Cherubism Mice Also Deficient in c-Fos Exhibit Inflammatory Bone Destruction Executed by Macrophages That Express MMP14 Despite the Absence of TRAP+ Osteoclasts.
Cherubism Mice Also Deficient in c-Fos Exhibit Inflammatory Bone Destruction Executed by Macrophages That Express MMP14 Despite the Absence of TRAP+ Osteoclasts.
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Cherubism小鼠也缺乏C-FOS表现出巨噬细胞执行的炎症骨破坏，尽管没有陷阱+破骨细胞，但表达MMP14。
DOI：
10.1002/jbmr.3295
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发表时间：
2018-01
期刊：
影响因子：
--
通讯作者：
Ueki Y
中科院分区：
文献类型：
--
作者：
Kittaka M;Mayahara K;Mukai T;Yoshimoto T;Yoshitaka T;Gorski JP;Ueki Y
目前认为，抗酒石酸酸性磷酸酶(TRAP+)阳性的破骨细胞是炎性关节炎局部骨破坏的唯一骨吸收细胞。最近，SH3区结合蛋白2(SH3BP2)纯合子功能获得突变的小鼠大猩猩模型(Sh3bp2KI/Ki)被证明发生了自体炎性关节破坏。在这里，我们证明了同样缺乏FBJ骨肉瘤癌基因(c-Fos)的Sh3bp2KI/Ki小鼠在12周龄时即使在没有破骨细胞的情况下仍然表现出明显的胫骨远端骨质侵蚀。基质金属蛋白酶(MMPs)所产生的骨吸收标志物ICTP水平升高，而组织蛋白酶K所产生的骨吸收标志物CTX水平未见升高。在c-Fos缺乏的Sh3bp2KI/Ki小鼠炎症关节中，胶原分解的基质金属蛋白酶水平升高。吸收坑内含有大量的F4/80+巨噬细胞，巨噬细胞的遗传耗竭挽救了这些侵蚀性改变。重要的是，给予NSC405020，一种针对血液粘连蛋白(PEX)区域的MMP14抑制剂，抑制了c-Fos缺陷的Sh3bp2KI/Ki小鼠的骨质侵蚀。在激活NF-κB通路后，c-Fos缺陷的Sh3bp2KI/Ki小鼠依赖M-CSF的巨噬细胞比野生型巨噬细胞表达更多的MMP14。有趣的是，RANKL缺陷的Sh3bp2KI/Ki小鼠没有表现出明显的骨质侵蚀，而c-Fos缺失确实恢复了RANKL缺陷的Sh3bp2KI/Ki小鼠的骨质侵蚀，这表明在该模型中，巨噬细胞的溶骨转化既需要c-Fos功能的丧失，也需要SH3BP2功能的获得。这些数据首次提供了破骨细胞以外的细胞可以在炎症性骨病中引起局灶性骨破坏的遗传学证据，并表明MMP14是c-Fos缺陷的Sh3bp2KI/Ki巨噬细胞病理性骨吸收能力的关键介质。综上所述，基于我们对缺乏破骨细胞的c-Fos缺陷小鼠的研究结果，破骨细胞是执行炎症性骨破坏的唯一细胞的范例可能需要重新评估。
Currently, it is believed that osteoclasts positive for tartrate-resistant acid phosphatase (TRAP+) are the exclusive bone-resorbing cells responsible for focal bone destruction in inflammatory arthritis. Recently, a mouse model of cherubism (Sh3bp2KI/KI) with a homozygous gain-of-function mutation in the SH3-domain binding protein 2 (SH3BP2) was shown to develop auto-inflammatory joint destruction. Here, we demonstrate that Sh3bp2KI/KI mice also deficient in the FBJ osteosarcoma oncogene (c-Fos) still exhibit noticeable bone erosion at the distal tibia even in the absence of osteoclasts at 12 weeks old. Levels of serum ICTP, a marker of bone resorption generated by matrix metalloproteinases (MMPs), were elevated, while levels of serum CTX, another resorption marker produced by cathepsin K, were not increased. Collagenolytic MMP levels were increased in the inflamed joints of the Sh3bp2KI/KI mice deficient in c-Fos. Resorption pits contained a large number of F4/80+ macrophages and genetic depletion of macrophages rescued these erosive changes. Importantly, administration of NSC405020, an MMP14 inhibitor targeted to the hemopexin (PEX) domain, suppressed bone erosion in c-Fos-deficient Sh3bp2KI/KI mice. After activation of the NF-κB pathway, M-CSF-dependent macrophages from c-Fos-deficient Sh3bp2KI/KI mice expressed increased amounts of MMP14 compared to wild-type macrophages. Interestingly, RANKL-deficient Sh3bp2KI/KI mice failed to show notable bone erosion, while c-Fos deletion did restore bone erosion to the RANKL-deficient Sh3bp2KI/KI mice, suggesting that osteolytic transformation of macrophages requires both loss-of-function of c-Fos and gain-of-function of SH3BP2 in this model. These data provide the first genetic evidence that cells other than osteoclasts can cause focal bone destruction in inflammatory bone disease and suggest that MMP14 is a key mediator conferring pathological bone-resorbing capacity on c-Fos-deficient Sh3bp2KI/KI macrophages. In summary, the paradigm that osteoclasts are the exclusive cells executing inflammatory bone destruction may need to be re-evaluated based on our findings with c-Fos-deficient cherubism mice lacking osteoclasts.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
15.3
作者：
Asagiri, M;Sato, K;Takayanagi, H
通讯作者：
Takayanagi, H
影响因子：
3.1
作者：
Maruyama, Kenta;Sano, Gen-ichiro;Matsuo, Koichi
通讯作者：
Matsuo, Koichi
DOI：
10.1124/jpet.106.109058
发表时间：
2006-12-01
影响因子：
3.5
作者：
Braselmann, Sylvia;Taylor, Vanessa;Masuda, Esteban S.
通讯作者：
Masuda, Esteban S.
影响因子：
15.9
作者：
Aliprantis, Antonios O.;Ueki, Yasuyoshi;Glimcher, Laurie H.
通讯作者：
Glimcher, Laurie H.