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dc.contributor.authorSchröder, Maria
dc.contributor.authorRiksen, Elisabeth Aurstad
dc.contributor.authorHe, Jianying
dc.contributor.authorSkallerud, Bjørn Helge
dc.contributor.authorMøller, Mona Elisabeth
dc.contributor.authorLian, Aina-Mari
dc.contributor.authorSyversen, Unni
dc.contributor.authorReseland, Janne Elin
dc.description.abstractRotational 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.en_US
dc.rightsNavngivelse 4.0 Internasjonal*
dc.titleVitamin K2 modulates vitamin D induced mechanical properties of human 3D bone spheroids in vitroen_US
dc.typePeer revieweden_US
dc.typeJournal articleen_US
dc.source.journalJBMR Plusen_US
dc.description.localcodeThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Received in original form October 27, 2019; revised form July 6, 2020; accepted July 8, 2020. Accepted manuscript online July 14, 2020. Address correspondence to: Janne E Reseland, Department of Biomaterials, Faculty of Dentistry, PO Box 1109 Blindern, N-0317 Oslo, Norway. E-mail: j.e. JBMR® Plus (WOA), Vol. 00, No. 00, Month 2020, e10394. DOI: 10.1002/jbm4.10394 © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.en_US

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