Local low-dose lovastatin delivery improves the bone-healing defect caused by Nf1 loss of function in osteoblasts.
Local low-dose lovastatin delivery improves the bone-healing defect caused by Nf1 loss of function in osteoblasts.
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DOI：
10.1002/jbmr.42
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发表时间：
2010-07
影响因子：
6.2
通讯作者：
Elefteriou, Florent
中科院分区：
文献类型：
--
作者：
Wang, Weixi;Nyman, Jeffry S.;Moss, Heather E.;Gutierrez, Gloria;Mundy, Gregory R.;Yang, Xiangli;Elefteriou, Florent
骨折后胫骨不连（假关节）导致I型神经纤维瘤病（NF1）患者终身残疾，这是一种由NF1基因突变引起的疾病。为了确定NF1在骨愈合中的作用，我们在成骨细胞缺乏NF1的条件小鼠模型中评估了骨愈合。采用闭合性胫骨远端骨折方案和纵向研究设计。骨折后21- 28天，野生型的骨痂体积如预期的那样减小，但小鼠的骨痂体积没有减小，这表明愈合延迟。在这两个时间点，与野生型对照相比，骨痂桥接皮质和小梁室的骨体积（BV/TV）和体积骨矿物质密度（vBMD）在3D显微计算机断层扫描中测量下降。组织形态学分析显示，骨折后21天，老茧中存在软骨残余，大量类骨，破骨细胞表面增加，并伴有骨桥蛋白，Rankl和Tgfβ的表达增加。骨折后28天用三点弯曲法测量的骨痂强度与野生型相比有所降低。重要的是，从临床角度来看，这种愈伤组织成熟和强度的缺陷可以通过局部递送低剂量洛伐他汀微颗粒来改善，该微颗粒成功地减少了突变小鼠的类骨体积和软骨残余数量，增加了愈伤组织的BV/TV和强度。因此，这些结果表明，成骨细胞Nf1缺失导致的功能障碍会损害愈伤组织成熟，削弱愈伤组织的力学性能，并提示局部给药低剂量洛伐他汀可能会改善Nf1患者的骨愈合。©2010美国骨与矿物研究学会。
Postfracture tibial nonunion (pseudoarthrosis) leads to lifelong disability in patients with neurofibromatosis type I (NF1), a disorder caused by mutations in the NF1 gene. To determine the contribution of NF1 in bone healing, we assessed bone healing in the conditional mouse model lacking Nf1 specifically in osteoblasts. A closed distal tibia fracture protocol and a longitudinal study design were used. During the 21- to 28-day postfracture period, callus volume, as expected, decreased in wild-type but not in mice, suggesting delayed healing. At these two time points, bone volume (BV/TV) and volumetric bone mineral density (vBMD) measured by 3D micro–computed tomography were decreased in callus-bridging cortices and trabecular compartments compared with wild-type controls. Histomorphometric analyses revealed the presence of cartilaginous remnants, a high amount of osteoid, and increased osteoclast surfaces in calluses 21 days after fracture, which was accompanied by increased expression of osteopontin, Rankl, and Tgfβ. Callus strength measured by three-point bending 28 days after fracture was reduced in versus wild-type calluses. Importantly, from a clinical point of view, this defect of callus maturation and strength could be ameliorated by local delivery of low-dose lovastatin microparticles, which successfully decreased osteoid volume and cartilaginous remnant number and increased callus BV/TV and strength in mutant mice. These results thus indicate that the dysfunctions caused by loss of Nf1 in osteoblasts impair callus maturation and weaken callus mechanical properties and suggest that local delivery of low-dose lovastatin may improve bone healing in NF1 patients. © 2010 American Society for Bone and Mineral Research.
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影响因子：
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作者：
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影响因子：
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作者：
Kolanczyk, Mateusz;Kuehnisch, Jirko;Kossler, Nadine;Osswald, Monika;Stumpp, Sabine;Thurisch, Boris;Kornak, Uwe;Mundlos, Stefan
通讯作者：
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作者：
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