Objective: to study the mechanism for the involvement of ТGFβ1 T(861-20)C in bone resorption in postmenopausal osteoporosis (OP). Material and methods. DNA from 158 postmenopausal women and patients with OP and from 89 healthy age-matched women was examined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (PCR-RFLP) analysis. Bone mineral density (BMD) was estimated by dual-energy X-ray absorptiometry. Standard biochemical protocols were used to detect alkaline phosphatase activity and calcium and phosphorus levels in serum. Total RNA was isolated from the peripheral blood of 32 patients with OP and 39 healthy donors and used for real-time PCR study. Results. No significant differences were found in the frequency of individual alleles and genotypes between the OP group and control donors. The minor T allele frequency was 0.27. There was a significant correlation of ТGFβ1 T(861-20)C polymorphism with low lumbar spine BMD (r=0.18; p=0.025) in Russian patients with OP. Age-adjusted (Z-score) BMD in CC genotype carriers turned to be significantly lower than that in CT and TT genotype carriers. This was accompanied by lower ТGFβ1 gene expression in the peripheral blood of CC genotype carriers (n=10) as compared to the combined group of carriers of two other genotypes (n=22) in the OP group (p=0.03). No changes in ТGFβ1 gene expression were seen in healthy women who were CC genotype carriers (n=18) as compared to the combined representatives of two other genotypes (n=21). Overall, the OP group exhibited significantly lower ТGFβ1 gene expression than the healthy controls (p=0.04). Conclusion. The association of ТGFβ1 (861-20)CC genotype with lower lumbar spine BMD in patients with OP is attended by decreased ТGFβ1 gene expression. Therefore, ТGFβ1 T(861-20)C polymorphism may be a predictor for the development of OP and the more severe form of the disease may be expected in (861-20)CC genotype carriers.

Objective: to study an association of bone mineral density (BMD) with the expression of genes associated with the proliferation, survival, and differentiation of osteocytes in the peripheral blood of postmenopausal women with osteoporosis (OP). Subjects and methods. Twenty-eight postmenopausal women with OP and 17 age-matched healthy women were examined. BMD was measured by X-ray absorptionmetry. Alkaline phosphatase activity and calcium and phosphorus levels in the blood were determined by conventional methods. RNA was isolated from the peripheral blood and used to estimate the gene expression, by using real-time polymerase chain reaction (RT-PCR). Results. The postmenopausal women with OP were observed to have a significant increase in the expression of ATG1 (serine-threonine kinase that is responsible for the generation of autophagic vacuoles) as compared to the healthy controls, which suggests that autophagy develops in the blood cells of these patients. This was attended by a considerable reduction in the expression of the mTOR (the mammalian target of rapamycin) gene, a regulator of protein synthesis and cell proliferation, and in that of the genes associated with the differentiation of osteoblasts: transforming growth factor β1 (TGF-β1), Runx 2 (Runt-related transcription factor 2) and total alkaline phosphatase (TAP), and the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β). The expression of mTOR, TGF- β1, Runx2, and IL-1β genes was positively correlated with BMD in individual areas of the hip. On the contrary, that of ATG1 and TAP was correlated negatively with BMD in this area and positively with that in the spine. Although the expression of the genes in question was not correlated with the serum levels of phosphorus and calcium, that of TGF-β1 was positively related to TAP activity in postmenopausal women with OP. Conclusion. In postmenopausal women with OP, bone loss is accompanied by a significant increase in the expression of the autophagy marker ATG1 and by a reduction in that of mTOR, which may be indicative of the inhibition of protein biosynthesis and cell proliferation and the suppression of the expression of the genes associated with the differentiation of osteoblasts and the proinflammatory cytokines TNF- α and IL-1β. The obtained data on gene expression may be used to search for new disease markers tested in peripheral blood.

Objective. Transforming growth factor β1 (TGF β1) prevails among growth factors in bone. It is produced by osteoblasts and is able to hamper osteoclast proliferation, activate and stimulate osteoblasts precursors proliferation and differentiation. At present several polymorphisms located in different regions of its sequence have been described for this gene. Several studies have shown an association between some polymorphisms of this gene and bone mass. The objective of the present study was to examine relationship between C-509T polymorphism located in gene TGF β1 promoter region with bone mineral density(BMD). There are only a few studies of relationship of this polymorphism with bone mass 23in European population. Such data for Russian population are not available.Material and methods. C-509T polymorphism was studied with PCR analysis in 159 pts with osteoporosis and in 152 healthy individuals. BMD was assessed in thoracic spine and standard regions of proximal femur with an X-ray bone densitometer.Results. C-509T allele frequencies and genotypes distribution were similar in osteoporosis and control. Mean femur neck BMD in women with osteoporosis was significantly higher in carriers of homozygote CC and heterozygote CT genotypes in comparison with homozygote TT genotype: 0,617±0,091 g/sm2, 0,626±0,064 g/sm2 and 0,555±0,074 g/sm2 respectively (p<0,005, ANOVA). Similar differences of BMD values between these genotypes were found in different femur regions and the whole femur. BMD analysis in CC+CT genotype carriers revealed presence of higher mean BMD values in all femur regions in comparison with TT genotype carriers among women with osteoporosis. Homozygote mutant genotype was not associated with fracture risk.

