Sakunrangsit Nithidol, Pholtaisong Jatuphol, Sucharitakul Jeerus, Wanna-Udom Sasithorn, Prombutara Pinidphon, Pisitkun Prapaporn, Leelahavanichkul Asada, Aporntewan Chatchawit, Greenblatt Matthew B, Lotinun Sutada
Skeletal Disorders Research Unit, Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok, 10330, Thailand.
Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok, 10330, Thailand.
Sci Rep. 2021 Sep 21;11(1):18726. doi: 10.1038/s41598-021-98108-3.
Patients with systemic lupus erythematosus (SLE) have increased inflammatory cytokines, leading to periodontitis and alveolar bone loss. However, the mechanisms driving this phenomenon are still unknown. Here, we have identified novel therapeutic targets for and mediators of lupus-mediated bone loss using RNA-sequencing (RNA-seq) in a FcγRIIB mouse model of lupus associated osteopenia. A total of 2,710 upregulated and 3,252 downregulated DEGs were identified. The GO and KEGG annotations revealed that osteoclast differentiation, bone mineralization, ossification, and myeloid cell development were downregulated. WikiPathways indicated that Hedgehog, TNFα NF-κB and Notch signaling pathway were also decreased. We identified downregulated targets, Sufu and Serpina12, that have important roles in bone homeostasis. Sufu and Serpina12 were related to Hedgehog signaling proteins, including Gli1, Gli2, Gli3, Ptch1, and Ptch2. Gene knockdown analysis demonstrated that Sufu, and Serpina12 contributed to osteoclastogenesis and osteoblastogenesis, respectively. Osteoclast and osteoblast marker genes were significantly decreased in Sufu-deficient and Serpina12-deficient cells, respectively. Our results suggest that alterations in Hedgehog signaling play an important role in the pathogenesis of osteopenia in FcγRIIB mice. The novel DEGs and pathways identified in this study provide new insight into the underlying mechanisms of mandibular bone loss during lupus development.
系统性红斑狼疮（SLE）患者体内炎性细胞因子增加，会导致牙周炎和牙槽骨丧失。然而，导致这种现象的机制仍不清楚。在此，我们在狼疮相关骨质减少的FcγRIIB小鼠模型中，利用RNA测序（RNA-seq）确定了狼疮介导的骨质流失的新治疗靶点和介质。共鉴定出2710个上调差异表达基因（DEG）和3252个下调DEG。基因本体论（GO）和京都基因与基因组百科全书（KEGG）注释显示，破骨细胞分化、骨矿化、骨化和髓样细胞发育均下调。维基通路（WikiPathways）表明，刺猬信号通路、肿瘤坏死因子α（TNFα）-核因子κB（NF-κB）和Notch信号通路也减少。我们确定了在骨稳态中起重要作用的下调靶点Sufu和丝氨酸蛋白酶抑制剂12（Serpina12）。Sufu和Serpina12与刺猬信号蛋白有关，包括Gli1、Gli2、Gli3、Patched1（Ptch1）和Patched2（Ptch2）。基因敲低分析表明，Sufu和Serpina12分别促进破骨细胞生成和成骨细胞生成。在Sufu缺陷细胞和Serpina12缺陷细胞中，破骨细胞和成骨细胞标记基因分别显著减少。我们的结果表明，刺猬信号通路的改变在FcγRIIB小鼠骨质减少的发病机制中起重要作用。本研究中确定的新DEG和信号通路为狼疮发展过程中下颌骨丢失的潜在机制提供了新的见解。
