Role of Fas and Treg cells in fracture healing as characterized in the fas-deficient (lpr) mouse model of lupus.
Role of Fas and Treg cells in fracture healing as characterized in the fas-deficient (lpr) mouse model of lupus.
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DOI：
10.1002/jbmr.2169
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发表时间：
2014-06
影响因子：
6.2
通讯作者：
Gerstenfeld, Louis C.
中科院分区：
文献类型：
--
作者：
Al-Sebaei, Maisa O.;Daukss, Dana M.;Belkina, Anna C.;Kakar, Sanjeev;Wigner, Nathan A.;Cusher, Daniel;Graves, Dana;Einhorn, Thomas;Morgan, Elise;Gerstenfeld, Louis C.
先前的研究表明，肿瘤坏死因子α（TNFα）信号的缺失会通过延迟软骨细胞凋亡和软骨吸收来延迟骨折愈合。机制研究表明 TNFα 诱导软骨细胞内 Fas 表达；然而，软骨细胞凋亡在多大程度上是由 TNFα 单独介导的，还是依赖于 Fas 的诱导，尚不清楚。通过评估 Fas 缺陷 B6.MRL/Faslpr/J 小鼠的骨折愈合情况解决了这个问题。 Fas 的缺失会延迟软骨吸收，但也会降低胼胝中的骨分数。骨分数的减少与 B6.MRL/Faslpr/J 愈伤组织中耦合骨转换率的升高有关，破骨细胞数量增加和成骨增加证明了这一点。凋亡标记 caspase 3 分析显示 B6.MRL/Faslpr/J 小鼠愈伤组织中阳性软骨细胞和破骨细胞较少。为了确定活跃的自身免疫状态是否会导致骨转换增加，我们评估了活化的 T 细胞和 Treg 细胞的水平。 B6.MRL/Faslpr/J 小鼠的脾脏和骨骼中 Treg 细胞均升高，但骨组织中活化 T 细胞的百分比降低。在软骨形成和吸收期间，骨折导致野生型和 B6.MRL/Faslpr/J 骨组织中 Treg 细胞全身性增加约 30% 至 60%，但骨中活化 T 细胞的数量减少（野生型）或保持不变（B6.MRL/Faslpr/J）。这些结果表明，在软骨吸收期间，活跃的自身免疫状态受到抑制，并表明 iTreg 细胞在此过程中发挥功能作用。这些数据表明，软骨细胞中 Fas 活性的丧失可延长软骨细胞的寿命，并且 Fas 与 TNFα 信号传导协同介导软骨细胞凋亡。相反，Fas 的系统性丧失会导致骨折愈合后期破骨细胞数量增加，并增加成骨作用。这些发现表明，存活软骨细胞的保留会局部抑制软骨吸收过程中的破骨细胞活性或基质蛋白水解。 © 2014 作者。 《Journal of Bone and Mineral Research》由 Wiley periodicals, Inc. 代表美国骨与矿物质研究学会出版。
Previous studies showed that loss of tumor necrosis factor α (TNFα) signaling delayed fracture healing by delaying chondrocyte apoptosis and cartilage resorption. Mechanistic studies showed that TNFα induced Fas expression within chondrocytes; however, the degree to which chondrocyte apoptosis is mediated by TNFα alone or dependent on the induction of Fas is unclear. This question was addressed by assessing fracture healing in Fas-deficient B6.MRL/Faslpr/J mice. Loss of Fas delayed cartilage resorption but also lowered bone fraction in the calluses. The reduced bone fraction was related to elevated rates of coupled bone turnover in the B6.MRL/Faslpr/J calluses, as evidenced by higher osteoclast numbers and increased osteogenesis. Analysis of the apoptotic marker caspase 3 showed fewer positive chondrocytes and osteoclasts in calluses of B6.MRL/Faslpr/J mice. To determine if an active autoimmune state contributed to increased bone turnover, the levels of activated T cells and Treg cells were assessed. B6.MRL/Faslpr/J mice had elevated Treg cells in both spleens and bones of B6.MRL/Faslpr/J but decreased percentage of activated T cells in bone tissues. Fracture led to ∼30% to 60% systemic increase in Treg cells in both wild-type and B6.MRL/Faslpr/J bone tissues during the period of cartilage formation and resorption but either decreased (wild type) or left unchanged (B6.MRL/Faslpr/J) the numbers of activated T cells in bone. These results show that an active autoimmune state is inhibited during the period of cartilage resorption and suggest that iTreg cells play a functional role in this process. These data show that loss of Fas activity specifically in chondrocytes prolonged the life span of chondrocytes and that Fas synergized with TNFα signaling to mediate chondrocyte apoptosis. Conversely, loss of Fas systemically led to increased osteoclast numbers during later periods of fracture healing and increased osteogenesis. These findings suggest that retention of viable chondrocytes locally inhibits osteoclast activity or matrix proteolysis during cartilage resorption. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
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影响因子：
3.8
作者：
Adamik, Juraj;Henkel, Matthew;Ray, Anuradha;Auron, Philip E.;Duerr, Richard;Barrie, Arthur
通讯作者：
Barrie, Arthur
DOI：
10.1196/annals.1346.056
发表时间：
2006-01-01
期刊：
SKELETAL DEVELOPMENT AND REMODELING IN HEALTH, DISEASE, AND AGING
影响因子：
--
作者：
Iqbal, Jameel
通讯作者：
Iqbal, Jameel
影响因子：
7
作者：
Kim, J.;Xu, M.;Grishko, V.
通讯作者：
Grishko, V.
影响因子：
2.6
作者：
Anam, K.;Amare, M.;Davis, T. A.
通讯作者：
Davis, T. A.
影响因子：
5.3
作者：
Gerstenfeld, L. C.;Al-Ghawas, M.;Einhorn, T. A.
通讯作者：
Einhorn, T. A.