Why SNP rs3755955 is associated with human bone mineral density? A molecular and cellular study in bone cells
Abstract
SNP rs3755955 (major/minor allele: G/A) located in Iduronidase-Alpha-L- (IDUA) gene was reported to be significant for human bone mineral density (BMD). This follow-up study was to uncover the underlying association mechanism through molecular and cellular functional assays relevant to bone. We tested the effects of single nucleotide polymorphisms (SNP) rs3755955 (defined allele G as wild-type and allele A as variant-type) on osteoblastic and osteoclastic functions, as well as protein phosphorylation in stably transfected human fetal osteoblast (hFOB) cell and mononuclear-macrophage (RAW264.7) cell. In hFOB cells, transfection with variant-type IDUA significantly decreased osteoblastic gene expression (OPN, COL1A1 and RANKL) (p < 0.01), impeded cell proliferation (p < 0.05), stimulated cell apoptosis (p < 0.001) and decreased ALP enzyme activity, as compared with that of wild-type IDUA transfection. In RAW264.7 cells, transfection with variant-type IDUA significantly inhibited cell apoptosis (p < 0.01), promoted osteoclastic precursor cell migration (p < 0.0001), growth (p < 0.01), osteoclastic gene expression (TRAP, RANK, Inte-αv and Cath-K) (p < 0.05) and TRAP enzyme activity (p < 0.001), as compared with that of wild-type IDUA transfection. In both hFOB and RAW264.7 cells, the total protein and IDUA protein-specific phosphorylation levels were significantly reduced by variant IDUA transfection, as compared with that of wild-type IDUA transfection (p < 0.05). Variant…
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