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USF3 modulates osteoporosis risk by targeting WNT16, RANKL and RUNX2
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  • Weiyuan Ye,
  • Ya Wang,
  • Sasa Hou,
  • Bing Mei,
  • Xinhong Liu,
  • Han Huang,
  • Qian Zhou,
  • Yajing Niu,
  • Yuanyuan Chen,
  • Manling Zhang,
  • Qingyang Huang
Weiyuan Ye
Central China Normal University
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Ya Wang
Central China Normal University
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Sasa Hou
Central China Normal University
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Bing Mei
Central China Normal University
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Xinhong Liu
Central China Normal University
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Han Huang
Central China Normal University
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Qian Zhou
Central China Normal University
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Yajing Niu
Central China Normal University
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Yuanyuan Chen
Central China Normal University
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Manling Zhang
Central China Normal University
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Qingyang Huang
Central China Normal University
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Abstract

Osteoporotic fractures cause major morbidity and mortality in the aging population. Genome-wide association studies (GWAS) have identified USF3 as the novel susceptibility gene of osteoporosis. However, the functional role in bone metabolism and the target gene of the bHLH transcription factor USF3 are unclear. Here we show that USF3 enhances osteoblast differentiation and suppresses osteoclastogenesis in cultured human osteoblast-like U-2OS cells. Mechanistic studies revealed that transcription factor USF3 antagonistically interacts with anti-osteogenic TWIST1/TCF12 heterodimer in the WNT16 and RUNX2 promoter, and counteracts CREB1 and JUN/FOS in the RANKL promoter. Importantly, the osteoporosis GWAS lead SNP rs2908007 risk A allele abolishes USF3 binding in the WNT16 promoter, conferring allele-specific downregulation of the osteoclastogenesis suppressor WNT16. While the risk G allele of osteoporosis GWAS lead SNP rs4531631 facilitates binding of CREB1 and JUN/FOS in the RANKL promoter, resulting in enhanced transactivation of RANKL, the principal contributor to osteoclastogenesis. Our findings uncovered functional mechanisms of osteoporosis novel GWAS associated gene USF3 and lead SNPs rs2908007 and rs4531631 in the regulation of bone formation and resorption.

Peer review status:UNDER REVIEW

11 Jul 2020Submitted to Human Mutation
16 Jul 2020Submission Checks Completed
16 Jul 2020Assigned to Editor
27 Jul 2020Reviewer(s) Assigned
14 Aug 2020Review(s) Completed, Editorial Evaluation Pending
18 Aug 2020Editorial Decision: Revise Minor
04 Sep 20201st Revision Received
10 Sep 2020Submission Checks Completed
10 Sep 2020Assigned to Editor
16 Sep 2020Reviewer(s) Assigned