Full-length bovine spp24 [spp24 (24-203)] inhibits BMP-2 induced bone formation
Full-length bovine spp24 [spp24 (24-203)] inhibits BMP-2 induced bone formation
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DOI：
10.1002/jor.20580
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发表时间：
2008-06-01
影响因子：
2.8
通讯作者：
Brochmann, Elsa J.
中科院分区：
文献类型：
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作者：
Sintuu, Chananit;Murray, Samuel S.;Brochmann, Elsa J.
分泌磷蛋白 24 kDa (spp24) 是一种骨基质蛋白。它包含一个 TGF-β 受体 II 同源 1 (TRH1) 结构域。基于 TRH1 结构域序列的环状合成 19 个氨基酸肽（骨形态发生蛋白结合肽或 BBP）可增强 BMP-2 诱导的成骨作用。许多观察结果表明，这种蛋白质的不同大小形式对 BMP-2 诱导的成骨有非常不同的影响（抑制或增强）。使用全长（fl）牛 spp24 [Met（His）（6）-spp24（残基 24-203）] 的稳定重组 Met（His）（6）标记的分泌形式和表达 fl 牛 spp24（残基 1-203）的转基因（TG）小鼠，我们已经证明 spp24 抑制 BMP-2 诱导的骨形成。在雄性小鼠的异位骨形成生物测定中确定了 Met(His)(6)-spp24 (24-203) 的作用。植入5μg BMP-2刺激骨形成，通过密度测量评估骨面积和矿物质含量。当 Met(His)(6)-spp24 (24-203) 与 BMP-2 一起植入时，会引起 BMP-2 治疗的异位骨形成的剂量依赖性减少。当添加 50 倍过量 (w/w) 时，Met(His)(6)-spp24 (24-203) 完全消除了 BMP-2 的影响，而添加 10 倍过量则没有效果。在TG雌性小鼠中，骨钙素启动子控制下的fl bovine spp24 (1-203)的组成型表达降低了3月龄时的股骨和椎骨骨矿物质密度，并降低了8月龄时的股骨BMD，但对雄性小鼠没有影响，雄性小鼠表现出比雌性更少的骨钙素启动子驱动的基因转录。组织形态计量学分析表明，3 个月大的 TG 雌性小鼠的骨体积和小梁厚度低于性别和年龄匹配的野生型 (WT) 对照。因此，fl spp24 及其分泌亚型（Met(His)(6)-spp24 [24-203]）含有 BMP 结合或 TRH1 基序，可抑制雄性小鼠的异位骨形成，并对表达人类转基因的雌性小鼠的 BMD 和与骨量和形成相关的组织学参数产生不利影响。在这些条件下，fl spp24 在体内充当 BMP 拮抗剂。 2008 年骨科研究学会。* 由 Wiley periodicals, Inc. 出版。
Secreted phosphoprotein 24 kDa (spp24) is a bone matrix protein. It contains a TGF-beta receptor II homology 1(TRH1) domain. A cyclic, synthetic 19 amino acid peptide (bone morphogenetic protein binding peptide or BBP) based on the sequence of the TRH1 domain enhances BMP-2 induced osteogenesis. Many observations suggest that different size forms of this protein have very different effects (inhibiting or enhancing) on BMP-2 induced osteogenesis. Using the stable recombinant Met(His)(6)-tagged secretory form of full-length (fl) bovine spp24 [Met(His)(6)-spp24 (residues 24-203)] and transgenic (TG) mice expressing fl bovine spp24 (residues 1-203), we have demonstrated that spp24 inhibits BMP-2 induced bone formation. The effects of Met(His)(6)-spp24 (24-203) were determined in the ectopic bone-forming bioassay in male mice. Implantation of 5 mu g of BMP-2 stimulated bone formation, assessed densitometrically as bone area and mineral content. When Met(His)(6)-spp24 (24-203) was implanted with BMP-2, it elicited a dose-dependent decrease in BMP-2-medicated ectopic bone formation. When added at a 50-fold excess (w/w), Met(His)(6)-spp24 (24-203) completely ablated the effects of BMP-2, while addition of a 10-fold excess had no effect. Constitutive expression of fl bovine spp24 (1-203) under the control of the osteocalcin promoter in TG female mice reduced femoral and vertebral bone mineral density at 3 months of age and reduced femoral BMD at 8 months of age, but had no effects in male mice, which can exhibit less osteocalcin-promoter driven gene transcription than females. Histomorphometric analysis demonstrated that bone volume and trabecular thickness were lower in TG female mice at 3 months of age than in sex- and age-matched wild type (WT) controls. Thus, fl spp24 and its secretory isoform (Met(His)(6)-spp24 [24-203]), which contain a BMP-binding or TRH1 motif, inhibit ectopic bone formation in male mice and adversely affects BMD and histological parameters related to bone mass and formation in female mice expressing the human transgene. Under these conditions, fl spp24 acts as a BMP antagonist in vivo. 2008 Orthopaedic Research Society.* Published by Wiley Periodicals, Inc.