A rescue diet raises the plasma calcium concentration and ameliorates rheumatoid arthritis in mice: Role of CaSR-mediated inhibition of osteoclastogenesis
A rescue diet raises the plasma calcium concentration and ameliorates rheumatoid arthritis in mice: Role of CaSR-mediated inhibition of osteoclastogenesis
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DOI：
10.1096/fj.202200761rrr
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发表时间：
2023-01-01
期刊：
影响因子：
4.8
通讯作者：
Sun，Wen
中科院分区：
文献类型：
--
作者：
Yang，Qiudong;Zhao，Ziwei;Sun，Wen
钙通过与钙敏感受体（CaSR）结合来调节骨细胞的募集、分化和功能。然而，高细胞外钙（Ca 2 +e）诱导的CaSR在调节类风湿关节炎（RA）破骨细胞形成中的作用尚不清楚。在这里，我们使用TNFα转基因（TNFTG）RA小鼠及其野生型（WT）同窝仔，喂食正常或救援饮食（高钙、高磷和高乳糖饮食，称为救援饮食），以比较它们的关节骨表型。与正常饮食喂养的TNFTG小鼠相比，关节骨体积和软骨面积增加，而炎症面积、侵蚀表面、TRAP+表面和破骨细胞相关基因表达在补救饮食喂养的TNFTG小鼠中减少。此外，TNFTG小鼠喂养补救饲料，发现表现出更多的CaSR+面积和更少的NFATc 1 +/TRAP+面积。在正常Ca ~（2+）浓度下，TNFTG小鼠的破骨细胞前体细胞（OCPs）比WT小鼠的OCPs形成更多的破骨细胞，但随着Ca ~（2+）浓度的升高，破骨细胞数量逐渐减少。同时，Ca 2 +e升高时CaSR表达增加，NF-κB/NFATc 1信号分子表达减少。最后，敲低CaSR可阻断高Ca ~（2+）e对破骨细胞分化的抑制。综上所述，我们的研究结果表明，高Ca 2 + e抑制RA小鼠破骨细胞分化部分通过CaSR/NF-κB/NFATc 1途径。
Calcium modulates bone cell recruitment, differentiation, and function by binding to the calcium‐sensing receptor (CaSR). However, the function of CaSR induced by high extracellular calcium (Ca2+e) in the regulation of osteoclast formation in rheumatoid arthritis (RA) remains unknown. Here, we used TNFα‐transgenic (TNFTG) RA mice and their wildtype (WT) littermates fed a normal or a rescue diet (high calcium, high phosphorus, and high lactose diet, termed rescue diet) to compare their joint bone phenotypes. In comparison to TNFTGmice fed the normal diet, articular bone volume and cartilage area are increased, whereas inflamed area, eroded surface, TRAP+surface, and osteoclast‐related genes expression are decreased in TNFTGmice fed the rescue diet. Besides, TNFTGmice fed the rescue diet were found to exhibit more CaSR+area and less NFATc1+/TRAP+area. Furthermore, at normal Ca2+econcentrations, osteoclast precursors (OCPs) from TNFTGmice formed more osteoclasts than OCPs from WT mice, but the number of osteoclasts gradually decreased when the Ca2+econcentration increased. Meanwhile, the expression of CaSR increased responding to a high level of Ca2+e, whereas the expression of NF‐κB/NFATc1 signaling molecules decreased. At last, the knockdown of CaSR blocked the inhibition of osteoclast differentiation attributed to high Ca2+e. Taken together, our findings indicate that high Ca2+einhibits osteoclast differentiation in RA mice partially through the CaSR/NF‐κB/NFATc1 pathway.