Megalin mediates 25‐hydroxyvitamin D<sub>3</sub>actions in human mesenchymal stem cells

Gao, Yuan; Zhou, Shuanhu; Luu, Simon; Glowacki, Julie

doi:10.1096/fj.201802578r

Cited by 15 publications

(20 citation statements)

References 43 publications

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“…Increased levels of 25‐hydroxyvitamin D (25(OH)D) are associated with a decrease in relapses in MS observational studies 43,44 . In addition, the low‐density lipoprotein receptor‐related protein 2 (LRP2), previously associated with relapse hazard 6,7 and in the discovery cohort reaching HR = 1.17, 95% CI = 1.02–1.32, and p = 0.02, is a transmembrane receptor that mediates uptake and activation of 25(OH)D through endocytosis in renal 45 and mesenchymal stem cells 46 . Crosstalk between vitamin D and the Wnt pathway is suggested, with the direction of effect depending on the biological system.…”

Section: Discussionmentioning

confidence: 99%

“…43,44 In addition, the low-density lipoprotein receptor-related protein 2 (LRP2), previously associated with relapse hazard 6,7 and in the discovery cohort reaching HR = 1.17, 95% CI = 1.02-1.32, and p = 0.02, is a transmembrane receptor that mediates uptake and activation of 25(OH)D through endocytosis in renal 45 and mesenchymal stem cells. 46 Crosstalk between vitamin D and the Wnt pathway is suggested, with the direction of effect depending on the biological system. In cancer cells, vitamin D can act as an antagonist of Wnt/β-catenin, but it may act as a co-activator in other cell types, such as osteoblasts and keratinocytes.…”

Section: May 2021 891mentioning

confidence: 99%

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Genetic Variation in WNT9B Increases Relapse Hazard in Multiple Sclerosis

Vandebergh

Andlauer

Zhou

et al. 2021

Annals of Neurology

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Objective: Many multiple sclerosis (MS) genetic susceptibility variants have been identified, but understanding disease heterogeneity remains a key challenge. Relapses are a core feature of MS and a common primary outcome of clinical trials, with prevention of relapses benefiting patients immediately and potentially limiting long-term disability accrual. We aim to identify genetic variation associated with relapse hazard in MS by analyzing the largest study population to date. Methods: We performed a genomewide association study (GWAS) in a discovery cohort and investigated the genomewide significant variants in a replication cohort. Combining both cohorts, we captured a total of 2,231 relapses occurring before the start of any immunomodulatory treatment in 991 patients. For assessing time to relapse, we applied a survival analysis utilizing Cox proportional hazards models. We also investigated the association between MS genetic risk scores and relapse hazard and performed a gene ontology pathway analysis. Results: The low-frequency genetic variant rs11871306 within WNT9B reached genomewide significance in predicting relapse hazard and replicated (meta-analysis hazard ratio (HR) = 2.15, 95% confidence interval (CI) = 1.70-2.78, p = 2.07 × 10 −10 ). A pathway analysis identified an association of the pathway "response to vitamin D" with relapse hazard (p = 4.33 × 10 −6 ). The MS genetic risk scores, however, were not associated with relapse hazard. Interpretation: Genetic factors underlying disease heterogeneity differ from variants associated with MS susceptibility. Our findings imply that genetic variation within the Wnt signaling and vitamin D pathways contributes to differences in relapse occurrence. The present study highlights these cross-talking pathways as potential modulators of MS disease activity.

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Section: Discussionmentioning

confidence: 99%

Section: May 2021 891mentioning

confidence: 99%

Genetic Variation in WNT9B Increases Relapse Hazard in Multiple Sclerosis

Vandebergh

Andlauer

Zhou

et al. 2021

Annals of Neurology

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“…However, inside these cells 25(OH)D 3 binds to HSPA (heat shock protein family A (Hsp70)) proteins for shuttling to mitochondria and the nucleus [ 53 ] (Figure 2,3). Some 20 years ago the membrane proteins LRP2 (LDL receptor‐related protein 2, also called megalin) and cubilin (CUBN) were found to be involved in the endocytosis of vitamin D compounds bound to DBP [ 54‐56 ] (Figure 2,2). Thus, 25(OH)D 3 is transported bound to DBP into proximal tubules of the kidneys, which is the main organ where it is hydroxylated by CYP27B1 into 1,25(OH) 2 D 3 .…”

Section: Evidence For Membrane Signalling Of Vitamin Dmentioning

confidence: 99%

Vitamin D receptor(s): In the nucleus but also at membranes?

