Common Histological Features Suggesting Enchondral Ossification Pathways in Calciphylaxis of Various Origins: A Study of Human Subcutaneous Tissue Biopsies.

Calciphylaxis is a rare, yet underdiagnosed condition causing high mortality in patients with severe renal and cardiovascular disease. Since knowledge of the pathophysiology of calciphylaxis is limited, a differential analysis of histological alterations in patient subgroups with various comorbidities might expose different disease phenotypes and allow deeper insights into the pathophysiology of the condition. Histological markers of osteogenesis and calcification were investigated in a group of 18 patients with clinically and histologically verified calciphylaxis, using immunohistochemical staining. Analysis of staining intensity and distribution of marker proteins in histological structures was performed to evaluate distinct patterns between subgroups with different clinical comorbidities in comparison with a control group. In all cases, immunohistochemical staining for bone matrix proteins, bone-morphogenic proteins and matrix-Gla proteins co-localized with subcutaneous vascular and interstitial calcifications. Significant expression of bone-morphogenic protein-7 and active matrix-Gla protein was observed. Mortality was associated with renal comorbidities and increased expression of bone-morphogenic protein-7. However, no distinct histological patterns were found between subgroups with renal disease, warfarin intake or coexisting micro- and macro-angiopathies. The upregulation of osteogenic markers (including bone-morphogenic protein-7) plays a major role in the development of calciphylaxis. Clinical outcome correlates with kidney function and phosphate handling, suggesting different pathophysiological mechanisms. However, biopsy  at late-stage disease shows a common histological phenotype, involving enchondral ossification.

Enhanced vitamin K expenditure as a major contributor to vitamin K deficiency in COVID-19.

OBJECTIVES: Vitamin K deficiency consistently associates with worse clinical outcome in COVID-19 patients. However, whether this is due to increased expenditure during inflammation or poor vitamin K status prior to infection remained unknown. METHODS: Dp-ucMGP levels of 128 individuals were measured for the post-MONICA study and were compared to SARS-CoV-2 PCR testing results. RESULTS: Dp-ucMGP levels prior to COVID-19 infection were not significantly different comparing PCR-negative, PCR-positive and not hospitalized, and PCR-positive and hospitalized patients. CONCLUSION: In this study, we demonstrate normal vitamin K status prior to infection in SARS-CoV-2 positive patients, supporting the theory of increased utilisation during disease.

Comment on Kremer et al. Kidney Function-Dependence of Vitamin K-Status Parameters: Results from the TransplantLines Biobank and Cohort Studies. Nutrients 2021, 13, 3069.

In the article "Kidney Function-Dependence of Vitamin K-Status Parameters: Results from the TransplantLines Biobank and Cohort Studies", Kremer et al. [...].

Association of desphospho-uncarboxylated matrix gla protein with incident cardiovascular disease and all-cause mortality: Results from the prospective Bruneck Study.

BACKGROUND AND AIMS: Matrix Gla protein (MGP), a vitamin K-dependent protein, is a potent inhibitor of vascular calcification. Desphospho-uncarboxylated MGP (dp-ucMGP), a marker of vitamin K insufficiency, has been shown to predict cardiovascular disease (CVD) and all-cause mortality in high-risk populations. Whether the increased risk associated with dp-ucMGP also applies to the general, and especially, the elderly population has not yet been fully elucidated. METHODS AND RESULTS: Plasma dp-ucMGP was measured in 684 individuals aged 50-89 years of the prospective population-based Bruneck Study (baseline evaluation in 2000). Baseline median dp-ucMGP was 478.4 (IQR 335.0-635.2) pmol/L. Over a median follow-up of 15.5 years, 163 CVD events occurred and 235 participants died. Age-/sex-adjusted hazard ratios (HRs) per 1-SD higher level of loge transformed dp-ucMGP were 1.30 (95%CI: 1.09-1.55; p=0.004) for incident CVD and 1.36 (95%CI: 1.17-1.57; p<0.001) for all-cause mortality. After multivariable adjustment, the associations remained significant with HRs of 1.23 (95%CI: 1.02-1.47, p=0.029) for CVD and 1.40 (95%CI: 1.20-1.64; p<0.001) for all-cause mortality. The associations remained virtually unchanged after additional adjustment for dietary quality as measured with the Alternative Healthy Eating Index. We found no association of dp-ucMGP with myocardial infarction and sudden cardiac deaths, but a strong association with other vascular deaths and non-vascular/non-cancer deaths. CONCLUSIONS: This study shows a significant association of plasma dp-ucMGP with incident CVD and a significant and even stronger association with all-cause mortality. Clinical trials are needed to investigate whether vitamin K substitution results in improved health outcomes.

