Vitamin D receptor gene start codon polymorphism (FokI) and bone mineral density in healthy male subjects.

OBJECTIVE: The genetic factors determining peak bone mineral density (BMD) in men are not well characterized. Recent studies have investigated the relationship between the start codon polymorphism (SCP) of the vitamin D receptor (VDR) gene and BMD in different populations. We have now examined the relationship between SCP of the VDR gene and BMD in a group of healthy Caucasian men from the north-east of England. SUBJECTS: Ninety-six healthy men (median age 50, range 40.0-77.0 years). MEASUREMENTS: Analysis of the FokI genotypes of SCP of the VDR and measurements of BMD at the femoral neck and lumbar spine were performed. RESULTS: FF, Ff and ff VDR FokI genotypes were found to have the highest, intermediate and the lowest lumbar spine BMD, respectively (Mean +/- SD, for FF 1.07 +/- 0.14, Ff 1.05 +/- 0.16 and ff 0.95 +/- 0.10 g/cm2). There was a significant difference in spine BMD between FF and ff genotypes (P < 0.05, analysis of variance [ANOVA]), but no such difference was apparent between Ff and ff (P > 0.05, ANOVA). Interestingly, there was no association between FokI polymorphism and femoral neck BMD (Mean +/- SD, for FF 0.85 +/- 0.12, Ff 0.87 +/- 0.15 and ff 0.83 +/- 0.15 g/cm2). The distribution of FokI VDR genotypes approached Hardy-Weinberg equilibrium and was similar to that reported for women from different ethnic groups, as the prevalence of FF and ff genotypes was 44% and 16%, respectively. CONCLUSION: The study shows that in this population of healthy men there is a weak association between lumbar spine bone mineral density and FokI restriction fragment length polymorphism at the translation initiation site of the vitamin D receptor gene.

Vitamin D binding protein gene in male osteoporosis: association of plasma DBP and bone mineral density with (TAAA)(n)-Alu polymorphism in DBP.

Vitamin D binding protein (DBP) is a major carrier protein for the vitamin D metabolites, but may also play an important role in osteoclast differentiation. Polymorphisms of the DBP gene have been reported, including (TAAA)(n)-Alu repeat polymorphisms downstream of intron 8. We have examined the relationship between polymorphisms of the DBP gene and bone mineral density (BMD) and vertebral fractures in a group of 26 men with vertebral fractures but no underlying secondary cause of osteoporosis (median age 64, ages 27-72 years) and 21 male control subjects (median age 65, ages 40-77 years). There was no apparent effect of DBP phenotype on BMD, but there was a relationship between certain genotypes of (TAAA)(n)-Alu repeats and reduced BMD and vertebral fracture. Lumbar spine and femoral neck BMD were significantly lower in men with 10/8 genotype than 10/10 genotype (P < 0.05). Furthermore, the predominant genotype in men with vertebral fractures was 10/8, whereas the most common genotype in control subjects was 10/10 (odds ratio 56; 95% confidence interval 7-445). Plasma DBP was higher in men with 10/8 genotype than those with 10/10 genotype (P < 0.05), and patients with vertebral fractures were found to have higher levels than control subjects (P < 0.0005). Although our study is small because of the relative rarity of idiopathic osteoporosis in men, the results suggest that (TAAA)(n)-Alu polymorphism may have an important effect on plasma levels of DBP, bone density and fracture risk in men.

Protein kinase C dependent induction of pp125FAK in monocytes by colony stimulating factor-GM: evidence for a synergistic effect by the cytokine and 1,25 dihydroxyvitamin D3.

The differentiation of monocytes into osteoclasts has been recently achieved in vitro in a suitable milieu containing morphogens that includes 1,25 dihydroxyvitamin D3, colony stimulating factors, interleukins and the presence of cells of osteoblastic lineage. However, the precise role of these factors in the osteoclastic differentiation process has not yet been examined. Since our previous studies have shown that osteoclasts express a much higher level of focal adhesion kinase (pp125FAK) than cells of macrophage/monocytic lineage, the present study was carried out to ascertain which morphogens are involved in increasing the expression of the kinase during the differentiation of monocytes to osteoclasts. We demonstrate that a marked increase in the expression of pp125FAK occurs only after prolonged exposure to hCSF-GM and combination of hCSF-GM and 1,25 (OH)2 D3. The hCSF-GM was found to be a more potent stimulator of pp125FAK induction than 1,25 (OH)2 D3; interestingly, the presence of both hCSF-GM and 1,25 (OH)2 D3 showed co-operative effect. Furthermore, the presence of a protein kinase C inhibitor, bisindolylmaleimide (GF 109203X), blocked hCSF-GM-mediated induction of focal adhesion kinase, implicating an important role for protein kinase C in the induction of pp125FAK.