Small leucine rich proteoglycans, a novel link to osteoclastogenesis.
Small leucine rich proteoglycans, a novel link to osteoclastogenesis.
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DOI：
10.1038/s41598-017-12651-6
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发表时间：
2017-10-03
影响因子：
4.6
通讯作者：
Young MF
中科院分区：
文献类型：
--
作者：
Kram V;Kilts TM;Bhattacharyya N;Li L;Young MF
Biglycan(BGN)和Fibromodin(Fmod)是富含亮氨酸的蛋白多糖小家族(SLRP)的亚型。在这项研究中，我们检测了BgnFmod双基因敲除(BgnFmod KO)小鼠的骨骼表型，发现它们比WT小，骨量明显减少。BgnFmod KO小鼠的低骨量(LBM)表型是由于BgnFmod KO小鼠的成骨细胞和破骨细胞比WT小鼠具有更高的分化潜能和更活跃的表型所致。通过多种方法，我们发现BGN和Fmod都以剂量依赖的方式与肿瘤坏死因子α和RANKL直接结合，尽管BgnFmod KO来源的成骨细胞同时表达更高水平的肿瘤坏死因子α和RANKL，但BgnFmod KO来源的成骨细胞不能将这些细胞因子保留在细胞附近，从而导致肿瘤坏死因子α和RANKL信号的增加和促进破骨细胞的形成。此外，在破骨细胞前体培养中加入BGN或Fmod可显著减弱细胞形成TRAP阳性多核巨细胞的能力。综上所述，我们的研究结果表明，骨形成细胞表达的BGN和Fmod是一种新型的偶联细胞外基质成分，通过截留肿瘤坏死因子α和/或RANKL来控制骨量，从而调节其生物利用度，从而调节破骨细胞的形成。
Biglycan (Bgn) and Fibromodulin (Fmod) are subtypes of the small leucine-rich family of proteoglycans (SLRP). In this study we examined the skeletal phenotype of BgnFmod double knockout (BgnFmod KO) mice and found they were smaller in size and have markedly reduced bone mass compared to WT. The low bone mass (LBM) phenotype is the result of both the osteoblasts and osteoclasts from BgnFmod KO mice having higher differentiation potential and being more active compared to WT mice. Using multiple approaches, we showed that both Bgn and Fmod directly bind TNFα as well as RANKL in a dose dependent manner and that despite expressing higher levels of both TNFα and RANKL, BgnFmod KO derived osteoblasts cannot retain these cytokines in the vicinity of the cells, which leads to elevated TNFα and RANKL signaling and enhanced osteoclastogenesis. Furthermore, adding either Bgn or Fmod to osteoclast precursor cultures significantly attenuated the cells ability to form TRAP positive, multinucleated giant cells. In summary, our data indicates that Bgn and Fmod expressed by the bone forming cells, are novel coupling ECM components that control bone mass through sequestration of TNFα and/or RANKL, thereby adjusting their bioavailability in order to regulate osteoclastogenesis.
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影响因子：
15.3
作者：
Asagiri, M;Sato, K;Takayanagi, H
通讯作者：
Takayanagi, H
影响因子：
82.9
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64.8
作者：
Anderson, DM;Maraskovsky, E;Galibert, L
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Galibert, L