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\begin{document}

\title{\emph{USF3} modulates osteoporosis risk by targeting \emph{WNT16},
\emph{RANKL} and \emph{RUNX2}}



\author[1]{Weiyuan Ye}%
\author[1]{Ya Wang}%
\author[1]{Sasa Hou}%
\author[1]{Bing Mei}%
\author[1]{Xinhong Liu}%
\author[1]{Han  Huang}%
\author[1]{ Qian  Zhou}%
\author[1]{Yajing  Niu}%
\author[1]{Yuanyuan   Chen}%
\author[1]{Manling  Zhang}%
\author[1]{Qingyang Huang}%
\affil[1]{Central China Normal University}%


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  \date{May 26, 2024}


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\begin{abstract}
Osteoporotic fractures cause major morbidity and mortality in the aging
population. Genome-wide association studies (GWAS) have identified
\emph{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 \emph{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 \emph{WNT16} and
\emph{RUNX2} promoter, and counteracts CREB1 and JUN/FOS in the
\emph{RANKL} promoter. Importantly, the osteoporosis GWAS lead SNP
rs2908007 risk A allele abolishes USF3 binding in the \emph{WNT16}
promoter, conferring allele-specific downregulation of the
osteoclastogenesis suppressor \emph{WNT16}. While the risk G allele of
osteoporosis GWAS lead SNP rs4531631 facilitates binding of CREB1 and
JUN/FOS in the \emph{RANKL} promoter, resulting in enhanced
transactivation of \emph{RANKL}, the principal contributor to
osteoclastogenesis. Our findings uncovered functional mechanisms of
osteoporosis novel GWAS associated gene \emph{USF3} and lead SNPs
rs2908007 and rs4531631 in the regulation of bone formation and
resorption.%
\end{abstract}%



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