Dysequilibrium of the PTH-FGF23-vitamin D Axis in Relapsing Remitting Multiple Sclerosis; a Longitudinal Study

Overview

Journal Mol Med

Publisher Biomed Central

Specialties General Medicine
Molecular Biology

Date 2018 Aug 24

PMID 30134801

Citations 4

Authors

Mark Simon Stein

Gregory John Ward

Helmut Butzkueven

Trevor John Kilpatrick

Leonard Charles Harrison

Affiliations

Soon will be listed here.

Abstract

Background: Parathyroid glands of people with relapsing remitting multiple sclerosis (RRMS) fail to respond to low serum 25-hydroxyvitamin D (25OHD) and low serum calcium, which are stimuli for parathyroid hormone (PTH) secretion. This led us to hypothesise: that there is suppression of PTH in RRMS due to higher than normal serum concentrations of fibroblast growth factor 23 (FGF23). We therefore sought evidence for dysregulation of the PTH-FGF23-vitamin D axis in RRMS.

Methods: Longitudinal study (winter to summer) with fasting venepunctures. For RRMS subjects who recruited a healthy control (HC) friend, pairs analyses were performed. For each pair, the within-pair difference of the variable of interest was calculated (RRMS minus HC). Then, the median of the differences from all pairs was compared against a median of zero (Wilcoxon) and the 95% confidence interval of that median difference (CI) was calculated (Sign Test).

Results: RRMS had lower winter PTH than HC, P = 0.005, (CI -2.4 to 0.5 pmol/L, n = 28 pairs), and lower summer PTH, P = 0.04, (CI -1.8 to 0.5, n = 21 pairs). Lower PTH associates physiologically with lower intact FGF23 (iFGF23), yet RRMS had higher iFGF23 than HC in winter, P = 0.04, (CI -3 to 15 pg/mL, n = 28 pairs) and iFGF23 levels comparable to HC in summer, P = 0.14, (CI -5 to 13, n = 21 pairs). As PTH stimulates and FGF23 reduces, renal 1-alpha hydroxylase enzyme activity, which synthesises serum 1,25-dihyroxyvitamin D (1,25(OH)D) from serum 25OHD, we examined the ratio of serum 1,25(OH)D to serum 25OHD. In winter, this ratio was lower in RRMS versus HC, P = 0.013, (CI -1.2 to - 0.3, n = 28 pairs).

Conclusions: This study revealed a dysequilibrium of the PTH-FGF23-vitamin D axis in RRMS, with lower plasma PTH, higher plasma iFGF23 and a lower serum 1,25(OH)D to 25OHD ratio in RRMS compared with HC subjects. This dysequilibrium is consistent with the study hypothesis that in RRMS there is suppression of the parathyroid glands by inappropriately high plasma concentrations of iFGF23. Studying the basis of this dysequilibrium may provide insight into the pathogenesis of RRMS.

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References

Nguyen-Yamamoto L, Karaplis A, St-Arnaud R, Goltzman D . Fibroblast Growth Factor 23 Regulation by Systemic and Local Osteoblast-Synthesized 1,25-Dihydroxyvitamin D. J Am Soc Nephrol. 2016; 28(2):586-597. PMC: 5280015. DOI: 10.1681/ASN.2016010066. View

Shimada T, Yamazaki Y, Takahashi M, Hasegawa H, Urakawa I, Oshima T . Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism. Am J Physiol Renal Physiol. 2005; 289(5):F1088-95. DOI: 10.1152/ajprenal.00474.2004. View

Bacchetta J, Sea J, Chun R, Lisse T, Wesseling-Perry K, Gales B . Fibroblast growth factor 23 inhibits extrarenal synthesis of 1,25-dihydroxyvitamin D in human monocytes. J Bone Miner Res. 2012; 28(1):46-55. PMC: 3511915. DOI: 10.1002/jbmr.1740. View

Glendenning P, Laffer L, Weber H, Musk A, Vasikaran S . Parathyroid hormone is more stable in EDTA plasma than in serum. Clin Chem. 2002; 48(5):766-7. View

