Cortical bone resorption during exercise is interleukin-6 genotype-dependent

Dhamrait, Sukhbir S.; James, L; Brull, David; Myerson, Saul G.; Hawe, Emma; Pennell, Dudley J.; Humphries, Steve E.; Haddad, Fares S.; Montgomery, Hugh

doi:10.1007/s00421-002-0750-x

Cited by 31 publications

(17 citation statements)

References 28 publications

(47 reference statements)

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“…In keeping with this hypothesis, modulation by genetic variants of the skeletal response induced by strenuous exercise has previously been reported 16,17 . By expressing exon 18 alleles in the context of their haplotype in vitro, we found the T variant to be associated with a significantly decreased response to canonical Wnt3a signaling.…”

Section: Discussionsupporting

confidence: 63%

“…Nevertheless, there is some evidence that genetic variation may influence the response of muscles and the skeleton to intense physical training. 16,17 Recently, mutations in the lipoprotein receptor-related protein 5 (LRP5) gene have been demonstrated to result in different single gene disorders with either a high or low BMD phenotype 18 . Thus in the autosomal recessive disorder, osteoporosis-pseudoglioma syndrome (OPPG), very low bone mass and blindness have been linked to loss-of-function mutations in the LRP5 gene.…”

Section: Introductionmentioning

confidence: 99%

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Genetic variation at the low-density lipoprotein receptor-related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men

Kiel¹,

Ferrari²,

Cupples³

et al. 2007

Bone

103

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Polymorphisms in the LRP5 gene have been associated with bone mineral density (BMD) in men and/or women. However, the functional basis for this association remains obscure. We hypothesized that LRP5 alleles could modulate Wnt signaling and the relationship between physical activity and BMD.This genetic association study was performed in the population-based Framingham Study Offspring Cohort, and included a subset of 1797 unrelated individuals who provided blood samples for DNA and who had BMD measurements of the hip and spine. Ten single-nucleotide polymorphisms (SNPs) spanning the LRP5 gene were genotyped and used for association and interaction analyses with BMD by regression methods. LRP5 haplotypes were transiently co-expressed with Wnt3a, MesD and Dkk1 in HEK293 cells and their activity evaluated by the TCF-Lef reporter assay.Six out of ten SNPs in LRP5 were associated with one or more of the femur or spine BMDs in men or women after adjustment for covariates, and these associations differed between genders. In men ≤age 60 years, 3 SNPs were significantly associated with BMD: rs2306862 on Exon 10 with femoral neck BMD (p=0.01) and Ward's BMD (p=0.01); rs4988321/p. V667M with Ward's BMD (p=0.02); and intronic rs901825 with trochanter BMD (p=0.03). In women, 3 SNPs in intron 2 were significantly associated with BMD: rs4988330 for trochanter (p=0.01) and spine BMD (p=0.003); rs312778 with femoral neck BMD (p=0.05); and rs4988331 with spine BMD (p=0.04). For each additional rare allele, BMD changed by 3-5% in males and 2-4% in females. Moreover, there was a significant interaction between physical activity and rs2306862 in exon 10 (p for interaction=0.02) and rs3736228/p. A1330V in exon 18 (p for interaction=0.05) on spine BMD in men. In both cases, the TT genotype was associated with lower BMD in men with higher physical activity scores, conversely with higher BMD in men with lower physical activity scores. In vitro, TCF-Lef activity Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In summary, genetic variation in exons 10 and 18 of the LRP5 gene modulates Wnt signaling and the relationship between physical activity and BMD in men. These observations suggest that Wnt-LRP5 may play a role in the adaptation of bone to mechanical load in humans, and may explain some gender-related differences in bone mass. NIH Public Access

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Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Genetic variation at the low-density lipoprotein receptor-related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men

Kiel¹,

Ferrari²,

Cupples³

et al. 2007

Bone

103

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“…However, many studies revealed that the anabolic response of bone to mechanical loading or exercise is highly variable among individuals, (37,38) and similar findings also were found among several inbred strains of mice. (39,40) These results suggest that genetic factors govern the response to mechanical loading in humans and animals.…”