Nanoencapsulation of Gla-Rich Protein (GRP) as a Novel Approach to Target Inflammation.

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-1ß, 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.

Nutrient-Optimized Beef Enhances Blood Levels of Vitamin D and Selenium among Young Women.

Bovine meat provides healthy nutrients but has also been negatively linked to greenhouse gases and non-communicable diseases. A double-blind intervention study was carried out to compare beef meat from bulls fed with feed supplemented with selenium, vitamin D, E, K (SeDEK-feed), and n-3, or REGULAR feed. Thirty-four young healthy women (19-29 years old) consumed 300 g of these beef types per day for 6 days in a cross-over design. Diet registrations, blood samples, anthropometric measurements, and clinical data were collected four times. Both beef diets were higher than their habitual diet in protein, fat, saturated fat, and several micronutrients; contained more vegetables and fewer carbohydrates and were followed by a higher feeling of satiety. The SeDEK beef had higher amounts of selenium, vitamin 25-hydroxyvitamin D3 (25(OH)D3), E, and K (MK4), and increased serum selenium and 25(OH)D3 from the participants' normal values if they were below 85 µg/L of selenium and 30 nmol of 25(OH)D3/L, respectively. Our study showed that optimized beef increased serum selenium in young women having moderate selenium levels and improved blood 25(OH)D3 in a woman having low to normal 25(OH)D3. Meat should be optimized to increase specific consumer groups' needs for selenium and vitamin D.

Comment on Sobczyk, M.K.; Gaunt, T.R. The Effect of Circulating Zinc, Selenium, Copper and Vitamin K1 on COVID-19 Outcomes: A Mendelian Randomization Study. Nutrients 2022, 14, 233.

Sobczyk and Gaunt genetically predicted circulating zinc, selenium, copper, and vitamin K1 levels-instead of directly measuring nutrients in blood-and hypothesized that these levels would associate with SARS-CoV-2 infection and COVID-19 severity [...].

The Active Isoforms of MGP Are Expressed in Healthy and Varicose Veins without Calcification.

Matrix Gla protein (MGP), a local inhibitor of tissue mineralization, is associated with vascular calcification. Depending on the carboxylation and phosphorylation status, MGP has active conformations, e.g., carboxylated MGP (cMGP) and phosphorylated MGP (pMGP), but also inactive conformations, e.g., uncarboxylated MGP (ucMGP) and dephosphorylated MGP (dpMGP). Our purpose was to assess the presence of all MGP conformations in healthy veins (HV) and varicose veins (VV), concurrently with the analysis of circulating total MGP (tMGP) before and after the surgical stripping of VV. We collected samples from the great saphenous vein, considered as control group, and tissue from VV, designated as VV group. Plasma levels of tMGP were significantly decreased after the surgical removal of the VV (before 59.5 ± 17.2 vs. after 38.1 ± 11.3, p < 0.001). By using immunohistochemistry staining, we identified local cMGP and pMGP in the control and VV groups, both without calcification, while ucMGP and dpMGP were absent. cMGP was observed in the nucleus and cytoplasm and pMGP in the nucleus of cells belonging to the tunica media, tunica intima and vasa vasorum. Therefore, the active conformations of MGP (cMGP and pMGP) are prevalent in HV and VV without calcification, affirming their anti-calcifying role in veins.

Low vitamin K status, high sclerostin and mortality risk of stable coronary heart disease patients.

