期刊
HUMAN MUTATION
卷 42, 期 1, 页码 37-49出版社
WILEY-HINDAWI
DOI: 10.1002/humu.24126
关键词
GWAS SNP; osteoporosis; RANKL; RUNX2; USF3; WNT16
资金
- National Natural Science Foundation of China [31371275, 30971635]
- Fundamental Research Funds for the Central Universities [CCNU19TS083, CCNU18ZDPY05]
It was found that USF3 enhances osteoblast differentiation and suppresses osteoclastogenesis, interacting antagonistically with important proteins in bone metabolism. Additionally, two osteoporosis-associated gene variants, rs2908007 and rs4531631, play crucial roles in regulating bone formation and resorption.
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 basic helix-loop-helix 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 variant g.1744A>G (rs2908007A>G) located in the WNT16 promoter confers G-allele-specific transcriptional modulation by USF3, TWIST1/TCF12 and TBX5/TBX15, and USF3 transactivates the osteoclastogenesis suppressor WNT16 promoter activity and antagonizes the repression of WNT16 by TWIST1 and TCF12. The risk G allele of osteoporosis GWAS variant g.3260A>G (rs4531631A>G) in the RANKL promoter facilitates the binding of CREB1 and JUN/FOS and enhances transactivation of the osteoclastogenesis contributor RANKL that is inhibited by USF3. Our findings uncovered the functional mechanisms of osteoporosis novel GWAS-associated gene USF3 and lead single nucleotide polymorphisms rs2908007 and rs4531631 in the regulation of bone formation and resorption.
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