The Heparin-binding Domain of IGFBP-2 Has Insulin-like Growth Factor Binding-independent Biologic Activity in the Growing Skeleton
The Heparin-binding Domain of IGFBP-2 Has Insulin-like Growth Factor Binding-independent Biologic Activity in the Growing Skeleton
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DOI：
10.1074/jbc.m110.193334
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发表时间：
2011-04-22
影响因子：
4.8
通讯作者：
Rosen, Clifford J.
中科院分区：
文献类型：
--
作者：
Kawai, Masanobu;Breggia, Anne C.;Rosen, Clifford J.
胰岛素样生长因子结合蛋白2（IGFBP-2）是六种高度保守的IGFBP家族的成员，其是胰岛素样生长因子（IGFs）的载体。IGFBP-2水平在新生儿快速生长期间和骨获得高峰时升高。相反，Igfbp 2（-/-）小鼠具有低骨量，伴有成骨细胞数量减少、骨形成率低和PTEN表达增加。在目前的研究中，我们假设IGFBP-2增加骨量部分是通过其肝素结合域（HBD）的活性。我们合成了一种对IGFBP-2有特异性的HBD肽，并在体外证明了它能挽救Igfbp 2（-/-）骨髓基质细胞和颅骨成骨细胞的矿化表型。与其细胞作用一致，HBD肽离体刺激掌骨骨膜扩张。此外，给予Igfbp 2（-/-）小鼠HBD肽增加成骨细胞数量，抑制骨髓脂肪生成，恢复骨小梁质量，减少骨吸收。Igfbp 2-/-小鼠中的Skills拯救的特征在于减少的PTEN表达，随后响应于IGF-I增强的Akt磷酸化和通过两种机制增加的β-连环蛋白信号传导：1）刺激其胞质积累和2）增加丝氨酸552的磷酸化。我们的结论是IGFBP-2的HBD肽通过激活IGF-I/Akt和β-catenin信号通路具有合成代谢活性。这些数据支持越来越多的证据表明IGFBP-2不仅仅是一种转运蛋白，而是与IGF-I协调作用以刺激生长和骨骼获得。
Insulin-like growth factor-binding protein 2 (IGFBP-2) is a member of a family of six highly conserved IGFBPs that are carriers for the insulin-like growth factors (IGFs). IGFBP-2 levels rise during rapid neonatal growth and at the time of peak bone acquisition. In contrast, Igfbp2(-/-) mice have low bone mass accompanied by reduced osteoblast numbers, low bone formation rates, and increased PTEN expression. In the current study, we postulated that IGFBP-2 increased bone mass partly through the activity of its heparin-binding domain (HBD). We synthesized a HBD peptide specific for IGFBP-2 and demonstrated in vitro that it rescued the mineralization phenotype of Igfbp2(-/-) bone marrow stromal cells and calvarial osteoblasts. Consistent with its cellular actions, the HBD peptide ex vivo stimulated metacarpal periosteal expansion. Furthermore, administration of HBD peptide to Igfbp2(-/-) mice increased osteoblast number, suppressed marrow adipogenesis, restored trabecular bone mass, and reduced bone resorption. Skeletal rescue in the Igfbp2-/- mice was characterized by reduced PTEN expression followed by enhanced Akt phosphorylation in response to IGF-I and increased beta-catenin signaling through two mechanisms: 1) stimulation of its cytosolic accumulation and 2) increased phosphorylation of serine 552. We conclude that the HBD peptide of IGFBP-2 has anabolic activity by activating IGF-I/Akt and beta-catenin signaling pathways. These data support a growing body of evidence that IGFBP-2 is not just a transport protein but rather that it functions coordinately with IGF-I to stimulate growth and skeletal acquisition.