Heparanase Stimulates Chondrogenesis and Is Up-Regulated in Human Ectopic Cartilage A Mechanism Possibly Involved in Hereditary Multiple Exostoses
Heparanase Stimulates Chondrogenesis and Is Up-Regulated in Human Ectopic Cartilage A Mechanism Possibly Involved in Hereditary Multiple Exostoses
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DOI：
10.1016/j.ajpath.2015.02.014
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发表时间：
2015-06-01
影响因子：
6
通讯作者：
Pacifici, Maurizio
中科院分区：
文献类型：
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作者：
Huegel, Julianne;Enomoto-Iwamoto, Motomi;Pacifici, Maurizio
遗传性多发性外生骨病是一种儿童骨骼疾病，其特征是在生长中的骨骼元素旁边形成称为外生骨病的良性软骨肿瘤。遗传性多发性外生骨病患者携带硫酸肝素合成酶EXT1或EXT2的杂合突变，但研究表明，EXT单倍体不足和随之而来的部分HS缺陷不足以形成外生骨病。为了寻找其他途径，我们分析了肝素酶在人类外植体中的存在和分布。肝素酶很容易在大多数软骨细胞中检测到，特别是在细胞簇中。然而，在未受影响的人的对照生长板中，肝素酶仅在肥厚带检测到。外源性肝素酶处理小鼠胚胎肢体间充质微团培养可显著刺激软骨形成和骨形态发生蛋白信号，Smad1/5/8磷酸化显示。它还能刺激细胞迁移和增殖。用化学拮抗剂Surfen或细菌肝素酶治疗干扰HS功能可上调内源性肝素酶基因表达，这表明一种反直觉的反馈机制会导致HS进一步减少和信号传导增加。因此，我们测试了一种有效的肝素酶抑制剂（SST0001），它能强烈抑制软骨形成。我们的数据清楚地表明，肝素酶能够刺激软骨形成、骨形态发生蛋白信号传导、细胞迁移和软骨细胞增殖。这些特性可能使肝素酶在外生性增生的发生和发病机制中发挥作用，从而使其成为遗传性多发性外生性增生的一个可能的治疗靶点。
Hereditary multiple exostoses is a pediatric skeletal disorder characterized by benign cartilaginous tumors called exostoses that form next to growing skeletal elements. Hereditary multiple exostoses patients carry heterozygous mutations in the heparan sulfate (HS)-synthesizing enzymes EXT1 or EXT2, but studies suggest that EXT haploinsufficiency and ensuing partial HS deficiency are insufficient for exostosis formation. Searching for additional pathways, we analyzed presence and distribution of heparanase in human exostoses. Heparanase was readily detectable in most chondrocytes, particularly in cell clusters. In control growth plates from unaffected persons, however, heparanase was detectable only in hypertrophic zone. Treatment of mouse embryo Limb mesenchymal micromass cultures with exogenous heparanase greatly stimulated chondrogenesis and bone morphogenetic protein signaling as revealed by Smad1/5/8 phosphorylation. It also stimulated cell migration and proliferation. Interfering with HS function both with the chemical antagonist Surfen or treatment with bacterial heparitinase up-regulated endogenous heparanase gene expression, suggesting a counterintuitive feedback mechanism that would result in further HS reduction and increased signaling. Thus, we tested a potent heparanase inhibitor (SST0001), which strongly inhibited chondrogenesis. Our data clearly indicate that heparanase is able to stimulate chondrogenesis, bone morphogenetic protein signaling, cell migration, and cell proliferation in chondrogenic cells. These properties may allow heparanase to play a role in exostosis genesis and pathogenesis, thus making it a conceivable therapeutic target in hereditary multiple exostoses.