serum osteocalcin levels are recognized as a promising marker for osteoporosis. On the other hand, matrix Gla protein and Ucma/GRP are associated with osteoarthritis. This review focuses on the roles of these three VKDPs, osteocalcin, matrix Gla protein and Ucma/GRP, in skeletal development and disease but will also summarize the roles the other skeletal VKDPs (periostin, protein S and GAS6) in skeletal biology. Full article
(This article belongs to the Special Issue Vitamin K and Vitamin K-Dependent Proteins in Homeostasis and Pathology)
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