한빛사논문
- 조회537
Jung-Min Kim1, Yeon-Suk Yang1, Jun Xie2,3,4, Oksun Lee1, JiHea Kim1, Jaehyoung Hong5, Brigitte Boldyreff6, Odile Filhol7, Hyonho Chun5, Matthew B. Greenblatt8,9, Guangping Gao2,3,4,10 and Jae-Hyuck Shim1,2,10,*
1Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. 2Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA. 3Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA. 4Viral Vector Core, University of Massachusetts Medical School, Worcester, MA 01605, USA. 5Department of Mathematical Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. 6KinaseDetect ApS, 6340 Krusaa, Denmark. 7Interdisciplinary Research Institute of Grenoble, IRIG-Biosanté, University Grenoble Alpes, CEA, UMR 1292, F-38000 Grenoble, France. 8Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA. 9Hospital for Special Surgery, New York, NY 10021, USA. 10Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA.
*Corresponding author.
Abstract
Osteocytes play a critical role in bone remodeling through the secretion of paracrine factors regulating the differentiation and activity of osteoblasts and osteoclasts. Sclerostin is a key osteocyte-derived factor that suppresses bone formation and promotes bone resorption, therefore regulators of sclerostin secretion are a likely source of new therapeutic strategies for treatment of skeletal disorders. Here, we demonstrate that protein kinase CK2 (casein kinase 2) controls sclerostin expression in osteocytes via the deubiquitinase ubiquitin-specific peptidase 4 (USP4)-mediated stabilization of Sirtuin1 (SIRT1). Deletion of CK2 regulatory subunit, Csnk2b, in osteocytes (Csnk2bDmp1) results in low bone mass due to elevated levels of sclerostin. This phenotype in Csnk2bDmp1 mice was partly reversed when sclerostin expression was downregulated by a single intravenous injection with bone-targeting adeno-associated virus 9 (AAV9) carrying an artificial-microRNA that targets Sost. Mechanistically, CK2-induced phosphorylation of USP4 is important for stabilization of SIRT1 by suppressing ubiquitin-dependent proteasomal degradation. Upregulated expression of SIRT1 inhibits sclerostin transcription in osteocytes. Collectively, the CK2-USP4-SIRT1 pathway is crucial for the regulation of sclerostin expression in osteocytes to maintain bone homeostasis.
논문정보
- Research article
- 2022년 02월 (BRIC 등록일 2022-04-12)
- 국내+국외 연구진
- 의약학 > 응용의학
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