Accepted Lancaster et al - Dec 2013
➤ Gửi thông báo lỗi ⚠️ Báo cáo tài liệu vi phạmNội dung chi tiết: Accepted Lancaster et al - Dec 2013
Accepted Lancaster et al - Dec 2013
24,25-Dihydroxyvitamin D3 cooperates with a stable, fluoromethylene LPA receptor agonist to secure human (MG63) osteoblast maturationSarah Tamar Lanca Accepted Lancaster et al - Dec 2013aster1, Julia Blackburn1, Ashley Blom1, Makoto Makishima2, Michiyasu Ishizawa2, Jason Peter Mansell3*'■ Musculoskeletal Research Unit. Avon Orthopaedic Centre. Southmead Hospital. Bristol. BS10 5NB. UK.• Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine Accepted Lancaster et al - Dec 2013, 30-1 Oyaguchi-kamicho. Itabashi-ku. Tokyo 173-8610, Japan.Department of Biological. Biomedical & Analytical Sciences. University of the West of EnglAccepted Lancaster et al - Dec 2013
and. Frenchay Campus, Coldharbour Lane, Bristol, BS16 1QY.’Corresponding authorDr. Jason Peter MansellSenior LecturerDepartment of Biological. Biomedi24,25-Dihydroxyvitamin D3 cooperates with a stable, fluoromethylene LPA receptor agonist to secure human (MG63) osteoblast maturationSarah Tamar Lanca Accepted Lancaster et al - Dec 2013is.ac.ukAbstractvitamin D receptor (VDR) agonists supporting human osteoblast (hOB) differentiation in the absence of bone resorption are attractive agents in a bone regenerative setting. One potential candidate fulfilling these roles is 24.25-dihydroxy vitamin D3 (24.25D). Over forty years ago it w Accepted Lancaster et al - Dec 2013as reported that supraphysiological levels of 24.25D could stimulate intestinal calcium uptake and aid bone repair without causing bone calcium mobiliAccepted Lancaster et al - Dec 2013
sation. VDR agonists co-operate with certain growth factors to enhance hOB differentiation but whether 24.25D might act similarly in promoting cellula24,25-Dihydroxyvitamin D3 cooperates with a stable, fluoromethylene LPA receptor agonist to secure human (MG63) osteoblast maturationSarah Tamar Lanca Accepted Lancaster et al - Dec 2013co-treated MG63 hOBs with 24.25D and a phosphatase-resistant LPA analog. In isolation 24.25D inhibited proliferation and stimulated osteocalcin expression. When coadministered with the LPA analog there were synergistic increases in alkaline phosphatase (ALP). These are encouraging findings which may Accepted Lancaster et al - Dec 2013 help realise the future application of 24.25D in promoting osseous repair.Key words: Human osteoblasts: 24.25-dihydroxy vitamin D3: LysophosphatidicAccepted Lancaster et al - Dec 2013
acid:Differentiation: Alkaline phosphatase: Osteocalcin.IntroductionCytochrome p450-dependent 24R-hydroxylase (CYP24 or CYP24A1) converts renal 25-hyd24,25-Dihydroxyvitamin D3 cooperates with a stable, fluoromethylene LPA receptor agonist to secure human (MG63) osteoblast maturationSarah Tamar Lanca Accepted Lancaster et al - Dec 2013ards metabolite excretion as calcitroic acid and that 24R.25D should be thought of as a biologically inactive catabolite . In stark contrast are the multitude of reports indicating that 24R.25D does indeed exhibit biological activity, findings which could include a role for this particular metabolit Accepted Lancaster et al - Dec 2013e in bone .With a circulating concentration of approximately 6nM , 24R.25D is the most abundant dihydroxylated vitamin D3 metabolite. Whilst it is widAccepted Lancaster et al - Dec 2013
ely recognised that the other renal vitamin D3 metabolite, 1,25-dihydroxyvitamin D3 (1.25D), has a vital role to play in skeletal development and mine24,25-Dihydroxyvitamin D3 cooperates with a stable, fluoromethylene LPA receptor agonist to secure human (MG63) osteoblast maturationSarah Tamar Lanca Accepted Lancaster et al - Dec 2013one fide role to play in skeletal physiology there are varied and compelling reports detailing how this particular vitamin D3 metabolite contributes to mammalian bone metabolism . It is beyond the bounds of this particular report to look at each of these studies in the detail with which they deserve Accepted Lancaster et al - Dec 2013 but a table (Table 1) summarising the historical developments pertaining to 24R.25D action for human bone forming osteoblasts is provided.Despite theAccepted Lancaster et al - Dec 2013
