BACKGROUND Vitamin D-binding protein (DBP), also referred to as group-specific component of serum or Gc-globulin, is the main transporter of vitamin D and its metabolites in the bloodstream. It has a molecular weight between 52–59 kDa. Unlike other hydrophobic hormone-binding systems, it circulates in a considerably higher titer compared to its ligands. It is found in the bloodstream at a level between 300–600 µg/mL. The DBP-gene is a member of a multigene cluster that includes albumin, α-fetoprotein, and α-albumin/afamin. All four genes are expressed predominantly in the liver with overlapping developmental profiles.DBP is a highly polymorphic serum protein with three common alleles (Gc1F, Gc1S and Gc2) and more than 120 rare variants. The presence of unique alleles is a useful tool for anthropological studies to discriminate and to reveal ancestral links between populations. Many studies have discussed the link between DBP-phenotypes and susceptibility or resistance to osteoporosis, Graves' disease, Hashimoto's thyroiditis, diabetes, COPD, AIDS, multiple sclerosis, sarcoidosis and rheumatic fever. Apart from its specific sterol binding capacity, DBP exerts several other important biological functions such as actin scavenging, fatty acid transport, macrophage activation and chemotaxis.1
DBP is an abundant multifunctional protein that often requires cell surface binding to mediate some of its diverse functions. DBP binds to several different molecules on the external face of the plasma membrane indicating that it may possess distinct cell binding sequences. Almost all vitamin D metabolites circulate bound to either DBP (high affinity for vitamin D ligands) or serum albumin (high abundance but low affinity for vitamin D ligands).2 Two functions of DBP involve skeletal metabolism: The first one is through the vitamin D endocrine system. Vitamin D is an important cofactor of calcium absorption in intestine and reabsorption in kidney, which plays an essential role in regulating serum calcium and phosphate homeostasis as well as bone metabolism. DBP binds to vitamin D metabolites (e.g., 25-hydroxyvitamin D3 [25(OH)D3], the major circulating metabolite, and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active form of vitamin D) at the sterol binding domain (domain I); transports vitamin D to liver, kidney, bone, and other target tissues; and stores and prolongs the half-life of the circulating vitamin D metabolites. Vitamin D metabolites are strongly and positively correlated to DBP levels in serum. Besides its role in vitamin D metabolism, serum DBP can also be converted to a DBP-macrophage activating factor (DBP-MAF) by the deglycosylation of DBP at the non-sterol binding domain (domain III), which involves the osteoclast activating domain. DBPMAF plays a role in osteoclast differentiation and mediates bone resorption by directly activating osteoclasts. Hence, the contribution of DBP to bone metabolism is not only through assisting the vitamin D endocrine system but also directly influencing bone resorption. In addition, there is evidence to suggest an interaction of DBP with calcium intake. Both DBPMAF and low calcium intake can influence osteoclast number and activity. Thus, DBP and the vitamin D–VDR system might influence bone resorption (via osteoclasts) and bone formation (via osteoblasts), respectively, which could result in osteoporosis. In addition, DBP-maf has been shown to be a potent antiangiogenic and antitumorigenic molecule. Its primary antitumor mechanisms are immunological, due to its activation of macrophages.3
1. Holick, M.F.: Ann. Epider. 19:73-78, 2007
2. Powe, C.E. et al: Hypertension 56:758-63, 2010
3. Rehder,D.S. et al: Protein Sci. 18:2036-42, 2009
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