Fra-1/AP-1 Impairs Inflammatory Responses and Chondrogenesis in Fracture Healing
Fra-1/AP-1 Impairs Inflammatory Responses and Chondrogenesis in Fracture Healing
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DOI：
10.1359/jbmr.090603
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发表时间：
2009-12-01
影响因子：
6.2
通讯作者：
Matsuo, Koichi
中科院分区：
文献类型：
--
作者：
Yamaguchi, Toru;Takada, Yasunari;Matsuo, Koichi
炎症不可避免地伴随着各种组织的损伤，包括骨骼。转录因子激活蛋白-1(AP-1)的一种成分Fra-1在不同组织中的转基因过表达可渐进性和全局性地促进骨形成，但对Fra-1/AP-1对骨折愈合的可能作用知之甚少。我们制作了小鼠胫骨骨干的横断性骨折，并从放射学、组织学和免疫学的角度检查了骨折愈合情况。值得注意的是，尽管Fra-1转基因(TG)小鼠骨痂中的骨形成率较高，但骨折愈合仍被推迟。在这些小鼠中，骨折部位周围的软骨生成受到损害，导致纤维组织积累，这干扰了跨越骨痂的骨桥的形成。奇怪的是，骨折后立即，Fra-1TG小鼠体内炎性介质TNF-α、IL-6和COX-2的诱导显著受到抑制，随后SOX-9和BMP-2的表达减少。由于这些小鼠的血清前列腺素E-2(PGE(2))水平极低，我们使用缓释载体将PGE(2)注射到骨折部位。PGE(2)能显著减少Fra-1TG小鼠体内纤维组织的堆积，部分恢复骨折处的软骨生成。这些数据表明，含有转录因子FRA-1的AP-1抑制骨折诱导的软骨内成骨和骨桥的形成，可能是通过抑制炎症诱导的软骨形成。《矿工杂志》2009；24：2056-2065。2009年6月29日在线发布；DOI：10.1359/JBMR.090603
Inflammation inevitably follows injury of various tissues, including bone. Transgenic overexpression of Fra-1, a component of the transcription factor activator protein-1 (AP-1), in various tissues progressively and globally enhances bone formation, but little is known about the possible effects of Fra-1/ AP-1 on fracture healing. We created a transverse fracture of the mouse tibial diaphysis and examined fracture healing radiologically, histologically, and immunologically. Strikingly, fracture union was delayed even though the bone formation rate in callus was higher in Fra-1 transgenic (Tg) mice. In these mice, chondrogenesis around the fracture site was impaired, resulting in accumulation of fibrous tissue, which interferes with the formation of a bony bridge across the callus. Curiously, immediately after fracture, induction of the inflammatory mediators TNF-alpha, interleukin (IL)-6, and Cox-2 was significantly suppressed in Fra-1 Tg mice followed, by the reduced expression of Sox-9 and BMP-2. Because serum prostaglandin E-2 (PGE(2)) levels were dramatically low in these mice, we administered PGE(2) to the fracture site using a slowrelease carrier. The accumulation of fibrous tissue in Fra-1 Tg mice was significantly reduced by PGE(2) administration, and chondrogenesis near the fracture site was partially restored. These data suggest that the Fra-1-containing transcription factor AP-1 inhibits fracture-induced endochondral ossification and bony bridge formation presumably through suppression of inflammation-induced chondrogenesis. J Bone Miner Res 2009;24:2056-2065. Published online on June 29, 2009; doi: 10.1359/JBMR.090603