Żmijewski

Carlberg

2020

Experimental Dermatology

106

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Secosteroids are steroid compounds with an open Bring commonly found in fungi (vitamin D 2), plants, invertebrates and vertebrates (vitamin D 3). Evolutionary, vitamin D 3 is a very old molecule, [1] which is created in a non-enzymatic reaction when the direct cholesterol precursor 7-dehydrocholesterol is exposed to UV-B (290-320 nm), [2,3] that is, cholesterol synthesizing species use(d) vitamin D 3 for UV-B scavenging [4] (Figure 1). This implies that also humans can synthesize vitamin D 3 in their skin. Through the action of a variety of cytochrome P450 (CYP) enzymes numerous vitamin D metabolites are created, [5] of which 25-hydroxyvitamin D 3 (25(OH)D 3) is the most stable (serum half-life some 3 weeks [6]) and abundant (a vitamin D sufficient person should have 25(OH)D 3 serum concentration of at least 75 nM [7]). The starting point of what is called today vitamin D endocrinology was some 550 million years ago, when in a boneless fish a receptor evolved that bound with high affinity the metabolite 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3). [8] This high affinity

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“…Megalin, also known as Lrp2 (low-density lipoprotein-related protein 2) or gp330, is a transmembrane receptor for serum DBP in renal cells and is essential for the uptake of the 25(OH)D3-DBP complex [63]. The 58-kD DBP is the main transporter for Vitamin D 3 metabolites in the circulation.…”

Section: Megalin Cubilin and Vitamin D: A Synergy Into Proximal Tubumentioning

confidence: 99%

Protective Role of Vitamin D in Renal Tubulopathies

et al. 2020

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Vitamin D is tightly linked with renal tubular homeostasis: the mitochondria of proximal convoluted tubule cells are the production site of 1α,25-dihydroxyvitamin D3. Patients with renal impairment or tubular injury often suffer from chronic inflammation. This alteration comes from oxidative stress, acidosis, decreased clearance of inflammatory cytokines and stimulation of inflammatory factors. The challenge is to find the right formula for each patient to correctly modulate the landscape of treatment and preserve the essential functions of the organism without perturbating its homeostasis. The complexity of the counter-regulation mechanisms and the different axis involved in the Vitamin D equilibrium pose a major issue on Vitamin D as a potential effective anti-inflammatory drug. The therapeutic use of this compound should be able to inhibit the development of inflammation without interfering with normal homeostasis. Megalin-Cubilin-Amnionless and the FGF23-Klotho axis represent two Vitamin D-linked mechanisms that could modulate and ameliorate the damage response at the renal tubular level, balancing Vitamin D therapy with an effect potent enough to contrast the inflammatory cascades, but which avoids potential severe side effects.

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Megalin mediates 25‐hydroxyvitamin D₃actions in human mesenchymal stem cells

Cited by 15 publications

References 43 publications

Genetic Variation in WNT9B Increases Relapse Hazard in Multiple Sclerosis

Genetic Variation in WNT9B Increases Relapse Hazard in Multiple Sclerosis

Vitamin D receptor(s): In the nucleus but also at membranes?

Protective Role of Vitamin D in Renal Tubulopathies

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Megalin mediates 25‐hydroxyvitamin D3actions in human mesenchymal stem cells

Cited by 15 publications

References 43 publications

Genetic Variation in WNT9B Increases Relapse Hazard in Multiple Sclerosis

Genetic Variation in WNT9B Increases Relapse Hazard in Multiple Sclerosis

Vitamin D receptor(s): In the nucleus but also at membranes?

Protective Role of Vitamin D in Renal Tubulopathies

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Megalin mediates 25‐hydroxyvitamin D₃actions in human mesenchymal stem cells