Treatment With a Soluble Bone Morphogenetic Protein Type 1A Receptor (BMPR1A) Fusion Protein Increases Bone Mass and Bone Formation in Mice Subjected to Hindlimb Unloading.
Treatment With a Soluble Bone Morphogenetic Protein Type 1A Receptor (BMPR1A) Fusion Protein Increases Bone Mass and Bone Formation in Mice Subjected to Hindlimb Unloading.
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DOI：
10.1002/jbm4.10012
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发表时间：
2017-10
期刊：
影响因子：
3.8
通讯作者：
Bouxsein ML
中科院分区：
文献类型：
--
作者：
Ko FC;Van Vliet M;Ellman R;Grasso D;Brooks DJ;Spatz JM;Conlon C;Aguirre JI;Wronski TJ;Bouxsein ML
先前的研究表明，可溶性鼠BMPR 1A融合蛋白（mBMPR 1A-mFc）以高亲和力结合BMP 2和BMP 4，阻止下游信号传导。此外，用mBMPR 1A-mFc治疗完整和卵巢切除小鼠，通过增加骨形成和减少再吸收，导致骨量增加，骨微结构和强度改善。在本研究中，我们测试了mBMPR 1A-mFc对通过尾部悬吊与笼对照（CON）进行21天后肢去负荷（HLU）引起的废用性骨丢失的影响。将成年雌性C57 BL/6 J小鼠（12周龄）分配到四组之一（每组n = 10）：CON-VEH; CON-mBMPR 1A-mFc; HLU-VEH;和HLU-mBMPR 1A-mFc。小鼠皮下注射VEH或mBMPR 1A-mFc（4.5 mg/kg，2×/周）。HLU-VEH组腿部BMD下降（-5.3% ± 1.3%），而HLU-mBMPR 1A-mFc组无变化（-0.3% ± 0.9%，p < 0.05，相对于HLU-VEH）。CON‐ mBMPR 1A ‐mFc组的腿部BMD增加显著高于CON‐VEH组（10.2% ± 0.6% vs 4.4% ± 0.8%）。在股骨中，与CON‐VEH小鼠相比，HLU‐VEH小鼠的骨小梁和皮质骨微结构更差，而mBMPR 1A ‐mFc治疗3周导致HLU和CON组的Tb.BV/TV、Tb.Th和中段Ct.Th均高于相当的VEH治疗对照组（p < 0.05）。HLU-mBMPR 1A-mFc小鼠的失败负荷也比VEH处理的小鼠高21%（p < 0.05）。动态组织形态测定表明，mBMPR 1A-mFc处理导致矿化表面和矿物质沉积率显著增加，导致mBMPR 1A-mFc处理的CON和HLU动物的骨形成率分别是VEH组的3.5倍和5倍。在CON和HLU组中，mBMPR 1A-mFc处理的小鼠具有相似的成骨细胞表面，但破骨细胞表面显著低于VEH处理的动物。总之，这些发现表明，在废用性骨丢失的情况下，可溶性BMPR 1A融合蛋白治疗可能有助于维持骨骼完整性。© 2017 The Authors JBMR Plus由Wiley Periodicals，Inc.出版。美国骨与矿物质研究协会（American Society for Bone and Mineral Research）
Previous work has shown that the soluble murine BMPR1A–fusion protein (mBMPR1A‐mFc) binds to BMP2 and BMP4 with high affinity, preventing downstream signaling. Further, treatment of intact and ovariectomized mice with mBMPR1A‐mFc leads to increased bone mass, and improved bone microarchitecture and strength, via increased bone formation and reduced resorption. In this study, we tested the effects of mBMPR1A‐mFc on disuse‐induced bone loss caused by 21 days of hindlimb unloading (HLU) via tail suspension versus cage controls (CONs). Adult female C57BL/6J mice (12 weeks old) were assigned to one of four groups (n = 10 each): CON‐VEH; CON‐mBMPR1A‐mFc; HLU‐VEH; and HLU‐mBMPR1A‐mFc. Mice were injected subcutaneously with VEH or mBMPR1A‐mFc (4.5 mg/kg, 2×/week). Leg BMD declined in the HLU‐VEH group (–5.3% ± 1.3%), whereas it was unchanged in HLU‐mBMPR1A‐mFc (–0.3% ± 0.9%, p < 0.05 versus HLU‐VEH). Leg BMD increased significantly more in CON‐mBMPR1A‐mFc than CON‐VEH (10.2% ± 0.6% versus 4.4% ± 0.8%). In the femur, trabecular, and cortical bone microarchitecture was worse in the HLU‐VEH compared to CON‐VEH mice, whereas mBMPR1A‐mFc treatment for 3 weeks led to greater Tb.BV/TV, Tb.Th, and midshaft Ct.Th in both the HLU and CON groups compared to comparable VEH‐treated counterparts (p < 0.05). HLU‐mBMPR1A‐mFc mice also had 21% greater failure load (p < 0.05) compared to their VEH‐treated counterparts. Dynamic histomorphometry indicated that treatment with mBMPR1A‐mFc led to significantly greater mineralizing surface and mineral apposition rate, resulting in a 3.5‐fold and fivefold higher bone formation rate in the mBMPR1A‐mFc‐treated CON and HLU animals versus VEH groups, respectively. mBMPR1A‐mFc‐treated mice had a similar osteoblast surface but significantly lower osteoclast surface than VEH‐treated animals in both the CON and HLU groups. Altogether, these findings suggest that treatment with the soluble BMPR1A fusion protein may be useful for maintenance of skeletal integrity in the setting of disuse‐induced bone loss. © 2017 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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影响因子：
4
作者：
LeBlanc, A.;Matsumoto, T.;Ohshima, H.
通讯作者：
Ohshima, H.
影响因子：
5.9
作者：
Smith SM;McCoy T;Gazda D;Morgan JL;Heer M;Zwart SR
通讯作者：
Zwart SR
影响因子：
6.2
作者：
Devlin, Maureen J.;Cloutier, Alison M.;Thomas, Nishina A.;Panus, David A.;Lotinun, Sutada;Pinz, Ilka;Baron, Roland;Rosen, Clifford J.;Bouxsein, Mary L.
通讯作者：
Bouxsein, Mary L.
影响因子：
3.7
作者：
Moriishi T;Fukuyama R;Ito M;Miyazaki T;Maeno T;Kawai Y;Komori H;Komori T
通讯作者：
Komori T
DOI：
10.1359/jbmr.090806
发表时间：
2010-02
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Kamiya N;Kobayashi T;Mochida Y;Yu PB;Yamauchi M;Kronenberg HM;Mishina Y
通讯作者：
Mishina Y