硬骨素
骨细胞
化学
细胞生物学
下调和上调
骨重建
骨吸收
泛素
成骨细胞
酪蛋白激酶1
内科学
内分泌学
作者
JiHea Kim,Yeon-Suk Yang,Jun Xie,Oksun Lee,Jaehyoung Hong,Brigitte Boldyreff,Odile Filhol-Cochet,Hyunho Chun,Matthew B. Greenblatt,Guangping Gao,Jae-Hyuck Shim
标识
DOI:10.1038/s41418-022-00952-x
摘要
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.
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