Aim: We explored whether matrix Gla protein (MGP, natural calcification inhibitor) and sclerostin (glycoprotein responsible for osteoblast differentiation) interact in terms of mortality risk in coronary patients. Methods: 945 patients after myocardial infarction and/or coronary revascularization were followed in a prospective study. All-cause death, fatal or nonfatal cardiovascular events and heart failure hospitalizations were registered. Results: Either high desphospho-uncarboxylated MGP (dp-ucMGP) or high sclerostin were independently associated with 5-year all-cause/cardiovascular mortality. However, we observed an additional mortality risk in the coincidence of both factors. Concomitantly high dp-ucMGP (≥884 pmol/l) plus sclerostin (≥589 ng/l) were associated with increased all-cause mortality risk compared with 'normal' concentrations of both factors (HRR 3.71 [95% CI: 2.07-6.62, p < 0.0001]), or if only one biomarker has been increased. A similar pattern was observed for fatal, but not for nonfatal cardiovascular events. Conclusion: Concomitantly high MGP and sclerostin indicate increased mortality risk, which probably reflects their role in cardiovascular calcifications.

The coincidence of low vitamin K status and high expression of growth differentiation factor 15 may indicate increased mortality risk in stable coronary heart disease patients.

BACKGROUND AND AIMS: Matrix Gla protein (MGP) is a natural inhibitor of vascular calcification critically dependent on circulating vitamin K status. Growth differentiation factor 15 (GDF-15) is a regulatory cytokine mainly of the inflammatory and angiogenesis pathways, but potentially also involved in bone mineralization. We sought to determine whether these two circulating biomarkers jointly influenced morbidity and mortality risk in patients with chronic coronary heart disease (CHD). METHODS AND RESULTS: 894 patients ≥6 months after myocardial infarction and/or coronary revascularization at baseline were followed in a prospective study. All-cause and cardiovascular mortality, non-fatal cardiovascular events (myocardial infarction, stroke, any revascularization), and hospitalization for heart failure (HF) were followed as outcomes. Desphospho-uncarboxylated MGP (dp-ucMGP) was used as a biomarker of vitamin K status. Both, increased concentrations of dp-ucMGP (≥884 pmol/L) and GDF-15 (≥1339 pg/mL) were identified as independent predictors of 5-year all-cause or cardiovascular mortality. However, their coincidence further increased mortality risk. The highest risk was observed in patients with high dp-ucMGP plus high GDF-15, not only when compared with those with "normal" concentrations of both biomarkers [HR 5.51 (95% CI 2.91-10.44), p < 0.0001 and 6.79 (95% CI 3.06-15.08), p < 0.0001 for all-cause and cardiovascular mortality, respectively], but even when compared with patients with only one factor increased. This pattern was less convincing with non-fatal cardiovascular events or hospitalization for HF. CONCLUSIONS: The individual coincidence of low vitamin K status (high dp-ucMGP) and high GDF-15 expression predicts poor survival of stable CHD patients.

Reduced Vitamin K Status as a Potentially Modifiable Risk Factor of Severe Coronavirus Disease 2019.

BACKGROUND: Respiratory failure and thromboembolism are frequent in severe acute respiratory syndrome coronavirus 2-infected patients. Vitamin K activates both hepatic coagulation factors and extrahepatic endothelial anticoagulant protein S, required for thrombosis prevention. In times of vitamin K insufficiency, hepatic procoagulant factors are preferentially activated over extrahepatic proteins. Vitamin K also activates matrix Gla protein (MGP), which protects against pulmonary and vascular elastic fiber damage. We hypothesized that vitamin K may be implicated in coronavirus disease 2019 (COVID-19), linking pulmonary and thromboembolic disease. METHODS: A total of 135 hospitalized COVID-19 patients were compared with 184 historic controls. Inactive vitamin K-dependent MGP (desphospho-uncarboxylated [dp-uc] MGP) and prothrombin (PIVKA-II) were measured inversely related to extrahepatic and hepatic vitamin K status, respectively. Desmosine was measured to quantify the rate of elastic fiber degradation. Arterial calcification severity was assessed using computed tomography. RESULTS: dp-ucMGP was elevated in COVID-19 patients compared with controls (P < .001), with even higher dp-ucMGP in patients with poor outcomes (P < .001). PIVKA-II was normal in 82.1% of patients. dp-ucMGP was correlated with desmosine (P < .001) and with coronary artery (P = .002) and thoracic aortic (P < .001) calcification scores. CONCLUSIONS: dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insufficiency, which was related to poor outcome; hepatic procoagulant factor II remained unaffected. These data suggest pneumonia-induced extrahepatic vitamin K depletion leading to accelerated elastic fiber damage and thrombosis in severe COVID-19 due to impaired activation of MGP and endothelial protein S, respectively.

