Vitamin D in Clinical Medicine. Группа авторов

whites, and wrongly concluded that the levels of calculated bioavailable 25(OH)D would be similar in both groups. The authors suggested that these findings could justify the fact that blacks have higher bone mass than whites, despite consistently lower 25(OH)D concentrations [36]. However, later publications have shown that the assay used by Powe et al. was a determinant. The monoclonal assay used reported lower values in blacks because the antibody does not properly recognize the Gc1F form, the most frequent DBP polymorphism in this population, calling the conclusion of this study into question [5]. Subsequently, Henderson et al. [22 ]measured DBP by mass spectrometry and found no differences between races. Recently, Nielson et al. [38 ]evaluated men from different ethnic backgrounds measuring DBP of all samples by 2 different methods, by polyclonal radial immunodiffusion assay and by monoclonal ELISA. They demonstrated that the mean DBP measured by monoclonal assay in subjects of African ancestry was approximately 50% lower than that measured by polyclonal immunoassay. Using the polyclonal antibodies, they did not find any difference between races in the mean of DBP concentrations. The free 25(OH)D was lower in the African descendants living in the United States compared to those still living in Africa, similar to the results for total 25(OH)D. The authors pointed out that the normal range defined by the Institute of Medicine (IOF) should apply to all Americans, no matter what their ethnic background is, and that total 25(OH)D can be used in the general population for the evaluation of vitamin D status.

In a population of Chinese postmenopausal women, the bioavailable and not the total 25(OH)D was an independent predictor factor for bone mineral density. Bioavailable 25(OH)D was calculated based on DBP levels taking into account the correspondent genotype. The authors suggested that the bioavailable vitamin D increases BMD through modulating the bone turnover process, inhibiting PTH excretion and stimulating OPG production [39]. In another study, in Danish premenopausal women, Lauridsen et al. [40 ]found a strong correlation between fractures and Gc phenotypes. They found a 3 times lower fracture risk in women with the Gc2-2 phenotype compared to those with the Gc1-1 phenotypes. The differences were even more striking for fractures caused by low-energy traumas, and they hypothesized that Gc plays a physiological role in osteoclast activity.

      It seems that these controversial results may be caused by the different profile of the studied populations, especially because there is a strong linkage between the Gc phenotype and ethnic background. In these two studies (Chinese and Danish), the populations tend to be more homogeneous, and the results may not be transferred to other populations.

      Conclusion

      The DBP belongs to the albuminoid gene family, initially denominated as a groupspecific component (Gc-globulin). It is a 458-amino acid multifunctional protein with 51- to 58-kDa molecular weight, synthesized by the liver, and secreted into circulation in large concentrations. It is the major transporter of vitamin D metabolites and exhibits different affinity for the multiple compounds. Although vitamin D binding is the main function of DBP, and even responsible for its name, the protein has another important function, which makes its physiology unique and complex. Actin scavenging is a known vital function of DBP, important to avoid actin polymerization and, consequently, tissue damage. Also considered an acute phase reactant, DBP is the precursor of signal MAF (Gc-MAF). Furthermore, DBP is highly polymorphic, with a characteristic distribution among different racial groups. Although its concentration is closely related to the total 25(OH)D, the relevance of the free and bound circulating hormone in human physiology remains unclear.

      References

1Cooke NE, Haddad JG: Vitamin D binding protein (Gc-globulin). Endocr Rev 1989;10:294–307.

2Speeckaert M, Huang G, Delanghe JR, Taes YE: Biological and clinical aspects of the vitamin D binding protein (Gc-globulin) and its polymorphism. Clin Chim Acta 2006;372:33–42.

3Benis KA, Schneider GB: The effects of vitamin D binding protein-macrophage activating factor and colony-stimulating factor-1 on hematopoietic cells in normal and osteopetrotic rats. Blood 1996;88:2898–2905.

4Schneider GB, Benis KA, Flay NW, Ireland RA, Popoff SN: Effects of vitamin D binding protein-macrophage activating factor (DBP-MAF) infusion on bone resorption in two osteopetrotic mutations. Bone 1995;16:657–662.

5Hollis BW, Bikle DD: Vitamin D-binding protein and vitamin D in blacks and whites. N Engl J Med 2014;370:879–880.

6Nykjaer A, Fyfe JC, Kozyraki R, Leheste JR, Jacobsen C, Nielsen MS, et al: Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3). Proc Natl Acad Sci USA 2001;98:13895–13900.

7Daiger SP, Schanfield MS, Cavalli-Sforza LL: Group-specific component (Gc) proteins bind vitamin D and 25-hydroxyvitamin D. Proc Natl Acad Sci USA 1975;72:2076–2080.

8Gibbs PE, Dugaiczyk A: Origin of structural domains of the serum-albumin gene family and a predicted structure of the gene for vitamin D-binding protein. Mol Biol Evol 1987;4:364–379.

9Cooke NE, Willard HF, David EV, George DL: Direct regional assignment of the gene for vitamin D binding protein (Gc-globulin) to human chromosome 4q11-q13 and identification of an associated DNA polymorphism. Hum Genet 1986;73:225–229.

10Svasti J, Kurosky A, Bennett A, Bowman BH: Molecular basis for the three major forms of human serum vitamin D binding protein (group-specific component). Biochemistry 1979;18:1611–1617.

11Fu L, Borges CR, Rehder DS, Wong BY, Williams R, Carpenter TO, et al: Characterization of additional vitamin D binding protein variants. J Steroid Biochem Mol Biol 2016;159:54–59.

12White P, Cooke N: The multifunctional properties and characteristics of vitamin D-binding protein. Trends Endocrinol Metab 2000;11:320–327.

13Gomme PT, Bertolini J: Therapeutic potential of vitamin D-binding protein. Trends Biotechnol 2004;22:340–345.

14McLeod JF, Cooke NE: The vitamin D-binding protein, alpha-fetoprotein, albumin multigene family: detection of transcripts in multiple tissues. J Biol Chem 1989;264:21760–21769.

15Cooke NE, McLeod JF, Wang XK, Ray K: Vitamin D binding protein: genomic structure, functional domains, and mRNA expression in tissues. J Steroid Biochem Mol Biol 1991;40:787–793.

16Bhan I: Vitamin d binding protein and bone health. Int J Endocrinol 2014;2014:561214.