180 women with primary postmenopausal osteoporosis (OP) (mean age 67,5+7,8 years) were included. 118 postmenopausal women without osteoporosis and osteopenia (mean age 63,8±8,1 years) formed control group. Higher frequency of LRP5 gene CT genotype was revealed in pts with OP in comparison with control (OR=2,2; p=0,005). Tendency to increase of gene BMP4 AA genotype and gene TGFfi CC genotype was found in pts with OP in comparison with control. But the difference was not statistically significant. OP pts showed accumulation of CTCC (gene LRP5 and TGFfil combination) and CTAV (gene LRP5 and BMP4 combination) compounds increasing risk of the disease by a factor of 4 (p=0,0004) and 2,5 (p=0,035) respectively. Association was revealed between LRP5 and TGFfil (r=0,26; p=0,001), between polymorphisms of these genes and alkaline phosphatase level (r=0,22; p=0,004 and r=0,16; p=0,04 respectively), between gene BMP4 polymorphisms and serum osteoprotegerin concentration (r=0,2; p=0,0l6). Combined LRP5/TGF$1 genotype was associated with femur neck BMD (r=0,20; p=0,014) and LRP5/BMP4 - with trochanter BMD (r=0.16; p=0,055). Carriers of gene LRP5 CT genotype, gene TGFfil TT genotype and gene BMP4 W genotype had lower mean BMD values in femur neck and trochanter.

Objective. To assess frequency distribution of estrogenic receptor (ER)a and ERfl gene polymorphisms and their influence on bone mineral density (BMD) in groups of postmenopausal women with and without osteoporosis (OP). Material and methods. 200 residents of Moscow and Moscow region were divided into two groups considering BMD values according to WHO criteria; OP group and healthy control group Results. Differences of genotype and their combinations frequency distribution between OP and control groups show presence OP risk and protector genotypes. ER gene important role in pathogenesis of postmenopausal osteoporosis and possibility to use these genetic markers for assessment of risk of OP development in Russian population was confirmed.

180 women with primary postmenopausal osteoporosis (OP) (mean age 67,5+7,8 years) were included. 118 postmenopausal women without osteoporosis and osteopenia (mean age 63,8±8,1 years) formed control group. Higher frequency of LRP5 gene CT genotype was revealed in pts with OP in comparison with control (OR=2,2; p=0,005). Tendency to increase of gene BMP4 AA genotype and gene TGFfi CC genotype was found in pts with OP in comparison with control. But the difference was not statistically significant. OP pts showed accumulation of CTCC (gene LRP5 and TGFfil combination) and CTAV (gene LRP5 and BMP4 combination) compounds increasing risk of the disease by a factor of 4 (p=0,0004) and 2,5 (p=0,035) respectively. Association was revealed between LRP5 and TGFfil (r=0,26; p=0,001), between polymorphisms of these genes and alkaline phosphatase level (r=0,22; p=0,004 and r=0,16; p=0,04 respectively), between gene BMP4 polymorphisms and serum osteoprotegerin concentration (r=0,2; p=0,0l6). Combined LRP5/TGF$1 genotype was associated with femur neck BMD (r=0,20; p=0,014) and LRP5/BMP4 - with trochanter BMD (r=0.16; p=0,055). Carriers of gene LRP5 CT genotype, gene TGFfil TT genotype and gene BMP4 W genotype had lower mean BMD values in femur neck and trochanter.

Objective. To study BMP4 gene polymorphisms effect on bone mineral density (BMD) and bone remodeling markers in healthy postmenopausal women and women with osteoporosis. Material and methods. 272 women were dilivered in 2 groups from BMD: postmenopausal women (control group) and women with osteoporosis Results. Significant association of exon 4 6007C→T polymorphism with lumbar spine BMD and bone remodeling markers was revealed. This polymorphism encodes amino acid substitution in polypeptide sequence (C allele encodes alanin and T allele valine). Homozygous AA genotype accumulation was revealed in group of pts with osteoporosis. Carriers of this genotype showed significantly lower spine BMD values in comparison with AV genotype carriers. Healthy control did not have such a relationship. Mean values of femoral neck BMD did not correlate with homozygous AA genotype in pts with osteoporosis and in control group. But mean spine and femoral neck BMD values were significantly lower in carriers of all three genotypes (mean by 26%) than in control (p=0,001). Study of alkaline phosphatase concentration variability and crosslaps in pts with osteoporosis revealed lower alkaline phosphatase mean value and higher crosslaps mean value in genotype AA carriers Conclusion. Gene BMP4 6007C→T polymorphism leads to substitution of alanin (in presence of С allele) to valin (in presence of T allele) in BMP4 protein polypeptide sequence what modulates its functional activity. This polymorphism is associated with lumbar spine BMD and bone remodeling level in postmenopausal women.

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