Vitamin K2 and the calcium paradox

Vascular calcification, bone loss, and increased fracture risk are age-associated disorders. Several epidemiological studies have suggested a relationship between vascular calcification, impaired bone metabolism, and increased mortality. An intriguing question is whether the presence of impaired bone metabolism impacts vascular calcification, demonstrating actual crosstalk between these tissues. Additionally, vascular calcification is characterized by vascular smooth muscle cells' transition towards an osteoblast-like (bone) phenotype, promoting the release of the vesicular structures and subsequent mineralization. Several players promote mineralization of the vasculature and bone metabolism, like phosphorus and calcium, which impact supersaturation and expression of osteogenic factors. Bone loss is common in the aging population, especially in postmenopausal women. Also, patients suffering from chronic kidney disease (CKD) often suffering from adynamic bone. Moreover, postmenopausal women and CKD patients are at increased risk of developing vascular calcification. Inadequate calcium intake can lead to decreased bone mineral density, increasing the risk of bone fractures. Supplemental calcium promotes bone mineral density and strength and can prevent osteoporosis (i.e., porous bones). Average daily recommended intakes of calcium differ with age, with the aging population needing the most. Even though dairy products represent a rich source of calcium, approximately 43% of the U.S. population and 70% of older women regularly take calcium supplements. Calcium supplementation is supported by several studies backing its benefits for bone health and osteoporosis prevention, as well as for overall health. Calcium supplements are also given to CKD patients to bind phosphate in food, reduce uptake, and reduce circulating phosphate levels. Increased phosphate levels in CKD patients are associated with increased vascular calcification and mortality. Recent scientific evidence suggests that high calcium consumption accelerates calcium deposits in blood vessel walls and soft tissues, which may raise the risk of heart disease. Studies in an in vivo animal model for vascular calcification has answered whether vitamin K2 (MK-7) should be co-supplemented with phosphate binders to reduce the magnitude of vascular calcification effectively. This provides background for medical guidelines for nephrologists in clinical practice. In vitro studies using induced pluripotent stem cells (iPSCs cells) helped to elucidate the molecular mechanisms of bone formation. We implemented novel protocols for iPSCs differentiation and the effect of Vitamin K2 (MK-7) in osteogenic differentiation. Utilizing iPSCs instead of standard cell lines prevent costly and time-consuming animal work and provides a limitless supply of these cells without violating the ethical implications associated with use of traditional primary stem cells. Studies on VSMCs and chondrocytes in vitro provide mechanistic insights and molecular mechanisms of vascular calcification and osteoarthritis. This in vitro model directly translates into clinical practice.

Studies in an in vivo animal model for vascular calcification has answered whether vitamin K2 (MK-7) should be co-supplemented with phosphate binders to reduce the magnitude of vascular calcification effectively. This provides background for medical guidelines for nephrologists in clinical practice. In vitro studies using induced pluripotent stem cells (iPSCs cells) helped to elucidate the molecular mechanisms of bone formation. We implemented novel protocols for iPSCs differentiation and the effect of Vitamin K2 (MK-7) in osteogenic differentiation. Utilizing iPSCs instead of standard cell lines prevent costly and time-consuming animal work and provides a limitless supply of these cells without violating the ethical implications associated with use of traditional primary stem cells. Studies on VSMCs and chondrocytes in vitro provide mechanistic insights and molecular mechanisms of vascular calcification and osteoarthritis. This model translates directly into clinical practice.

Dette doktorgradsprosjektet sikte mot å klarlegge mer av bakgrunnen for en gunstig rolle av vitamin K2 (MK7) som behandlingsalternativ for det såkalte "kalsiumparadokset" mellom bein metabolisme og arterielle forkalkninger. Hovedmålet med dette prosjektet er å gjennomføre pre-kliniske studier for å undersøke og forstå en tidligere dokumentert gunstig rolle av vitamin K2 (MK7) på osteoporose hos friske postmenopausale individer og individer med nyresvikt. Videre vil opptak og fordeling vev hos friske postmenopausale individer med nyresvikt bli undersøkt. Synergier i mer komplekse kosttilskudd, som vitamin K2 i forbindelse med kalsium og vitamin D vil også bli undersøkt. I første del skal kandidaten produsere en sammenskrivning av tilgjengelig litteratur som omhandler spesielt koblingen mellom utvikling av bentap og hjerte- og karsykdom i både friske og syke individer ("Kalsiumparadokset"). I andre del Andre skal kandidaten anvende en musemodell til å studere fordeling av vitamin K i vev - bein, hjerte, hjerne, arterier og lever. I tredje del skal kandidaten anvende musemodeller til å studere forholdet mellom bentap og arteriell kalsifisering i en representativ musemodell med mus som har fått menopause indusert gjennom ovarioektomi. Videre skal han anvende en annen musemodell for å studere effekten av vitamin K i individer med kronisk leversvikt indusert ved nefrektomi eller adenindiett. Prosjektet fokuserer på direkte studier av mekanistiske sammenhenger som av etiske grunner er vanskelig eller umulig å studere direkte i mennesker. NattoPharma har bidratt til og finansier flere studier som viser statistisk korrelasjon mellom bentap og utvikling av arteriell kalsifisering. Resultene av dette prosjektet vil gå dypere ned i denne hypotesen for å se etter direkte fysiologiske sammenhenger. Dette er av stor betydning for NattoPharma ved fremtidige fremstøt overfor potensielle legemiddelpartnere.