State Key Laboratory of Membrane Biology, School of Medicine, Center for Synthetic and Systems Biology, Tsinghua University, 100084 Beijing, China.
Department of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama 35294-2182, USA.
Int J Biol Sci. 2022 Aug 29;18(14):5522-5538. doi: 10.7150/ijbs.72211. eCollection 2022.
Cathepsins play a role in regulation of cell function through their presence in the cell nucleus. However, the role of Cathepsin K (Ctsk) as an epigenetic regulator in osteoclasts remains unknown. Our data demonstrated that mice have a striking phenotype with a 5-fold increase in bone volume compared with WT. RNA-seq analysis of , and osteoclasts revealed their distinct functions in gene expression regulation, including reduced expression, increased expression, and in signaling pathways activity regulation. Western blots and qPCR data validated these changes. ATAC-seq profiling of , and osteoclasts indicated the changes resulted from reduced chromatin openness in the promoter region of and increased chromatin openness in Nfatc1 promoter in osteoclasts compared to that in osteoclasts of WT, and . We found co-localization of Ctsk with c-Fos and cleavage of H3K27me3 in wild-type osteoclasts. Remarkably, cleavage of H3K27me3 was blocked in osteoclasts of and mice, suggesting that Ctsk may epigenetically regulate distinctive groups of genes' expression by regulating proteolysis of H3K27me3. double knockout dramatically protects against ovariectomy induced bone loss. We found that Ctsk may function as an essential epigenetic regulator in modulating levels of H3K27me3 in osteoclast activation and maintaining bone homeostasis. Our study revealed complementary and unique functions of Ctsk as epigenetic regulators for maintaining osteoclast activation and bone homeostasis by orchestrating multiple signaling pathways and targeting both Ctsk and Mmp9 is a novel therapeutic approach for osteolytic diseases such as osteoporosis.
组织蛋白酶通过存在于细胞核中来调节细胞功能。然而，组织蛋白酶 K（Ctsk）作为破骨细胞中的表观遗传调节剂的作用仍然未知。我们的数据表明，与 WT 相比， 小鼠具有明显的表型，骨量增加了 5 倍。对 、 和 破骨细胞的 RNA-seq 分析表明，它们在基因表达调控中具有不同的功能，包括 表达减少、 表达增加以及信号通路活性调节。Western blot 和 qPCR 数据验证了这些变化。对 、 和 破骨细胞的 ATAC-seq 分析表明，与 WT、 和 相比， 破骨细胞中 和 Nfatc1 启动子区域的染色质开放性降低，而 破骨细胞中 Nfatc1 启动子的染色质开放性增加，导致了这些变化。我们发现 Ctsk 与 c-Fos 共定位，并在野生型破骨细胞中切割 H3K27me3。值得注意的是，在 和 小鼠的破骨细胞中，H3K27me3 的切割被阻断，表明 Ctsk 可能通过调节 H3K27me3 的蛋白水解来表观遗传地上调特定基因表达组的表达。 双敲除可显著防止卵巢切除引起的骨丢失。我们发现 Ctsk 可能作为一种必需的表观遗传调节剂，通过调节破骨细胞激活过程中 H3K27me3 的水平来维持骨稳态。我们的研究揭示了 Ctsk 作为表观遗传调节剂在维持破骨细胞激活和骨稳态中的互补和独特功能，通过协调多个信号通路并靶向 Ctsk 和 Mmp9，为骨质疏松等溶骨性疾病提供了一种新的治疗方法。
