Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
Center for Healthy Aging, Technische Universität Dresden Technical University Medical Center, Dresden, Germany.
J Bone Miner Res. 2017 Oct;32(10):2116-2127. doi: 10.1002/jbmr.3196. Epub 2017 Aug 31.
Macrophages have established roles supporting bone formation. Despite their professional phagocytic nature, the role of macrophage phagocytosis in bone homeostasis is not well understood. Interestingly, apoptosis is a pivotal feature of cellular regulation and the primary fate of osteoblasts is apoptosis. Efferocytosis (phagocytosis of apoptotic cells) is a key physiologic process for the homeostasis of many tissues, and is associated with expression of osteoinductive factors. To test effects of macrophage depletion and compromised phagocytosis on bone, 16-week-old male C57BL/6J mice were treated with trabectedin-a chemotherapeutic with established anti-macrophage effects. Trabectedin treatment reduced F4/80+ and CD68+ macrophages in the bone marrow as assessed by flow cytometry, osteal macrophages near the bone surface, and macrophage viability in vitro. Trabectedin treatment significantly reduced marrow gene expression of key phagocytic factors (Mfge8, Mrc1), and macrophages from treated mice had a reduced ability to phagocytose apoptotic mimicry beads. Macrophages cultured in vitro and treated with trabectedin displayed reduced efferocytosis of apoptotic osteoblasts. Moreover, efferocytosis increased macrophage osteoinductive TGF-β production and this increase was inhibited by trabectedin. Long-term (6-week) treatment of 16-week-old C57BL/6J mice with trabectedin significantly reduced trabecular BV/TV and cortical BMD. Although trabectedin reduced osteoclast numbers in vitro, osteoclast surface in vivo was not altered. Trabectedin treatment reduced serum P1NP as well as MS/BS and BFR/BS, and inhibited mineralization and Runx2 gene expression of osteoblast cultures. Finally, intermittent PTH 1-34 (iPTH) treatment was administered in combination with trabectedin, and iPTH increased trabecular bone volume fraction (BV/TV) in trabectedin-treated mice. Collectively, the data support a model whereby trabectedin significantly reduces bone mass due to compromised macrophages and efferocytosis, but also due to direct effects on osteoblasts. This data has immediate clinical relevance in light of increasing use of trabectedin in oncology. © 2017 American Society for Bone and Mineral Research.
巨噬细胞在支持骨形成方面具有明确的作用。尽管其具有专业的吞噬特性，但巨噬细胞吞噬作用在骨稳态中的作用尚不清楚。有趣的是，细胞凋亡是细胞调控的关键特征，成骨细胞的主要命运是凋亡。噬作用（吞噬凋亡细胞）是许多组织稳态的关键生理过程，与成骨诱导因子的表达有关。为了测试巨噬细胞耗竭和吞噬作用受损对骨骼的影响，用已证实具有抗巨噬细胞作用的化疗药物 trabectedin 处理 16 周龄雄性 C57BL/6J 小鼠。trabectedin 处理通过流式细胞术降低了骨髓中 F4/80+和 CD68+巨噬细胞、骨表面附近的骨巨噬细胞和体外巨噬细胞活力。trabectedin 处理显著降低了关键吞噬因子（Mfge8、Mrc1）的骨髓基因表达，并且来自处理小鼠的巨噬细胞吞噬凋亡模拟珠的能力降低。体外培养的巨噬细胞和用 trabectedin 处理的巨噬细胞显示出降低的凋亡成骨细胞噬作用。此外，噬作用增加了巨噬细胞成骨诱导 TGF-β的产生，而 trabectedin 抑制了这种增加。用 trabectedin 对 16 周龄 C57BL/6J 小鼠进行长期（6 周）处理显著降低了小梁 BV/TV 和皮质 BMD。尽管 trabectedin 降低了体外破骨细胞的数量，但体内破骨细胞表面没有改变。trabectedin 处理降低了血清 P1NP 以及 MS/BS 和 BFR/BS，并抑制了成骨细胞培养物的矿化和 Runx2 基因表达。最后，联合使用 trabectedin 给予间歇性甲状旁腺素 1-34（iPTH）治疗，iPTH 增加了 trabectedin 处理小鼠的小梁骨体积分数（BV/TV）。总之，这些数据支持一种模型，即 trabectedin 由于吞噬作用和噬作用受损而显著降低骨量，但也由于对成骨细胞的直接作用而降低骨量。鉴于 trabectedin 在肿瘤学中的应用日益增加，该数据具有直接的临床意义。
