Control of Megakaryocyte Expansion and Bone Marrow Fibrosis by Lysyl Oxidase
Control of Megakaryocyte Expansion and Bone Marrow Fibrosis by Lysyl Oxidase
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DOI：
10.1074/jbc.m111.243113
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发表时间：
2011-08-05
影响因子：
4.8
通讯作者：
Ravid, Katya
中科院分区：
文献类型：
--
作者：
Eliades, Alexia;Papadantonakis, Nikolaos;Ravid, Katya
赖氨酰氧化酶（LOX）是一种基质交联蛋白，已知其被选择性表达并增强纤维化表型。我们最近的一项研究表明，LOX氧化PDGF受体-β（PDGFR-β），导致下游信号放大。在这里，我们研究了LOX在血小板前体巨核细胞（MK）中的表达和功能。定向为MK谱系的细胞经历有丝分裂增殖以产生二倍体细胞，随后进行核内有丝分裂并获得多倍性。有趣的是，LOX表达在二倍体-四倍体MK中检测到，但在多倍体MK中很少。PDGFR-BB是MK中有丝分裂增殖的诱导剂。用β-氨基丙腈抑制LOX可降低PDGFR-BB与细胞的结合和下游信号传导，以及其对MK谱系的增殖作用。LOX活性的抑制对MK多倍体没有影响。我们接下来合理地解释了，在具有丰富的低倍性MK的系统中，LOX可以高度表达并且具有功能意义。因此，我们采用加塔-1（低）小鼠，其中低倍性MK增加，PDGF-BB水平增加，纤维基质广泛。与对照小鼠相比，来自这些小鼠的MK显示LOX的高表达。重要的是，用β-氨基丙腈治疗加塔-1（低）小鼠显著改善了骨髓纤维化表型和脾脏中的MK数量。因此，我们的体外和体内数据支持LOX通过PDGF-BB调节MK扩增的新作用，并表明LOX作为骨髓纤维化的新的潜在治疗靶点。
Lysyl oxidase (LOX), a matrix cross-linking protein, is known to be selectively expressed and to enhance a fibrotic phenotype. A recent study of ours showed that LOX oxidizes the PDGF receptor-beta (PDGFR-beta), leading to amplified downstream signaling. Here, we examined the expression and functions of LOX in megakaryocytes (MKs), the platelet precursors. Cells committed to the MK lineage undergo mitotic proliferation to yield diploid cells, followed by endomitosis and acquisition of polyploidy. Intriguingly, LOX expression is detected in diploid-tetraploid MKs, but scarce in polyploid MKs. PDGFR-BB is an inducer of mitotic proliferation in MKs. LOX inhibition with beta-aminopropionitrile reduces PDGFR-BB binding to cells and downstream signaling, as well as its proliferative effect on the MK lineage. Inhibition of LOX activity has no influence on MK polyploidy. We next rationalized that, in a system with an abundance of low ploidy MKs, LOX could be highly expressed and with functional significance. Thus, we resorted to GATA-1(low) mice, where there is an increase in low ploidy MKs, augmented levels of PDGF-BB, and an extensive matrix of fibers. MKs from these mice display high expression of LOX, compared with control mice. Importantly, treatment of GATA-1(low) mice with beta-aminopropionitrile significantly improves the bone marrow fibrotic phenotype, and MK number in the spleen. Thus, our in vitro and in vivo data support a novel role for LOX in regulating MK expansion by PDGF-BB and suggest LOX as a new potential therapeutic target for myelofibrosis.