Generation of 1,25-dihydroxyvitamin D3 in Cyp27b1 knockout mice by treatment with 25-hydroxyvitamin D3 rescued their rachitic phenotypes

Nishikawa, Miyu; Yasuda, Kaori; Takamatsu, Masashi; Abé, Keisuke; Nakagawa, Kimie; Tsugawa, Naoko; Hirota, Yoshio; Tanaka, Kazuma; Yamashita, Shigeaki; Ikushiro, Shinichi; Suda, Toshio; Okano, Toshio; Sakaki, Toshiyuki

doi:10.1016/j.jsbmb.2018.07.012

Cited by 25 publications

(31 citation statements)

References 45 publications

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“…2e, the plasma 1,25(OH) 2 D 3 level was significantly increased in Vdr (R270L) (t = 4.024, df = 8, p = 0.004) and Vdr-KO rats (t = 2.723, df = 5, p = 0.042) but was significantly decreased in Cyp27b1-KO rats (8.0 ± 3.2 pg/mL (mean ± SEM, n = 7)) compared to that in WT rats (24.8 ± 5.2 pg/mL, (mean ± SEM, n = 7)) (t = 2.771, df = 12, p = 0.017). This result was somewhat different from that in Cyp27b1-KO mice 12 , which showed no detectable 1,25(OH) 2 D 3 (<5 pg/mL). Supplementary Fig.…”

Section: Plasma Concentration Of 125(oh) 2 Dcontrasting

confidence: 87%

“…However, 1,25(OH) 2 D 3 was detected in the blood of Cyp27b1-KO rats at the same levels as in wild-type rats. As described in our previous study, the generation of 1,25(OH) 2 D 3 following 25(OH)D 3 administration was also observed in Cyp27b1-KO mice 12 . 1α-Hydroxylase activity toward 25(OH)D 3 in a liver mitochondrial fraction prepared from Cyp27b1-KO rats suggested that Cyp27a1, a 1α-hydroxylase abundant in the liver, is most likely responsible for the generation of 1,25(OH) 2 D 3 .…”

Section: Comparison Of Cyp27b1-ko Rats With Vdr (R270l) Rats and The supporting

confidence: 79%

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Generation of novel genetically modified rats to reveal the molecular mechanisms of vitamin D actions

Nishikawa

Yasuda

Takamatsu

et al. 2020

Sci Rep

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Recent studies have suggested that vitamin D activities involve vitamin D receptor (VDR)-dependent and VDR-independent effects of 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3) and 25-hydroxyvitamin D 3 (25(OH)D 3) and ligand-independent effects of the VDR. Here, we describe a novel in vivo system using genetically modified rats deficient in the Cyp27b1 or Vdr genes. Type II rickets model rats with a mutant Vdr (R270L), which recognizes 1,25(OH) 2 D 3 with an affinity equivalent to that for 25(OH)D 3 , were also generated. Although Cyp27b1-knockout (KO), Vdr-Ko, and Vdr (R270L) rats each showed rickets symptoms, including abnormal bone formation, they were significantly different from each other. Administration of 25(OH)D 3 reversed rickets symptoms in Cyp27b1-KO and Vdr (R270L) rats. Interestingly, 1,25(OH) 2 D 3 was synthesized in Cyp27b1-KO rats, probably by Cyp27a1. In contrast, the effects of 25(OH)D 3 on Vdr (R270L) rats strongly suggested a direct action of 25(OH)D 3 via VDR-genomic pathways. These results convincingly suggest the usefulness of our in vivo system. The active form of vitamin D 3 , 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3), plays important roles in osteogenesis, calcium homeostasis, cellular differentiation, and immune responses 1. 1,25(OH) 2 D 3 is generated by two hydroxylation steps from vitamin D 3 : C-25 hydroxylation by hepatic CYP2R1 and CYP27A1 and subsequent 1α-hydroxylation by renal 1α-hydroxylase (CYP27B1) 2. The vitamin D receptor (VDR) mediates the genomic action of active vitamin D 3. Binding of active vitamin D 3 to the VDR triggers its heterodimerization to the retinoid X receptor and subsequent translocation to the nucleus. This translocation results in regulating target gene expression by formation of the VDR complex on vitamin D-responsive elements in the promoter regions of target genes, such as osteocalcin and osteopontin in bones and the calcium channels and calbindins in intestines 3. CYP24A1, one of the well-known vitamin D target genes, is involved in inactivating 1,25(OH) 2 D 3 through sequential metabolism that starts with C-24 or C-23 hydroxylation of 1,25(OH) 2 D 3 4. A variety of vitamin D derivatives have been developed as drugs for rickets, osteoporosis, psoriasis, secondary hyperparathyroidism, and chronic kidney disease. Because all of these compounds show high affinity for the VDR, these pharmacological actions are considered to be VDR mediated. However, as with 1,25(OH) 2 D 3 , they might also have non-VDR-mediated actions. Thus, pharmacological action studies of vitamin D derivatives are essential for future drug discovery.

