Activation of hedgehog signaling by systemic agonist improves fracture healing in aged mice.
Activation of hedgehog signaling by systemic agonist improves fracture healing in aged mice.
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DOI：
10.1002/jor.24017
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发表时间：
2019-01
期刊：
影响因子：
--
通讯作者：
Gardner MJ
中科院分区：
文献类型：
--
作者：
McKenzie JA;Maschhoff C;Liu X;Migotsky N;Silva MJ;Gardner MJ
骨折愈合是一个复杂的过程，许多协调的生物学途径。该系统可能会发生错误，导致骨不连，从而导致患者严重发病。Hedgehog（Hh）信号通路在骨折愈合中上调。我们假设Hh信号通路可以被神经调节以积极影响骨折愈合。在老年小鼠（18个月，C57 BL/6雌性）中产生股骨骨干骨折，与年轻小鼠相比，老年小鼠具有钝化和延迟愈合反应，并用髓内钉稳定。为了激活Hh通路，我们使用激动剂（Hh-Ag 1.5 [Hh-Ag]）靶向受体Smoothened，并将其与载体对照进行比较。与对照组相比，激动剂组骨折骨痂中Hh靶基因的表达显著增加，表明途径激活。与完整股骨相比，骨折骨痂中成骨和软骨形成相关基因的表达大幅上调，尽管Hh激动剂治疗并不能一贯地增强这种反应。在术后第14天（POD），Hh-Ag组的盲法分级、放射学骨痂愈合评分显著较高，表明骨痂桥接较早。在microCT上，Hh-Ag处理导致在POD 21时骨痂体积（+40%）和骨体积（+25%）更大。到第14天，骨痂血管分布，如3D microCT血管造影血管体积所评估的，在Hh-Ag组中增加了85%。最后，Hh-Ag组的愈伤组织的机械强度在POD 21时显著大于对照组。总之，全身施用Hh激动剂似乎改善了小鼠骨折愈合受损模型中的骨和血管愈合反应。
Fracture healing is a complex process of many coordinated biological pathways. This system can go awry resulting in nonunion, which leads to significant patient morbidity. The Hedgehog (Hh) signaling pathway is upregulated in fracture healing. We hypothesized that the Hh signaling pathway can be pharmacologically modulated to positively affect fracture healing. Diaphyseal femur fractures were created in elderly mice (18 months, C57BL/6 females), which have a blunted and delayed healing response compared to younger mice, and were stabilized with intramedullary pins. To activate the Hh pathway we targeted the receptor Smoothened using an agonist (Hh-Ag1.5 [Hh-Ag]) and compared this to a vehicle control. Expression of Hh target genes were significantly increased in the fracture callus of the agonist group compared to controls, indicating pathway activation. Expression of osteogenic and chondrogenic-related genes was greatly upregulated in fracture callus vs. intact femora, although Hh agonist treatment did not consistently enhance this response. Blindly graded, radiographic callus healing scores were significantly higher in the Hh-Ag groups at post operative day (POD) 14, indicating earlier callus bridging. On microCT, Hh-Ag treatment led to greater callus volume (+40%) and bone volume (+25%) at POD21. By day 14, callus vascularity, as assessed by 3D microCT angiography vessel volume, was 85% greater in the Hh-Ag group. Finally, mechanical strength of the calluses in the Hh-Ag groups was significantly greater than in the control groups at POD21. In conclusion, systemic administration of a Hh agonist appears to improve the osseous and vascular healing responses in a mouse fracture healing-impaired model.
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外源刺猬拮抗剂延迟，但不能防止年轻小鼠骨折愈合。
影响因子：
4.1
作者：
Liu X;McKenzie JA;Maschhoff CW;Gardner MJ;Silva MJ
通讯作者：
Silva MJ
影响因子：
6.2
作者：
Halloran, BP;Ferguson, VL;Majumdar, S
通讯作者：
Majumdar, S
DOI：
10.1302/0301-620x.81b6.8851
发表时间：
1999-11-01
影响因子：
--
作者：
Iwasaki, M;Jikko, A;Le, AX
通讯作者：
Le, AX
影响因子：
--
作者：
Frank-Kamenetsky M;Zhang XM;Bottega S;Guicherit O;Wichterle H;Dudek H;Bumcrot D;Wang FY;Jones S;Shulok J;Rubin LL;Porter JA
通讯作者：
Porter JA
影响因子：
4.6
作者：
Long, FX;Chung, UI;McMahon, AP
通讯作者：
McMahon, AP