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首页> 外文期刊>Journal of orthopaedic research >Modeling bone morphogenetic protein and bisphosphonate combination therapy in wild-type and Nf1 haploinsufficient mice.
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Modeling bone morphogenetic protein and bisphosphonate combination therapy in wild-type and Nf1 haploinsufficient mice.

机译：在野生型和Nf1单倍体不足的小鼠中模拟骨形态发生蛋白和双膦酸盐联合治疗。

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Recombinant bone morphogenetic proteins (BMPs) show promise in treating the orthopedic complications associated with neurofibromatosis type 1 (NF1), such as congenital pseudarthrosis of the tibia. Minimal scientific information regarding the effects of BMP in the context of NF1 is available. As abnormalities in both bone formation and resorption have been documented in Nf1-deficient mice, we hypothesized that inadequate BMP-induced bone formation could be augmented by cotreatment with the bisphosphonate zoledronic acid (ZA). First, primary osteoblasts isolated from wild type (Nf1(+/+)) and Nf1-deficient (Nf1(+/-)) mice were cultured in the presence and absence of BMP-2. While Nf1(+/-) cells exhibited less osteogenic potential than Nf1(+/+) cells, alkaline phosphatase expression and matrix mineralization for both genotypes were enhanced by BMP-2 treatment. To model this response in vivo, 20 microg BMP-2 was implanted intramuscularly into the quadriceps of mice to induce heterotopic bone. Radiographs revealed significantly less net bone formation in Nf1(+/-) mice compared to Nf1(+/+) controls. To test the effect of an antiresorptive agent, mice were cotreated twice weekly from postoperative day 3 with 0.02 mg/kg ZA or with saline. ZA treatment led to a synergistic increase in the amount of heterotopic bone in both Nf1(+/+) and Nf1(+/-) mice compared with saline controls, as measured by DEXA and histomorphometry. Thus, the anabolic deficiency noted in Nf1(+/-) mice is amenable to stimulation by BMP-2, but mineralized tissue formation remains below that of Nf1(+/+) controls. Bisphosphonate combination therapy is superior to BMP therapy alone in terms of net bone production in vivo in both wild-type and Nf1-deficient mice.
机译：重组骨形态发生蛋白（BMP）在治疗与1型神经纤维瘤病（NF1）相关的整形外科并发症（如先天性胫骨假关节）方面显示出希望。可获得关于BMP在NF1情况下影响的基本科学信息。由于已经在Nf1缺乏的小鼠中记录了骨形成和吸收的异常，因此我们推测通过与双膦酸盐唑来膦酸（ZA）共同治疗可以增强BMP诱导的骨形成不足。首先，在存在和不存在BMP-2的情况下，培养从野生型（Nf1（+ / +））和Nf1缺陷型（Nf1（+/-））小鼠分离的原代成骨细胞。虽然Nf1（+/-）细胞显示出比Nf1（+ / +）细胞少的成骨潜能，但BMP-2处理增强了两种基因型的碱性磷酸酶表达和基质矿化作用。为了在体内模拟这种反应，将20微克BMP-2肌肉内植入小鼠股四头肌以诱导异位骨。射线照片显示，与Nf1（+ / +）对照相比，Nf1（+/-）小鼠的净骨形成明显减少。为了测试抗再吸收剂的作用，从术后第3天起每周两次用0.02 mg / kg ZA或盐水对小鼠进行共处理。 ZA治疗导致与盐水对照组相比，Nf1（+ / +）和Nf1（+/-）小鼠中异位骨量的协同增加，这是通过DEXA和组织形态学测量的。因此，在Nf1（+/-）小鼠中注意到的合成代谢缺乏可通过BMP-2刺激，但矿化的组织形成仍低于Nf1（+ / +）对照。就野生型和缺乏Nf1的小鼠体内的净骨生成而言，双膦酸盐联合治疗优于单独的BMP治疗。

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