Vitamin K metabolism as the potential missing link between lung damage and thromboembolism in Coronavirus disease 2019.

Coronavirus disease 2019 (Covid-19), caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, exerts far-reaching effects on public health and socio-economic welfare. The majority of infected individuals have mild to moderate symptoms, but a significant proportion develops respiratory failure due to pneumonia. Thrombosis is another frequent manifestation of Covid-19 that contributes to poor outcomes. Vitamin K plays a crucial role in the activation of both pro- and anticlotting factors in the liver and the activation of extrahepatically synthesised protein S which seems to be important in local thrombosis prevention. However, the role of vitamin K extends beyond coagulation. Matrix Gla protein (MGP) is a vitamin K-dependent inhibitor of soft tissue calcification and elastic fibre degradation. Severe extrahepatic vitamin K insufficiency was recently demonstrated in Covid-19 patients, with high inactive MGP levels correlating with elastic fibre degradation rates. This suggests that insufficient vitamin K-dependent MGP activation leaves elastic fibres unprotected against SARS-CoV-2-induced proteolysis. In contrast to MGP, Covid-19 patients have normal levels of activated factor II, in line with previous observations that vitamin K is preferentially transported to the liver for activation of procoagulant factors. We therefore expect that vitamin K-dependent endothelial protein S activation is also compromised, which would be compatible with enhanced thrombogenicity. Taking these data together, we propose a mechanism of pneumonia-induced vitamin K depletion, leading to a decrease in activated MGP and protein S, aggravating pulmonary damage and coagulopathy, respectively. Intervention trials should be conducted to assess whether vitamin K administration plays a role in the prevention and treatment of severe Covid-19.

High expression of Matrix Gla Protein in Schnyder corneal dystrophy patients points to an active role of vitamin K in corneal health.

PURPOSE: Schnyder corneal dystrophy (SCD) is a rare autosomal dominant disorder characterized by corneal lipid accumulation and caused by UBIAD1 pathogenic variants. UBIAD1 encodes a vitamin K (VK) biosynthetic enzyme. To assess the corneal and vascular VK status in SCD patients, we focused on matrix Gla protein (MGP), a VK-dependent protein. METHODS: Conformation-specific immunostainings of different MGP maturation forms were performed on corneal sections and primary keratocytes from corneal buttons of two SCD patients with UBIAD1 p.Asp112Asn and p.Asn102Ser pathogenic variants and unrelated donors. Native or UBIAD1-transfected keratocytes were used for gene expression analysis. Plasma samples from SCD patients (n = 12) and control individuals (n = 117) were subjected for inactive desphospho-uncarboxylated MGP level measurements with an ELISA assay. RESULTS: Substantial amounts of MGP were identified in human cornea and most of it in its fully matured and active form. The level of mature MGP did not differ between SCD and control corneas. In primary keratocytes from SCD patients, a highly increased MGP expression and presence of immature MGP forms were detected. Significantly elevated plasma concentration of inactive MGP was found in SCD patients. CONCLUSION: High amount of MGP and the predominance of mature MGP forms in human cornea indicate that VK metabolism is active in the visual system. Availability of MGP seems of vital importance for a healthy cornea and may be related to protection against corneal calcification. Systemic MGP findings reveal a poor vascular VK status in SCD patients and indicate that SCD may lead to cardiovascular consequences.

Amentadione from the Alga Cystoseira usneoides as a Novel Osteoarthritis Protective Agent in an Ex Vivo Co-Culture OA Model.

