Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0005940 (bone disease)
 7,459 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The plethora of actions attributed to 1,25(OH)2D3 throughout the body have suggested potential therapeutic applications for the treatment of hyperproliferative diseases, immune dysfunction, endocrine disorders, and metabolic bone disease. However, the potent calcemic activity of the natural vitamin D hormone has precluded its use in most cases. New vitamin D analogues are under development that display greater specificity, in most cases, by retaining the therapeutic properties of 1,25(OH)2D3, but with lower calcemic activity. Two analogues have been approved for use in patients: calcipotriol (Dovonex from Leo Pharmaceuticals, Copenhagen, Denmark) for the treatment of psoriasis; and 19-nor-1,25(OH)2D2 (Zemplar from Abbott Laboratories, Abbott Park, IL) for secondary hyperparathyroidism. Many others analogues are currently being tested in preclinical and clinical trials for the treatment of various types of cancer and osteoporosis, and for immunosuppression. The selectivity of the analogues can be attributed to the combined interactions with four proteins: the vitamin D receptor (VDR), the serum vitamin D binding protein (DBP), the vitamin D-24-hydroxylase and to a newly described membrane receptor. Low DBP affinity has been shown to be responsible for the reduced calcemic actions of calcipotriol and 22-oxacalcitriol (OCT), which is being tested for secondary hyperparathyroidism. However, the low calcemic activity of other analogues, including 19-nor-1,25(OH)2D2, involves other, as yet undefined, mechanisms. Understanding of the molecular basis for the selectivity of the vitamin D analogues will allow the design of more effective and safer vitamin D compounds for the treatment of a wide range of clinical disorders.
 ...
PMID:Vitamin D analogues. 980 41

The work presented here examines the possible effects of nutritional deficiencies on the characteristics of the plasma transport protein for vitamin D and its metabolites (vitamin D binding protein, DBP) in the growing rat. Deficiencies in both dietary protein intake and dietary energy intake may decrease the concentration of DBP in the circulation, although plasma DBP was not affected by dietary Ca deficiency. None of the dietary factors examined appears to influence the affinity of DBP for its major ligand, 25-hydroxycholecalciferol (25(OH)D(3)). Protein-deficient rats seemed to have difficulty in maintaining adequate concentrations of 1,25-dihydroxycholecalciferol (1,25(OH)(2)D(3)) in the circulation. The sensitivity of DBP to dietary protein and energy intake may constitute a novel mechanism that may help to explain the observed associations between malnutrition and the development of metabolic bone disease, through alterations to the cellular availability of vitamin D ligands to DBP.
 ...
PMID:Changes with malnutrition in the concentration of plasma vitamin D binding protein in growing rats. 1214 17

Osteoporosis is a bone disease leading to an increased fracture risk. It is considered a complex multifactorial genetic disorder with interaction of environmental and genetic factors. As a candidate gene for osteoporosis, we studied vitamin D binding protein (DBP, or group-specific component, Gc), which binds to and transports vitamin D to target tissues to maintain calcium homeostasis through the vitamin D endocrine system. DBP can also be converted to DBP-macrophage activating factor (DBP-MAF), which mediates bone resorption by directly activating osteoclasts. We summarized the genetic linkage structure of the DBP gene. We genotyped two single-nucleotide polymorphisms (SNPs, rs7041 = Glu416Asp and rs4588 = Thr420Lys) in 6,181 elderly Caucasians and investigated interactions of the DBP genotype with vitamin D receptor (VDR) genotype and dietary calcium intake in relation to fracture risk. Haplotypes of the DBP SNPs correspond to protein variations referred to as Gc1s (haplotype 1), Gc2 (haplotype 2), and Gc1f (haplotype3). In a subgroup of 1,312 subjects, DBP genotype was found to be associated with increased and decreased serum 25-(OH)D(3) for haplotype 1 (P = 3 x 10(-4)) and haplotype 2 (P = 3 x 10(-6)), respectively. Similar associations were observed for 1,25-(OH)(2)D(3). The DBP genotype was not significantly associated with fracture risk in the entire study population. Yet, we observed interaction between DBP and VDR haplotypes in determining fracture risk. In the DBP haplotype 1-carrier group, subjects of homozygous VDR block 5-haplotype 1 had 33% increased fracture risk compared to noncarriers (P = 0.005). In a subgroup with dietary calcium intake <1.09 g/day, the hazard ratio (95% confidence interval) for fracture risk of DBP hap1-homozygote versus noncarrier was 1.47 (1.06-2.05). All associations were independent of age and gender. Our study demonstrated that the genetic effect of the DBP gene on fracture risk appears only in combination with other genetic and environmental risk factors for bone metabolism.
 ...
PMID:Vitamin D binding protein genotype and osteoporosis. 1948 70