SH3BP2 gain-of-function mutation exacerbates inflammation and bone loss in a murine collagen-induced arthritis model.
SH3BP2 gain-of-function mutation exacerbates inflammation and bone loss in a murine collagen-induced arthritis model.
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DOI：
10.1371/journal.pone.0105518
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ueki Y
中科院分区：
文献类型：
--
作者：
Mukai T;Gallant R;Ishida S;Yoshitaka T;Kittaka M;Nishida K;Fox DA;Morita Y;Ueki Y
SH3BP2是一种信号转导蛋白，调节免疫和骨骼系统。SH3BP2的功能获得突变会导致以颌骨破坏为特征的天使症。本研究旨在利用胶原诱导性关节炎(CIA)模型研究SH3BP2在炎症性骨丢失中的作用。在野生型(Sh3bp2+/+)和杂合子P416RSH3BP2基因突变(Sh3bp2KI/+)小鼠中诱导CIA，建立SH3BP2功能获得模型。关节炎的严重程度通过评估足爪肿胀和关节的组织学分析来确定。用Micro-CT分析来确定骨丢失程度。通过定量炎症细胞因子和破骨细胞标志物的基因表达来评价关节的炎症和破骨细胞的形成。此外，T细胞和B细胞反应的参与分别通过引流淋巴细胞培养和测定血清抗小鼠II型胶原抗体水平来确定。最后，通过检测骨髓来源的M-α依赖的巨噬细胞产生肿瘤坏死因子-巨噬细胞因子的水平和破骨细胞的形成，确定SH3BP2突变在巨噬细胞激活和破骨细胞形成中的作用。Sh3bp2KI/+小鼠表现出更严重的炎症和骨丢失，并伴有破骨细胞数量的增加。Sh3bp2KI/+小鼠关节中肿瘤坏死因子-α和破骨细胞标志基因的表达水平较高。淋巴结细胞培养结果显示，Sh3bp2+/+细胞与Sh3bp2KI/+细胞在淋巴细胞增殖、产生干扰素-γ和IL-17方面无明显差异。Sh3bp2+/+和Sh3bp2KI/+小鼠血清抗II型胶原抗体水平相近。体外实验表明，Sh3bp2KI/+骨髓基质细胞产生的肿瘤坏死因子-α比Sh3bp2+/+骨髓基质细胞高，并且随着NFATc1核定位的增加，Sh3bp2KI/+骨髓基质细胞诱导的破骨细胞生成增强。SH3BP2的功能增强通过增加巨噬细胞的激活和破骨细胞的形成，增加了CIA模型的炎症和骨丢失。因此，调控SH3BP2的表达可能对类风湿关节炎的治疗具有潜在的作用。
SH3BP2 is a signaling adapter protein which regulates immune and skeletal systems. Gain-of-function mutations in SH3BP2 cause cherubism, characterized by jawbone destruction. This study was aimed to examine the role of SH3BP2 in inflammatory bone loss using a collagen-induced arthritis (CIA) model. CIA was induced in wild-type (Sh3bp2+/+) and heterozygous P416R SH3BP2 cherubism mutant knock-in (Sh3bp2KI/+) mice, an SH3BP2 gain-of-function model. Severity of the arthritis was determined by assessing the paw swelling and histological analyses of the joints. Micro-CT analysis was used to determine the levels of bone loss. Inflammation and osteoclastogenesis in the joints were evaluated by quantitating the gene expression of inflammatory cytokines and osteoclast markers. Furthermore, involvement of the T- and B-cell responses was determined by draining lymph node cell culture and measurement of the serum anti-mouse type II collagen antibody levels, respectively. Finally, roles of the SH3BP2 mutation in macrophage activation and osteoclastogenesis were determined by evaluating the TNF-α production levels and osteoclast formation in bone marrow-derived M-CSF-dependent macrophage (BMM) cultures. Sh3bp2KI/+ mice exhibited more severe inflammation and bone loss, accompanying an increased number of osteoclasts. The mRNA levels for TNF-α and osteoclast marker genes were higher in the joints of Sh3bp2KI/+ mice. Lymph node cell culture showed that lymphocyte proliferation and IFN-γ and IL-17 production were comparable between Sh3bp2+/+ and Sh3bp2KI/+ cells. Serum anti-type II collagen antibody levels were comparable between Sh3bp2+/+ and Sh3bp2KI/+ mice. In vitro experiments showed that TNF-α production in Sh3bp2KI/+ BMMs is elevated compared with Sh3bp2+/+ BMMs and that RANKL-induced osteoclastogenesis is enhanced in Sh3bp2KI/+ BMMs associated with increased NFATc1 nuclear localization. Gain-of-function of SH3BP2 augments inflammation and bone loss in the CIA model through increased macrophage activation and osteoclast formation. Therefore, modulation of the SH3BP2 expression may have therapeutic potential for the treatment of rheumatoid arthritis.
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影响因子：
3.7
作者：
Chihara, Kazuyasu;Kimura, Yukihiro;Sada, Kiyonao
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