Osteoarthritis (OA) remains a prevalent chronic disease without effective prevention and treatment. Amentadione (YP), a meroditerpenoid purified from the alga Cystoseira usneoides, has demonstrated anti-inflammatory activity. Here, we investigated the YP anti-osteoarthritic potential, by using a novel OA preclinical drug development pipeline designed to evaluate the anti-inflammatory and anti-mineralizing activities of potential OA-protective compounds. The workflow was based on in vitro primary cell cultures followed by human cartilage explants assays and a new OA co-culture model, combining cartilage explants with synoviocytes under interleukin-1ß (IL-1ß) or hydroxyapatite (HAP) stimulation. A combination of gene expression analysis and measurement of inflammatory mediators showed that the proposed model mimicked early disease stages, while YP counteracted inflammatory responses by downregulation of COX-2 and IL-6, improved cartilage homeostasis by downregulation of MMP3 and the chondrocytes hypertrophic differentiation factors Col10 and Runx2. Importantly, YP downregulated NF-κB gene expression and decreased phosphorylated IkBα/total IkBα ratio in chondrocytes. These results indicate the co-culture as a relevant pre-clinical OA model, and strongly suggest YP as a cartilage protective factor by inhibiting inflammatory, mineralizing, catabolic and differentiation processes during OA development, through inhibition of NF-κB signaling pathways, with high therapeutic potential.

Circulating Receptor Activator of Nuclear Factor kB Ligand and triglycerides are associated with progression of lower limb arterial calcification in type 2 diabetes: a prospective, observational cohort study.

BACKGROUND: Lower limb arterial calcification is a frequent, underestimated but serious complication of diabetes. The DIACART study is a prospective cohort study designed to evaluate the determinants of the progression of lower limb arterial calcification in 198 patients with type 2 diabetes. METHODS: Lower limb arterial calcification scores were determined by computed tomography at baseline and after a mean follow up of 31.20 ± 3.86 months. Serum RANKL (Receptor Activator of Nuclear factor kB Ligand) and bone remodeling, inflammatory and metabolic parameters were measured at baseline. The predictive effect of these markers on calcification progression was analyzed by a multivariate linear regression model. RESULTS: At baseline, mean ± SD and median lower limb arterial calcification scores were, 2364 ± 5613 and 527 respectively and at the end of the study, 3739 ± 6886 and 1355 respectively. Using multivariate analysis, the progression of lower limb arterial log calcification score was found to be associated with (ß coefficient [slope], 95% CI, p-value) baseline log(calcification score) (1.02, 1.00-1.04, p < 0.001), triglycerides (0.11, 0.03-0.20, p = 0.007), log(RANKL) (0.07, 0.02-0.11, p = 0.016), previous ischemic cardiomyopathy (0.36, 0.15-0.57, p = 0.001), statin use (0.39, 0.06-0.72, p = 0.023) and duration of follow up (0.04, 0.01-0.06, p = 0.004). CONCLUSION: In patients with type 2 diabetes, lower limb arterial calcification is frequent and can progress rapidly. Circulating RANKL and triglycerides are independently associated with this progression. These results open new therapeutic perspectives in peripheral diabetic calcifying arteriopathy. Trial registration NCT02431234.

Inactive matrix gla protein plasma levels are associated with peripheral neuropathy in Type 2 diabetes.

AIMS/HYPOTHESIS: Diabetic peripheral neuropathy is a frequent and severe complication of diabetes. As Matrix-gla-protein (MGP) is expressed in several components of the nervous system and is involved in some neurological disease, MGP could play a role in peripheral nervous system homeostasis. The aim of this study was to evaluate factors associated with sensitive diabetic neuropathy in Type 2 Diabetes, and, in particular, dephospho-uncarboxylated MGP (dp-ucMGP), the inactive form of MGP. METHODS: 198 patients with Type 2 Diabetes were included. Presence of sensitive diabetic neuropathy was defined by a neuropathy disability score (NDS) ≥6. Plasma levels of dp-ucMGP were measured by ELISA. RESULTS: In this cohort, the mean age was 64+/-8.4 years old, and 80% of patients were men. Peripheral neuropathy was present in 15.7% of the patients and was significantly associated (r = 0.51, p<0.0001) with dp-ucMGP levels (ß = -0.26, p = 0.045) after integrating effects of height (ß = -0.38, p = 0.01), insulin treatment (ß = 0.42, p = 0.002), retinopathy treated by laser (ß = 0.26, p = 0.02), and total cholesterol levels (ß = 0.3, p = 0.03) by multivariable analysis. CONCLUSIONS: The association between diabetic neuropathy and the inactive form of MGP suggests the existence of new pathophysiological pathways to explore. Further studies are needed to determine if dp-ucMGP may be used as a biomarker of sensitive neuropathy. Since dp-ucMGP is a marker of poor vitamin K status, clinical studies are warranted to explore the potential protective effect of high vitamin K intake on diabetic peripheral neuropathy.

