Bisphosphonates in vitro specifically inhibit, among the hematopoietic series, the development of the mouse mononuclear phagocyte lineage
Bisphosphonates in vitro specifically inhibit, among the hematopoietic series, the development of the mouse mononuclear phagocyte lineage
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双膦酸盐在体外特异性抑制造血系列中小鼠单核吞噬细胞谱系的发育
DOI：
10.1002/jbmr.5650051005
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发表时间：
1990
影响因子：
6.2
通讯作者：
H. Fleisch
中科院分区：
文献类型：
--
作者：
M. Cecchini;H. Fleisch
双膦酸盐（BP）是骨吸收的强效抑制剂。我们之前已经证明，4-氨基-1-羟基亚丁基-1，1-二膦酸酯（AHBuBP）、3-氨基-1-羟基亚丙基-1，1-二膦酸酯（AHPrBP）和二氯亚甲基二膦酸酯（Cl2MBP）在不影响非增殖细胞活力的浓度下抑制体外巨噬细胞增殖。在这项研究中，我们进一步研究了这三种BP的抗增殖作用是否在造血系列中优先于单核吞噬细胞系。BP不能抑制超过30 - 40%的[3H]胸苷（3H-TdR）掺入骨髓细胞中，骨髓细胞通过含有多系集落刺激活性的条件培养基（multi-CSA）刺激增殖。根据对多CSA和重组鼠粒细胞-巨噬细胞集落刺激因子（rmGM-CSF）在半固体培养基中诱导的集落的分析，出现了对含巨噬细胞集落特异性的剂量依赖性消失。相比之下，除巨噬细胞外的集落数量和组成，特别是粒细胞集落，不受这些化合物的影响，即使在高浓度（100 μ M）下，先前也显示对非增殖巨噬细胞具有毒性。由于巨噬细胞不同于多形性吞噬细胞，已知其具有高度胞饮性，因此可能通过这种方式，它们选择性地在细胞内浓缩BP，导致毒性浓度。我们推测BP除了对破骨细胞活性的影响外，还可能通过对破骨细胞前体和骨驻留巨噬细胞的类似机制在体内起作用，巨噬细胞是刺激骨吸收并导致破骨细胞募集和活性受损的细胞因子的来源。此外，它们对单核吞噬细胞谱系的特异性作用也可能与这些细胞参与的其他病理情况有关。
Bisphosphonates (BP) are powerful inhibitors of bone resorption. We have previously shown that 4‐amino‐1‐hydroxybutylidene‐1,1‐bisphosphonate (AHBuBP), 3‐amino‐1‐hydroxypropylidene‐1,1‐bisphosphonate (AHPrBP), and dichloromethylenebisphosphonate (Cl2MBP) inhibit the proliferation of macrophages in vitro at concentrations that do not affect the viability of nonproliferating cells. In this study we further investigated whether the antiproliferative effect of these three BP is, among the hematopoietic series, preferential to the mononuclear phagocyte lineage. BP were unable to inhibit more than 30–40% of the [3H]thymidine (3H‐TdR) incorporation into bone marrow cells stimulated to proliferate by multilineage colony‐stimulating activity containing conditioned medium (multi‐CSA). From the analysis of the colonies induced in semisolid medium by multi‐CSA and recombinant murine granulocyte‐macrophage colony stimulating factor (rmGM‐CSF), a dose‐dependent disappearance specific to the macrophage‐containing colonies emerged. In contrast, the number and composition of colonies other than macrophage and, in particular, the granulocyte colonies were not affected by these compounds, even at high concentrations (100 μM) previously also shown to be toxic for nonproliferating macrophages. Since the macrophages, differently from polymorphonuclear phagocytes, are known to be highly pinocytotic, it is possible that by this means they selectively concentrate BP intracellularly, leading to toxic concentrations. We postulate tht BP may also act in vivo in addition to their effect on osteoclast activity, by a similar mechanism on osteoclast precursors and on bone resident macrophages, a source of cytokines stimulating bone resorption and leading to impaired osteoclast recruitment and activity. Furthermore, their specific effect on the mononuclear phagocyte lineage may also be relevant in other pathologic situations in which these cells are involved.