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Section: Plasma Concentration Of 125(oh) 2 Dcontrasting

confidence: 87%

Section: Comparison Of Cyp27b1-ko Rats With Vdr (R270l) Rats and The supporting

confidence: 79%

Generation of novel genetically modified rats to reveal the molecular mechanisms of vitamin D actions

Nishikawa

Yasuda

Takamatsu

et al. 2020

Sci Rep

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“…Additionally, systemic inflammation, obesity, and parathyroid hormone levels have been associated with changes in circulating vitamin D levels. (12,(35)(36)(37)(38)(39)(40).…”

Section: Effect Of Storage Time and Seasonal Variation On Circulatingmentioning

confidence: 99%

Circulating Levels of Free 25(OH)D Increase at the Onset of Rheumatoid Arthritis

Anaparti

Meng

Mahadevappa

et al. 2019

Preprint

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Objective: Epidemiological studies suggest vitamin D deficiency as a potential risk factor for rheumatoid arthritis (RA) development, a chronic autoimmune disorder highly prevalent in indigenous North American (INA) population. We therefore profiled the circulating levels of 25-hydroxyvitaminD [25(OH)D], an active metabolite of vitamin D, in a cohort of at-risk first-degree relatives (FDR) of INA RA patients, a subset of whom subsequently developed RA (progressors). Methods: 2007 onward, serum samples from INA RA patients and FDR were collected at the time of a structured baseline visit and stored at -20°C. Anti-citrullinated protein antibodies (ACPA), 25(OH)D, hs-CRP, vitamin-D binding protein (VDBP) levels were determined using ELISA and rheumatoid factor (RF) seropositivity was determined by nephelometry. Results: We demonstrate that 25 (OH) D concentrations were lower in winter than summer (P=0.0538), and that serum 25(OH)D levels were higher in samples collected and stored after 2013 (P<0.0001). Analysis of samples obtained after 2013 demonstrated that 37.6% of study participants were 25(OH)D insufficient (<75nmol/L). Also, seropositive RA patients and FDR had lower 25(OH)D levels compared to ACPA-/FDR (P<0.05, P<0.01 respectively). Linear regression analysis showed 25(OH)D insufficiency was inversely associated with presence of RA autoantibodies. Longitudinal samples from 14 progressors demonstrated a consistent increase in 25(OH)D levels at the time they exhibited clinically detectable joint inflammation, without any significant change in VDBP levels. Conclusion:We demonstrate that 25(OH)D levels in serum increased at RA onset in progressors.The potential role that vitamin D metabolites and their downstream effects play in RA transition requires further investigation.

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“…In fact, the expected 1, 25-OH 2 D levels in 1α-hydroxylase deficiency are low, inappropriately normal 1, 25-OH 2 D levels also indicate that the enzyme activity is insufficient. Recently, Nishikawa N, et al (22) reported that liver mitochondrial CYP27A1 can catalyse 1α-hydroxylation of 25-OHD. A small increase in serum 1, 25-OH 2 D level has been observed in CYP27B1 knockout mice after given high dietary vitamin D, suggesting a conversion from 25-OHD to 1, 25-OH 2 D by a non-CYP27B1 enzyme.…”

Section: Discussionmentioning

confidence: 99%

Genetic and clinical characteristics of the patients with Vitamin D Dependent Rickets Type 1A

Dursun¹,

Özgürhan²,

Kırmızıbekmez³

et al. 2018

Jcrpe

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Objective: Vitamin D dependent rickets type 1A (VDDR1A) is an autosomal recessive disorder caused by mutations in the 25OHD 1α-hydroxylase gene (CYB27B1). As it may be confused with nutritional rickets and hypophosphatemic rickets, genetic analysis is important for making a correct diagnosis. Methods: We analysed genomic DNA from 11 patients from 8 different Turkish families. The patients were recruited for our studies if they presented with diagnosis of vitamin D dependent rickets.

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Generation of 1,25-dihydroxyvitamin D3 in Cyp27b1 knockout mice by treatment with 25-hydroxyvitamin D3 rescued their rachitic phenotypes

Cited by 25 publications

References 45 publications

Generation of novel genetically modified rats to reveal the molecular mechanisms of vitamin D actions

Generation of novel genetically modified rats to reveal the molecular mechanisms of vitamin D actions

Circulating Levels of Free 25(OH)D Increase at the Onset of Rheumatoid Arthritis

Genetic and clinical characteristics of the patients with Vitamin D Dependent Rickets Type 1A

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