Increasing age is associated with reduced bone mineral content and increased risk of fractures. This is caused by a relative insufficiency of osteoblasts compared with osteoclasts. We therefore ...wanted to examine the potential differences in proliferation, differentiation, and expression of cytokines between human osteoblasts (hOBs) obtained from young and elderly individuals. Cultures of hOBs were obtained from 11 elderly (73–85 years) and 15 young (21–27 years) healthy individuals. The cells were stimulated with hGH, IGF-I, hGH + IGF-I, and TGF-β1. Proliferation was evaluated by thymidine incorporation, and differentiation was evaluated by alkaline phosphatase, OPG, and PINP production. Expression of IL-6, TGF-β1, OPG, and RANKL was investigated using real-time PCR and three carefully selected housekeeping genes. Combined stimulation with hGH and IGF-I increased proliferation without differences between hOBs obtained from young and elderly individuals. hOBs from young individuals responded to stimulation with vitamin D with a more pronounced increase in alkaline phosphatase: 107 ± 17% vs. 43 ± 5%,
P
< 0.01. Stimulation with TGF-β1 decreased OPG production by hOBs from elderly individuals but not from young individuals,
P
< 0.05. hOBs from elderly individuals expressed significantly higher amounts of IL-6 mRNA (
P
< 0.05) and less OPG and TGF-β1 mRNA (
P
= 0.08 and
P
= 0.08, respectively) compared with hOBs from young individuals. In conclusion, hOBs from elderly individuals express more IL-6 mRNA and less OPG and TGF-β1 mRNA than hOBs from young individuals. This could partly explain the reduced bone mass and increased fracture risk seen in the elderly. hOBs from young and elderly individuals responded similarly to short-term stimulation of proliferation and differentiation.
CONTEXT Mutations in the low-density lipoprotein receptor–related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect ...osteoporosis risk in the general population. OBJECTIVE To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk. DESIGN AND SETTING Prospective, multicenter, collaborative study of individual-level data on 37 534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures. MAIN OUTCOME MEASURES Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures. RESULTS The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25 052 number of participants with available data; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 × 10−8), as was the Val1330 allele (n = 24 812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 × 10−9). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 × 10−5) and 8 mg/cm2 (P = 5.0 × 10−6) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio OR, 1.26; 95% confidence interval CI, 1.08-1.47 for Met667 2001 fractures among 20 488 individuals and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 1988 fractures among 20 096 individuals). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele 7876 fractures among 31 435 individuals)) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele 7802 fractures among 31 199 individuals). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments. CONCLUSIONS Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance herein, unadjusted P < 10−7 that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.
Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has ...suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COLIA1 alleles in relation to these phenotypes.
Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval CI) BMD values were 25 mg/cm2 (CI, 16 to 34 mg/cm2) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm2 (CI, 1 to 42 mg/cm2), (p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio OR = 1.01 CI, 0.95 to 1.08) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 CI, 1.00 to 1.77) that was independent of BMD, and unaltered in adjusted analyses.
Allowing for the inevitable heterogeneity between participating teams, this study-which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene-demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A study to examine whether mutations to low-density lipoprotein receptor-related protein 5 (LRP5) and LRP6 affected bone mineral density (BMD) and increased the risk of fractures was conducted. ...Results revealed that LRP5 variants were commonly associated with BMD and increased risk of fractures.
Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has ...suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COLIA1 alleles in relation to these phenotypes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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