Section: Introductionsupporting

confidence: 52%

“…(39,40) These results suggest that genetic factors govern the response to mechanical loading in humans and animals. Despite a few interesting loci in chromosomes found to be related to mechanosensitivity, (38,41,42) little is known about the genetic regulation of mechanical loading. Therefore, a genome-wide study would aid in understanding the anabolic response of bone to mechanical loading.…”

Section: Introductionmentioning

confidence: 99%

Mechanical stretching induces osteoprotegerin in differentiating C2C12 precursor cells through noncanonical Wnt Pathways

Chen

et al. 2010

Journal of Bone and Mineral Research

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Mechanical loading is known to be important for maintaining the formation and resorption rates of bone. To study the mechanisms by which mechanical loading regulates osteogenesis, we investigated the role of the Wnt pathway in C2C12 cells committed to osteogenic differentiation in response to cyclic mechanical stretching. Osteoprotegerin (OPG) acts as a decoy receptor for RANKL to inhibit osteoclastogenesis and resorption of bone. Our results demonstrate that stretching leads to a sustained increase in OPG expression in C2C12 cells. The expression of osteogenic marker genes, such as osteocalcin and alkaline phosphatase, was transiently decreased by stretching at 24 hours and returned to control levels at 48 hours. The addition of inhibitors of the canonical Wnt/b-catenin pathways, such as the secreted FZD-related peptide sRFP2, as well as siRNA-mediated knockdown, did not inhibit the effect of stretching on OPG expression. In contrast, treatment with inhibitors of noncanonical Wnt signaling, including KN93, and siRNA for Nemo-like kinase (NLK) blocked most of the mechanical inductive effect on OPG. Furthermore, stretching-induced OPG production in the culture medium was able to inhibit the osteoclast formation of bone marrow macrophages. These results suggest that mechanical stretching may play an important role in bone remodeling through the upregulation of OPG and that the mechanical signaling leading to OPG induction involves the noncanonical Wnt pathway. ß

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“…The Ϫ174 GϾC SNP in the promoter region of the IL-6 gene has gained considerable interest because it has been associated with a variety of disease states, such as Alzheimer disease, atherosclerosis, cardiovascular disease, cancer, NIDDM, osteoporosis, sepsis, and systemic-onset juvenile chronic arthritis (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). The results of the present study, which demonstrate the functionality of this SNP, highlight the results of previous association studies of major disease states.…”

Section: Discussionmentioning

confidence: 99%

Genetic Predisposition of the Interleukin-6 Response to Inflammation: Implications for a Variety of Major Diseases?

Held²,

et al. 2004

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Background: A single-nucleotide polymorphism (SNP) in the promoter region of the interleukin-6 (IL-6) gene at position ؊174 (G>C) has been reported to be associated with a variety of major diseases, such as Alzheimer disease, atherosclerosis, and cardiovascular disease, cancer, non-insulin-dependent diabetes mellitus, osteoporosis, sepsis, and systemic-onset juvenile chronic arthritis. However, authors of previous in vitro and in vivo studies have reported conflicting results regarding the functionality of this polymorphism. We therefore aimed to clarify the role of the ؊174 SNP for the induction of IL-6 in vivo. Methods: We vaccinated 20 and 18 healthy individuals homozygous for the ؊174 C and G alleles, respectively, with 1 mL of Salmonella typhii vaccine. IL-1␤, IL-6, and tumor necrosis factor-␣ (TNF-␣) were measured in the blood at baseline and up to 24 h after vaccination. Results: Individuals with the G genotype had significantly higher plasma IL-6 values at 6, 8, and 10 h after vaccination than did individuals with the C genotype (P <0.005). There were no differences between the two genotypes regarding serum concentrations of IL-1␤ and TNF-␣ before or after vaccination. Conclusions: The ؊174 G>C SNP in the promoter region of the IL-6 gene is functional in vivo with an increased inflammatory response associated with the G

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Cortical bone resorption during exercise is interleukin-6 genotype-dependent

Cited by 31 publications

References 28 publications

Genetic variation at the low-density lipoprotein receptor-related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men

Genetic variation at the low-density lipoprotein receptor-related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men

Mechanical stretching induces osteoprotegerin in differentiating C2C12 precursor cells through noncanonical Wnt Pathways

Genetic Predisposition of the Interleukin-6 Response to Inflammation: Implications for a Variety of Major Diseases?

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