Exogenous hedgehog antagonist delays but does not prevent fracture healing in young mice.
Exogenous hedgehog antagonist delays but does not prevent fracture healing in young mice.
复制标题
外源刺猬拮抗剂延迟，但不能防止年轻小鼠骨折愈合。
DOI：
10.1016/j.bone.2017.07.017
复制
发表时间：
2017-10
期刊：
影响因子：
4.1
通讯作者：
Silva MJ
中科院分区：
文献类型：
--
作者：
Liu X;McKenzie JA;Maschhoff CW;Gardner MJ;Silva MJ
骨折愈合概括了发育成骨的许多方面。刺猬 (Hh) 信号通路对骨骼发育至关重要，在骨折愈合过程中上调，但其重要性尚不清楚。我们的目标是评估 Hh 信号在软骨内骨折愈合中的功能重要性。我们在小鼠体内制造了闭合性横断股骨骨干骨折，用髓内钉稳定，并施用全身性 Hh 抑制剂或载体。由于 Hh 通路激活是由受体 Smoothened (Smo) 介导的，因此我们使用 Smo 拮抗剂 GDC-0449（GDC，50 mg/kg，每天两次）来靶向该通路。首先，在用载体治疗 10 周的雌性 C57BL/6 小鼠中，我们证实与完整骨相比，骨折愈伤组织中的 Hh 信号传导增加，目标基因 Ptch1 和 Gli1 上调超过 5 倍。此外，使用 10 周的雄性和雌性 Gli1 报告小鼠，我们在骨折后 7-10 天看到骨折愈伤组织的骨区域中报告基因的强烈激活。 GDC 治疗显着减弱了这些反应，表明有效抑制了骨折诱导的骨中 Hh 信号传导。此外，microCT 分析显示，GDC 治疗显着减少了非骨折部位（胫骨干骺端和骨干）的松质骨和皮质骨体积，表明该药物抑制了正常骨形成。 GDC 治疗对骨折愈合有一定影响，放射学证据显示骨痂矿化延迟（第 14 天时 Goldberg 评分显着降低）和 microCT（第 14 天骨痂 vBMD 减少），扭转恢复到正常的延迟（第 21 天峰值旋转扭矩升高）。另一方面，GDC 治疗不会抑制 qPCR 或软骨生成或血管生成的形态学测量，并且不会损害失效扭矩的恢复（第 14 天或 21 天），这是生物力学能力的测量。总之，GDC 治疗抑制了 Hh 信号传导，从而延迟但不阻止年轻小鼠的骨折愈合。我们得出的结论是，Hh 信号在骨折后被强烈诱导，并且可能在早期愈伤组织矿化中发挥作用，尽管它似乎不是最终愈合所必需的。
Fracture healing recapitulates many aspects of developmental osteogenesis. The hedgehog (Hh) signaling pathway, essential to skeletal development, is upregulated during fracture healing, although its importance is unclear. Our goal was to assess the functional importance of Hh signaling in endochondral fracture healing. We created closed, transverse diaphyseal femur fractures in mice, stabilized with an intramedullary pin, and administered a systemic Hh inhibitor or vehicle. Because Hh pathway activation is mediated by the receptor Smoothened (Smo), we used the Smo antagonist GDC-0449 (GDC, 50 mg/kg, twice daily) to target the pathway. First, in vehicle-treated 10-wk female C57BL/6 mice we confirmed that Hh signaling was increased in fracture callus compared to intact bone, with >5-fold upregulation of target genes Ptch1 and Gli1. Additionally, using 10-wk male and female Gli1 reporter mice, we saw a strong activation of the reporter in the osseous regions of the fracture callus 7–10 days after fracture. GDC treatment significantly blunted these responses, indicating effective inhibition of fracture-induced Hh signaling in bone. Moreover, microCT analysis revealed that GDC treatment significantly reduced cancellous and cortical bone volume at non-fracture sites (tibial metaphysis and diaphysis), suggesting that the drug inhibited normal bone formation. GDC treatment had a modest effect on fracture healing, with evidence of delayed callus mineralization radiographically (significantly lower Goldberg score at day 14) and by microCT (reduced callus vBMD at 14 days), and a delay in the recovery of torsional rotation to normal (elevated rotation-at-peak torque at 21 days). On the other hand, GDC treatment did not inhibit qPCR or morphological measures of chondrogenesis or angiogenesis, and did not impair the recovery of failure torque (at day 14 or 21), a measure of biomechanical competence. In summary, GDC treatment inhibited Hh signaling, which delayed but did not prevent fracture healing in young mice. We conclude that Hh signaling is strongly induced after fracture and may play a role in early callus mineralization, although it does not appear to be required for eventual healing.
登录
查看更多内容
影响因子：
2.6
作者：
Ferguson, C;Alpern, E;Helms, JA
通讯作者：
Helms, JA
DOI：
10.1038/nrrheum.2014.164
发表时间：
2015-01
期刊：
Nature reviews. Rheumatology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.6
作者：
Astorga, Jeanette;Carlsson, Peter
通讯作者：
Carlsson, Peter
影响因子：
4
作者：
Gerstenfeld, LC;Cullinane, DM;Einhorn, TA
通讯作者：
Einhorn, TA
影响因子：
4.2
作者：
Murakami, S;Noda, M
通讯作者：
Noda, M