Regulation of matrix metalloproteinases (MMP-2, -3, -9, and -13) by interleukin-1 and interleukin-6 in mouse calvaria: association of MMP induction with bone resorption.
Regulation of matrix metalloproteinases (MMP-2, -3, -9, and -13) by interleukin-1 and interleukin-6 in mouse calvaria: association of MMP induction with bone resorption.
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DOI：
10.1210/endo.139.3.5818
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发表时间：
1998-03
期刊：
影响因子：
4.8
通讯作者：
Kenichiro Kusano;C. Miyaura;Masaki Inada;T. Tamura;A. Ito;H. Nagase;K. Kamoi;T. Suda
中科院分区：
文献类型：
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作者：
Kenichiro Kusano;C. Miyaura;Masaki Inada;T. Tamura;A. Ito;H. Nagase;K. Kamoi;T. Suda
白介素1(IL-1)能显著诱导破骨细胞的形成，刺激小鼠颅骨的骨吸收。在可溶性IL-6受体(sIL-6R)存在下，IL-6同样可以诱导破骨细胞的形成，但在器官培养中，IL-6诱导骨吸收的能力弱于IL-1。为了研究IL-1和IL-6在骨吸收活性上的差异，我们检测了这两种细胞因子对基质金属蛋白酶(MMPs)的诱导作用。在小鼠颅骨培养中，IL-1显著增强了基质降解相关的基质金属蛋白酶-13(胶原酶3)、明胶酶A(明胶酶A)、明胶酶B(明胶酶B)和基质分解酶1(基质分解素1)的信使RNA(MRNA)的表达。MMPs的异羟甲酸酯抑制剂可显著抑制IL-1诱导的骨吸收活性。明胶酶谱显示，在颅骨培养的条件培养液中可检测到MMP2和MMP9的活性和活性，IL-1对这两种明胶酶的活性和活性均有明显的刺激作用。IL-6联合sIL-6R也能刺激这些MMPs的mRNA表达和生物学活性，但其作用比IL-1弱得多。经IL-1处理的颅骨条件培养液可降解天然I型胶原，但未检测到3/4和1/4长度的胶原片段，提示胶原酶和明胶酶协同作用将I型胶原降解为较小的片段。在小鼠成骨细胞中，可检测到MMP2、MMP3和MMP13mRNAs的表达，IL-1α在第2天和第5天可明显增强其表达。IL-6和sIL-6R在第2天也可诱导MMP13和MMP2mRNAs的表达，但表达是短暂的。这些结果表明，IL-1和IL-6诱导MMPs的能力与其各自的骨吸收活性密切相关，提示基质金属蛋白酶依赖性的降解在这两种细胞因子诱导的骨吸收中起着关键作用。
Interleukin-1 (IL-1) greatly induces osteoclast formation and stimulates bone resorption of mouse calvaria in culture. In the presence of soluble IL-6 receptor (sIL-6R), IL-6 similarly induces osteoclast formation, but the potency of IL-6 in inducing bone resorption in organ culture is weaker than that of IL-1. To study the differences in bone-resorbing activity between IL-1 and IL-6, we examined the effects of the two cytokines on the induction of matrix metalloproteinases (MMPs). In mouse calvarial cultures, IL-1 markedly enhanced the messenger RNA (mRNA) expression of MMP-13 (collagenase 3), MMP-2 (gelatinase A), MMP-9 (gelatinase B), and MMP-3 (stromelysin 1), which associated with increases in bone matrix degradation. A hydroxamate inhibitor of MMPs significantly suppressed bone-resorbing activity induced by IL-1. Gelatin zymography showed that both pro- and active-forms of MMP-2 and MMP-9 were detected in the conditioned medium collected from calvarial cultures, and IL-1 markedly stimulated both pro- and active-forms of the two gelatinases. IL-6 with sIL-6R also stimulated mRNA expression and biological activities of these MMPs, but the potency was much weaker than that of IL-1. Conditioned medium collected from IL-1-treated calvariae degraded native type I collagen, but 3/4- and 1/4-length collagen fragments were not detected, suggesting that both collagenases and gelatinases synergistically degraded type I collagen into smaller fragments. In mouse osteoblastic cells, the expression ofMMP-2, MMP-3, and MMP-13 mRNAs could be detected, and they were markedly enhanced by IL-1alpha on days 2 and 5. IL-6 with sIL-6R also induced expression of MMP-13 and MMP-2 mRNAs on day 2, but the expression was rather transient. These results demonstrate that the potency of induction of MMPs by IL-1 and IL-6 is closely linked to the respective bone-resorbing activity, suggesting that MMP-dependent degradation of bone matrix plays a key role in bone resorption induced by these cytokines.