Systemically available bone morphogenetic protein two and seven affect bone metabolism
Systemically available bone morphogenetic protein two and seven affect bone metabolism
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DOI：
10.1007/s00264-014-2425-8
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发表时间：
2014-09-01
影响因子：
2.7
通讯作者：
Vukicevic, Slobodan
中科院分区：
文献类型：
--
作者：
Dumic-Cule, Ivo;Brkljacic, Jelena;Vukicevic, Slobodan
骨形态发生蛋白（BMP）-2和-7用于长骨骨折、骨不连和脊柱融合的患者。目前尚不清楚局部骨骼给药后其潜在的全身生物利用度是否会影响骨骼代谢。为了回答这个问题，我们在一个新开发的低水平促钙激素的大鼠模型中研究了全身给予BMP-2和BMP-7对骨的影响，在大鼠中去除甲状腺和甲状旁腺（TPTx）导致促钙激素水平降低，随后通过微型计算机断层扫描评估了骨丢失（micro-CT）和测量血清骨形成和再吸收标志物，包括骨钙素、C-端肽、骨保护素和核因子κ-B配体的受体激活剂。通过BMP-2和BMP-7对成骨细胞和破骨细胞活性的体外研究补充了结果。所用的剂量是根据已发表的药效学研究和临床前BMP-2和BMP-7研究的生物利用度结果计算的。TPTx导致骨丢失，通过全身给予10-70 μ g/kg的BMP-2和10-250 μ g/kg的BMP-7可以恢复骨丢失。BMP-2表现出更高的能力，增强小梁微结构，而BMP-7增加小梁厚度。体外实验显示，BMP-2和-7在解偶联时增加了成骨细胞和破骨细胞的数量和活性。令人惊讶的是，BMP-2和-7在低促钙激素的体内环境中显示出骨体积的增加。从骨装置局部施用的BMP-2和-7可能在循环中部分可用，但不会介导全身性骨丢失。
Bone morphogenetic protein (BMP)-2 and -7 are used in patients with long-bone fractures, nonunions and spinal fusions. It is unknown whether their potential systemic bioavailability following local bone administration might affect skeletal metabolism. To answer this question, we examined effects of systemically administered BMP-2 and -7 on bone in a newly developed rat model with a low level of calciotropic hormones.Removal of thyroid and parathyroid glands (TPTx) in rats resulted in a decreased level of calciotropic hormones and subsequent bone loss assessed by micro computed tomography (micro-CT) and measurement of serum bone formation and resorption markers, including osteocalcin, C-telopeptide, osteoprotegerin and receptor activator of nuclear factor kappa-B ligand. Results were complemented with in vitro studies on osteoblast and osteoclast activity by both BMP-2 and -7. The doses used were calculated from published pharmacodynamic studies and bioavailability results from preclinical BMP-2 and -7 studies.TPTx resulted in bone loss, which was restored by systemic administration of 10-70 mu g/kg of BMP-2 and 10-250 mu g/kg of BMP-7. BMP-2 showed a higher capacity for enhancing trabecular microarchitecture, whereas BMP-7 augmented trabecular thickness. In vitro experiments revealed that BMP-2 and -7 when uncoupled increased the number and activity of both osteoblasts and osteoclasts.Surprisingly, both BMP-2 and -7 showed an increased bone volume in an in vivo environment of low calciotropic hormones. Locally administered BMP-2 and -7 from bone devices might become partially available in circulation but will not mediate systemic bone loss.