Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone
Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone
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DOI：
10.1073/pnas.1315153111
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发表时间：
2014-01-28
影响因子：
11.1
通讯作者：
McCauley, Laurie K.
中科院分区：
文献类型：
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作者：
Cho, Sun Wook;Soki, Fabiana N.;McCauley, Laurie K.
骨髓中的细胞亚群在骨骼稳态中发挥着独特而未被探索的功能。本研究利用靶向髓系细胞消融的小鼠模型描述了骨巨噬细胞在骨和甲状旁腺激素（PTH）依赖性骨合成代谢中的独特作用。在巨噬细胞fas诱导的凋亡（MAFIA）小鼠模型中，c-fms+髓系细胞的消耗[通过给药AP20187]减少了皮质和小梁骨量，减弱了pthinl诱导的小梁骨合成代谢，支持巨噬细胞在骨稳态中的积极功能。有趣的是，使用氯膦酸脂质体模型，靶向消耗成熟的吞噬巨噬细胞，发现相反的作用是增加小梁骨量和增加甲状旁腺激素诱导的合成代谢。与氯膦酸盐处理的小鼠相比，黑手党小鼠的凋亡细胞数量更多，骨髓中髓系细胞的流式细胞分析显示，黑手党小鼠的CD68（+）细胞减少，而氯膦酸脂质体处理的小鼠的CD68（+）和CD163（+）细胞增加。氯丙酸脂质体增加了efferocytosis（凋亡细胞的清除）和与交替活化的M2巨噬细胞相关的基因表达，以及与骨形成相关的基因表达，包括Wnt3a、Wnt10b和Tgfb1。综上所述，早期谱系巨噬细胞的消耗导致骨减少，PTH合成代谢作用减弱，而分化的巨噬细胞的消耗促进凋亡细胞的清除，并将骨髓转化为促PTH合成代谢增强的成骨环境。这些数据突出了骨巨噬细胞在骨骼稳态中的独特功能。
Cellular subpopulations in the bone marrow play distinct and unexplored functions in skeletal homeostasis. This study delineated a unique role of osteal macrophages in bone and parathyroid hormone (PTH)-dependent bone anabolism using murine models of targeted myeloid-lineage cell ablation. Depletion of c-fms+ myeloid lineage cells [via administration of AP20187 in the macrophage Fas-induced apoptosis (MAFIA) mouse model] reduced cortical and trabecular bone mass and attenuated PTHinduced trabecular bone anabolism, supporting the positive function of macrophages in bone homeostasis. Interestingly, using a clodronate liposome model with targeted depletion of mature phagocytic macrophages an opposite effect was found with increased trabecular bone mass and increased PTH-induced anabolism. Apoptotic cells were more numerous in MAFIA versus clodronate-treated mice and flow cytometric analyses of myeloid lineage cells in the bone marrow showed that MAFIA mice had reduced CD68(+) cells, whereas clodronate liposome-treated mice had increased CD68(+) and CD163(+) cells. Clodronate liposomes increased efferocytosis (clearance of apoptotic cells) and gene expression associated with alternatively activated M2 macrophages as well as expression of genes associated with bone formation including Wnt3a, Wnt10b, and Tgfb1. Taken together, depletion of early lineage macrophages resulted in osteopenia with blunted effects of PTH anabolic actions, whereas depletion of differentiated macrophages promoted apoptotic cell clearance and transformed the bone marrow to an osteogenic environment with enhanced PTH anabolism. These data highlight a unique function for osteal macrophages in skeletal homeostasis.