Warfarin-induced vitamin K deficiency affects spermatogenesis in Sprague-Dawley rats.

Vitamin K is present in the testes though its actual function in male reproduction is poorly understood. This study investigated the harmful effect of extrahepatic vitamin K insufficiency on the testicular structure. Sprague-Dawley rats were fed with a diet containing warfarin for 2, 4 and 8 weeks; control animals received a standard diet without warfarin. It was found that extrahepatic vitamin K deficiency that is induced by warfarin results in histopathological features that range from delayed spermiation, presence of multinucleated giant cells in the seminiferous tubules, germ cells degeneration, asthenozoospermia, oligozoospermia and increase in the percentage of abnormal sperm morphology when compared to the controls. Data obtained from the two groups were analysed using the Student t test. It is concluded that warfarin-induced vitamin K deficiency has a negative impact on spermatogenesis.

Renal Resistive Index Is Associated With Inactive Matrix Gla (γ-Carboxyglutamate) Protein in an Adult Population-Based Study.

Background Increased renal resistive index (RRI) has been associated with target organ damage as well as renal and cardiovascular outcomes. Matrix Gla (γ-carboxyglutamate) protein (MGP) is a strong inhibitor of soft tissue calcification. Its inactive form (dephospho-uncarboxylated MGP [dp-ucMGP]) has been associated with vascular stiffness, cardiovascular outcomes, and mortality. In this study, we hypothesized that high levels of dp-ucMGP were associated with increased RRI. Methods and Results We recruited participants via a multicenter family-based cross-sectional study in Switzerland. Levels of dp-ucMGP were measured in plasma by sandwich ELISA. RRI was measured by Doppler ultrasound in 3 segmental arteries in both kidneys. We used mixed regression models to assess the relationship between dp-ucMGP and RRI. We adjusted for common determinants of RRI as well as renal function and cardiovascular risk factors. We included 1006 participants in our analyses: 526 women and 480 men. Mean values were 0.44±0.20 nmol/L for dp-ucMGP and 64±5% for RRI. After multivariable adjustment, dp-ucMGP was positively associated with RRI (P=0.001). In subgroup analysis by age tertiles, this association was not significant in the youngest age group (<38 years; P=0.62), whereas it was significant in older age groups (38-55 and >55 years; P=0.016 and P<0.001, respectively). Conclusions Levels of dp-ucMGP are positively and independently associated with RRI after adjustment for common determinants of RRI, cardiovascular risk factors, and renal function. The stronger association among older adults is probably due, in part, to age-related arterial stiffness. RRI thus seems to reflect the global atherosclerotic burden in a general adult population.

Low Vitamin K Status Is Associated with Increased Elastin Degradation in Chronic Obstructive Pulmonary Disease.

Elastin degradation is accelerated in chronic obstructive pulmonary disease (COPD) and is partially regulated by Matrix Gla Protein (MGP), via a vitamin K-dependent pathway. The aim was to assess vitamin K status in COPD as well as associations between vitamin K status, elastin degradation, lung function parameters and mortality. A total of 192 COPD patients and 186 age-matched controls were included. In addition to this, 290 COPD patients from a second independent longitudinal cohort were also included. Vitamin K status was assessed by measuring plasma inactive MGP levels and rates of elastin degradation by measuring plasma desmosine levels. Reduced vitamin K status was found in COPD patients compared to smoking controls (p < 0.0005) and controls who had never smoked (p = 0.001). Vitamin K status was inversely associated with desmosine (cohort 1: p = 0.001; cohort 2: p = 0.004). Only few significant associations between vitamin K status and lung function parameters were found. Mortality was higher in COPD patients within the quartile with the lowest vitamin K status compared to those within the other quartiles (hazard ratio 1.85, 95% confidence interval (CI), 1.21-2.83, p = 0.005). In conclusion, we demonstrated reduced vitamin K status in COPD and an inverse association between vitamin K status and elastin degradation rate. Our results therefore suggest a potential role of vitamin K in COPD pathogenesis.