Senescent immune cells release grancalcin to promote skeletal aging
Senescent immune cells release grancalcin to promote skeletal aging
复制标题
衰老免疫细胞释放大钙素促进骨骼衰老
DOI：
10.1016/j.cmet.2021.08.009
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发表时间：
2021-10-05
期刊：
影响因子：
29
通讯作者：
Luo, Xiang-Hang
中科院分区：
文献类型：
--
作者：
Li, Chang-Jun;Xiao, Ye;Luo, Xiang-Hang
骨骼老化的特点是低骨转换和骨髓脂肪积累。然而，这种不平衡的潜在机制尚不清楚。在这里，我们发现在大鼠和小鼠的衰老过程中，促炎和衰老亚型的免疫细胞，包括巨噬细胞和中性粒细胞，在骨髓中积累并分泌大量的grancalcin。在幼鼠体内注射重组grancalcin足以诱导骨骼过早老化。相反，中性粒细胞和巨噬细胞中Gca的基因缺失延迟了骨骼衰老。在机制上，我们发现grancalcin与丛蛋白b2受体结合并部分失活其下游信号通路，从而抑制骨髓间充质基质细胞的成骨和促进脂肪生成。骨干细胞中Plexnb2的杂合基因缺失使gca基因敲除小鼠改善的骨表型失效。最后，我们开发了一种巨钙素中和抗体，并表明其治疗老年小鼠改善了骨骼健康。总之，我们的数据表明，grancalcin可能是治疗年龄相关性骨质疏松症的潜在靶点。
Skeletal aging is characterized by low bone turnover and marrow fat accumulation. However, the underlying mechanism for this imbalance is unclear. Here, we show that during aging in rats and mice proinflammatory and senescent subtypes of immune cells, including macrophages and neutrophils, accumulate in the bone marrow and secrete abundant grancalcin. The injection of recombinant grancalcin into young mice was sufficient to induce premature skeletal aging. In contrast, genetic deletion of Gca in neutrophils and macrophages delayed skeletal aging. Mechanistically, we found that grancalcin binds to the plexin-b2 receptor and partially inactivates its downstream signaling pathways, thus repressing osteogenesis and promoting adipogenesis of bone marrow mesenchymal stromal cells. Heterozygous genetic deletion of Plexnb2 in skeletal stem cells abrogated the improved bone phenotype of Gca-knockout mice. Finally, we developed a grancalcin-neutralizing antibody and showed that its treatment of older mice improved bone health. Together, our data suggest that grancalcin could be a potential target for the treatment of age-related osteoporosis.