Matrix metalloproteinase-7-dependent release of tumor necrosis factor-α in a model of herniated disc resorption
Matrix metalloproteinase-7-dependent release of tumor necrosis factor-α in a model of herniated disc resorption
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DOI：
10.1172/jci7091
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发表时间：
2000-01-01
影响因子：
15.9
通讯作者：
Matrisian, LM
中科院分区：
文献类型：
--
作者：
Haro, H;Crawford, HC;Matrisian, LM
椎间盘突出症（HD）是腰痛的主要原因之一，通常无需手术干预即可自行解决。骨吸收与浸润性巨噬细胞的显著增加有关，基质金属蛋白酶（MMP） MMP-3和MMP-7与这一现象有关。我们建立了一个小鼠器官培养模型，将完整的椎间盘与腹膜巨噬细胞共培养，以研究MMPs在骨吸收中的作用。利用从mmp缺失小鼠中分离的巨噬细胞，我们报道巨噬细胞产生的MMP-7是蛋白聚糖降解、湿重减轻和共培养椎间盘巨噬细胞浸润所必需的。缺乏mmp -7的巨噬细胞不能浸润椎间盘不能归因于巨噬细胞迁移的缺陷。MMP-7是腹膜巨噬细胞释放细胞因子tnf - α所必需的。可溶性tnf - α的产生对于诱导盘共培养的MMP-3至关重要，而MMP-3又是巨噬细胞趋化剂的产生和随后的巨噬细胞浸润所必需的。巨噬细胞释放tnf - α是必要的，但对于椎间盘吸收是不够的，椎间盘吸收需要巨噬细胞浸润。我们得出结论，巨噬细胞和软骨细胞之间在HD吸收过程中存在广泛的交流，而这种交流的一个重要组成部分是MMPs释放可溶性生物活性因子的需求。
Herniated disc (HD), one of the major causes of low back pain, is often resolved spontaneously without surgical intervention. Resorption is associated with a marked increase in infiltrating macrophages, and the matrix metalloproteinases (MMP) MMP-3 and MMP-7 have been implicated in this phenomenon We developed a murine organ culture model in which intact intervertebral discs were cocultured with peritoneal macrophages to investigate the role of MMPs in HD resorption. Using macrophages isolated from MMP-null mice, we report that macrophage-produced MMP-7 was required for proteoglycan degradation, loss of wet weight, and macrophage infiltration of cocultured discs. The inability of MMP-7-deficient macrophages to infiltrate discs could not be attributed to a defect in macrophage migration. MMP-7 was required for the release of the cytokine TNF-alpha from peritoneal macrophages. The generation of soluble TNF-alpha was essential for the induction of MMP-3 in disc cocultures, which in turn is required for the generation of a macrophage chemoattractant and subsequent macrophage infiltration. TNF-alpha release from macrophages was necessary but insufficient for disc resorption, which required macrophage infiltration. We conclude that there is extensive communication between macrophages and chondrocytes in HD resorption and that an essential component of this communication is the requirement for MMPs to release soluble bioactive factors.