1. Academic Validation
  2. Why SNP rs3755955 is associated with human bone mineral density? A molecular and cellular study in bone cells

Why SNP rs3755955 is associated with human bone mineral density? A molecular and cellular study in bone cells

  • Mol Cell Biochem. 2022 Feb;477(2):455-468. doi: 10.1007/s11010-021-04292-1.
Pei He  # 1 2 Fei Jiang  # 1 2 Long-Fei Wu 1 2 Xu Zhou 1 2 Shu-Feng Lei 1 2 Fei-Yan Deng 3 4
Affiliations

Affiliations

  • 1 Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, 215123, Jiangsu, People's Republic of China.
  • 2 Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou, 215123, Jiangsu, People's Republic of China.
  • 3 Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, 215123, Jiangsu, People's Republic of China. [email protected].
  • 4 Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou, 215123, Jiangsu, People's Republic of China. [email protected].
  • # Contributed equally.
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 allele A of phosSNP rs3755955 in IDUA gene regulates protein phosphorylation, inhibits osteoblast function and promotes osteoclastic activity. The SNP rs3755955 could alter IDUA protein phosphorylation, significantly regulates human osteoblastic and osteoclastic gene expression, and influences the growth, differentiation and activity of osteoblast and osteoclast, hence to affect BMD.

Keywords

BMD; Osteoblast; Osteoclast; Protein phosphorylation; SNP.

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