wealth of literature reporting on the effects of 1.25D for human osteoblasts (hOBs) only a handful of studies which describe the actions of 24R.25D f24,25-Dihydroxyvitamin D3 cooperates with a stable, fluoromethylene LPA receptor agonist to secure human (MG63) osteoblast maturationSarah Tamar Lanca Accepted Lancaster et al - Dec 2013own to synergistically co-operate with 1.25D; it is becoming clear that 1.25D often needs to interact with other factors to prosecute the desired response in target cells . In our hands we consistently find that hOBs do not mobilise alkaline phosphatase (ALP) when treated with 1.25D in a serum-free Accepted Lancaster et al - Dec 2013in vitro setting and will only do so when the cells are in receipt of both 1.25D and certain growth factors such as epidermal growth factor , lysophosAccepted Lancaster et al - Dec 2013
phatidic acid (LPA) or certain LPA receptor3selective agonists . Whilst a significant body of work is emerging on the role of LPA in osteoblast, and i24,25-Dihydroxyvitamin D3 cooperates with a stable, fluoromethylene LPA receptor agonist to secure human (MG63) osteoblast maturationSarah Tamar Lanca Accepted Lancaster et al - Dec 2013o the compelling co-operation between LPA and 1.25D on the process of hOB maturation there is also good evidence to indicate that total ALP levels are synergistically up-regulated when MG63 hOBs are co-stimulated with 1.25D and transforming growth factor beta . The significance of ALP in bone matrix Accepted Lancaster et al - Dec 2013 calcification is well established and subjects who lack ALP present with hypophosphatasia, a condition characterised by inadequately mineralised boneAccepted Lancaster et al - Dec 2013
collagen . Given that LPA and 1.25D act in concert to secure hOB formation and maturation . we wished to ascertain whether 24R.25D might act in a sim24,25-Dihydroxyvitamin D3 cooperates with a stable, fluoromethylene LPA receptor agonist to secure human (MG63) osteoblast maturationSarah Tamar Lanca Accepted Lancaster et al - Dec 2013-(oleoyloxy)butyl-l-phosphonate (FHBP, Fig. 1). Our focus for using FHBP stems from its development as a phosphatase-resistant. a-fluoromethylene LPA analog with selective agonistic activity for the LPA3 receptor. of relevance to hOB fate, we recently reported that much lower concentrations of this Accepted Lancaster et al - Dec 2013compound, relative to LPA, co-operate with 1.25D in driving hOB maturation . Importantly hOBs and human bone marrow stem cells express LPA3 receptorsAccepted Lancaster et al - Dec 2013
and so the application of LPA3 agonists is entirely appropriate when examining their interaction with non-calcaemic VDR ligands, since our programme o24,25-Dihydroxyvitamin D3 cooperates with a stable, fluoromethylene LPA receptor agonist to secure human (MG63) osteoblast maturationSarah Tamar Lanca Accepted Lancaster et al - Dec 2013turation is particularly appealing. Our findings provide further evidence that 24R.25D exhibits biological activity and that it is clearly not an inactive metabolite as many might think. It is conceivable therefore that this particular vitamin D34metabolite might find an application in a bone regene Accepted Lancaster et al - Dec 2013rative context by promoting hOB differentiation at bone biomaterial surfaces.5Materials & Methods24,25-Dihydroxyvitamin D3 cooperates with a stable, fluoromethylene LPA receptor agonist to secure human (MG63) osteoblast maturationSarah Tamar Lanca24,25-Dihydroxyvitamin D3 cooperates with a stable, fluoromethylene LPA receptor agonist to secure human (MG63) osteoblast maturationSarah Tamar LancaGọi ngay
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