한빛사논문
- 조회142
서울대학교 치의학대학원/치과대학
Shenzheng Mo 1,2,4, Min Kyung Kim 1,3,4, Ji Sun Jang 1,2, Seung Hye Lee 1,2, Seo Jin Hong 1, Suhan Jung 1 and Hong-Hee Kim 1,2,*
1Department of Cell and Developmental Biology, School of Dentistry, Seoul National University, Seoul 03080, Republic of Korea.
2Dental Research Institute, School of Dentistry, Seoul National University, Seoul 03080, Republic of Korea.
3Bone Science R&D Center, Tissue Regeneration Institute, Osstem Implant, Seoul 07789, Republic of Korea.
4These authors contributed equally: Shenzheng Mo, Min Kyung Kim.
*Corresponding author: correspondence to Hong-Hee Kim
Abstract
Bone homeostasis is maintained by an intricate balance between osteoclasts and osteoblasts, which becomes disturbed in osteoporosis. Metallothioneins (MTs) are major contributors in cellular zinc regulation. However, the role of MTs in bone cell regulation has remained unexplored. Single-cell RNA sequencing analysis discovered that, unlike the expression of other MT members, the expression of MT3 was unique to osteoclasts among various macrophage populations and was highly upregulated during osteoclast differentiation. This unique MT3 upregulation was validated experimentally and supported by ATAC sequencing data analyses. Downregulation of MT3 by gene knockdown or knockout resulted in excessive osteoclastogenesis and exacerbated bone loss in ovariectomy-induced osteoporosis. Transcriptome sequencing of MT3 knockdown osteoclasts and gene set enrichment analysis indicated that the oxidative stress and redox pathways were enriched, which was verified by MT3-dependent regulation of reactive oxygen species (ROS). In addition, MT3 deficiency increased the transcriptional activity of SP1 in a manner dependent on intracellular zinc levels. This MT3-zinc-SP1 axis was crucial for the control of osteoclasts, as zinc chelation and SP1 knockdown abrogated the promotion of SP1 activity and osteoclastogenesis by MT3 deletion. Moreover, SP1 bound to the NFATc1 promoter, and overexpression of an inactive SP1 mutant negated the effects of MT3 deletion on NFATc1 and osteoclastogenesis. In conclusion, MT3 plays a pivotal role in controlling osteoclastogenesis and bone metabolism via dual axes involving ROS and SP1. The present study demonstrated that MT3 elevation is a potential therapeutic strategy for osteolytic bone disorders, and it established for the first time that MT3 is a crucial bone mass regulator.
논문정보
- Research article
- 2024년 08월 (BRIC 등록일 2024-08-14)
- 국내 연구진
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