McKenna M, Murray B, Lonergan R, Segurado R, Tubridy N, Kilbane M . Analysing the effect of multiple sclerosis on vitamin D related biochemical markers of bone remodelling. J Steroid Biochem Mol Biol. 2017; 177:91-95. DOI: 10.1016/j.jsbmb.2017.09.002. View

Ben-Dov I, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-O M, Mohammadi M . The parathyroid is a target organ for FGF23 in rats. J Clin Invest. 2007; 117(12):4003-8. PMC: 2066196. DOI: 10.1172/JCI32409. View

Munger K, Levin L, Hollis B, Howard N, Ascherio A . Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006; 296(23):2832-8. DOI: 10.1001/jama.296.23.2832. View

Parfitt A, Gallagher J, Heaney R, JOHNSTON C, Neer R, WHEDON G . Vitamin D and bone health in the elderly. Am J Clin Nutr. 1982; 36(5 Suppl):1014-31. DOI: 10.1093/ajcn/36.5.1014. View

Durham B, Joseph F, Bailey L, Fraser W . The association of circulating ferritin with serum concentrations of fibroblast growth factor-23 measured by three commercial assays. Ann Clin Biochem. 2007; 44(Pt 5):463-6. DOI: 10.1258/000456307781646102. View

10.

Imel E, Peacock M, Pitukcheewanont P, Heller H, Ward L, Shulman D . Sensitivity of fibroblast growth factor 23 measurements in tumor-induced osteomalacia. J Clin Endocrinol Metab. 2006; 91(6):2055-61. DOI: 10.1210/jc.2005-2105. View

11.

Soilu-Hanninen M, Laaksonen M, Laitinen I, Eralinna J, Lilius E, Mononen I . A longitudinal study of serum 25-hydroxyvitamin D and intact parathyroid hormone levels indicate the importance of vitamin D and calcium homeostasis regulation in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2007; 79(2):152-7. DOI: 10.1136/jnnp.2006.105320. View

12.

Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T . Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab. 2002; 87(11):4957-60. DOI: 10.1210/jc.2002-021105. View

13.

Silver J, Naveh-Many T, Mayer H, Schmelzer H, Popovtzer M . Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J Clin Invest. 1986; 78(5):1296-301. PMC: 423816. DOI: 10.1172/JCI112714. View

14.

Lavi-Moshayoff V, Wasserman G, Meir T, Silver J, Naveh-Many T . PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. Am J Physiol Renal Physiol. 2010; 299(4):F882-9. DOI: 10.1152/ajprenal.00360.2010. View

15.

Tanaka Y, DeLuca H . Measurement of mammalian 25-hydroxyvitamin D3 24R-and 1 alpha-hydroxylase. Proc Natl Acad Sci U S A. 1981; 78(1):196-9. PMC: 319018. DOI: 10.1073/pnas.78.1.196. View

16.

Hollis B . Assessment of vitamin D nutritional and hormonal status: what to measure and how to do it. Calcif Tissue Int. 1996; 58(1):4-5. DOI: 10.1007/BF02509538. View

17.

Blau J, Collins M . The PTH-Vitamin D-FGF23 axis. Rev Endocr Metab Disord. 2015; 16(2):165-74. DOI: 10.1007/s11154-015-9318-z. View

18.

Braithwaite V, Prentice A, Doherty C, Prentice A . FGF23 is correlated with iron status but not with inflammation and decreases after iron supplementation: a supplementation study. Int J Pediatr Endocrinol. 2012; 2012(1):27. PMC: 3523041. DOI: 10.1186/1687-9856-2012-27. View

19.

Lonergan R, Kinsella K, FitzPatrick P, Brady J, Murray B, Dunne C . Multiple sclerosis prevalence in Ireland: relationship to vitamin D status and HLA genotype. J Neurol Neurosurg Psychiatry. 2011; 82(3):317-22. DOI: 10.1136/jnnp.2010.220988. View

20.

Quinn S, Thomsen A, Pang J, Kantham L, Brauner-Osborne H, Pollak M . Interactions between calcium and phosphorus in the regulation of the production of fibroblast growth factor 23 in vivo. Am J Physiol Endocrinol Metab. 2012; 304(3):E310-20. PMC: 3566433. DOI: 10.1152/ajpendo.00460.2012. View