Amphiregulin-EGFR signaling mediates the migration of bone marrow mesenchymal progenitors toward PTH-stimulated osteoblasts and osteocytes.
Amphiregulin-EGFR signaling mediates the migration of bone marrow mesenchymal progenitors toward PTH-stimulated osteoblasts and osteocytes.
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DOI：
10.1371/journal.pone.0050099
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Qin L
中科院分区：
文献类型：
--
作者：
Zhu J;Siclari VA;Liu F;Spatz JM;Chandra A;Divieti Pajevic P;Qin L
甲状旁腺激素（PTH）的间歇给药显着增加骨量，目前是骨质疏松症最有效的治疗方法之一。然而，详细的机制在很大程度上仍然是未知的。在这里，我们表明，条件培养基PTH处理成骨细胞和骨细胞含有可溶性趋化因子的骨髓间充质祖细胞，表达少量的PTH受体（PTH 1 R），并不响应PTH刺激增加cAMP的生产或迁移到PTH单独。PTH处理的成骨细胞的条件培养基升高了间充质祖细胞中磷酸化Akt和p38 MAPK的量，并且抑制这些途径阻断了这些祖细胞向条件培养基的迁移。我们以前和目前的研究表明，PTH刺激双调蛋白，表皮生长因子（EGF）样配体，通过表皮生长因子受体（EGFR）的信号，在成骨细胞和骨细胞的表达。有趣的是，PTH处理的成骨细胞的条件培养基增加了间充质祖细胞中EGFR的磷酸化。使用几种不同的方法，包括抑制剂，中和抗体，和siRNA，我们证明，PTH增加双调蛋白从成骨细胞的释放，其作用于间充质祖细胞上表达的EGFR，刺激Akt和p38 MAPK通路，随后促进其在体外的迁移。此外，EGFR信号转导的失活，特别是在骨祖细胞/成骨细胞衰减PTH对骨形成的合成代谢作用。综上所述，这些结果表明PTH对骨质疏松症的治疗作用的新机制和EGFR信号传导在介导PTH对骨的合成代谢作用中的重要作用。
Intermittent administration of parathyroid hormone (PTH) dramatically increases bone mass and currently is one of the most effective treatments for osteoporosis. However, the detailed mechanisms are still largely unknown. Here we demonstrate that conditioned media from PTH-treated osteoblastic and osteocytic cells contain soluble chemotactic factors for bone marrow mesenchymal progenitors, which express a low amount of PTH receptor (PTH1R) and do not respond to PTH stimulation by increasing cAMP production or migrating toward PTH alone. Conditioned media from PTH-treated osteoblasts elevated phosphorylated Akt and p38MAPK amounts in mesenchymal progenitors and inhibition of these pathways blocked the migration of these progenitors toward conditioned media. Our previous and current studies revealed that PTH stimulates the expression of amphiregulin, an epidermal growth factor (EGF)-like ligand that signals through the EGF receptor (EGFR), in both osteoblasts and osteocytes. Interestingly, conditioned media from PTH-treated osteoblasts increased EGFR phosphorylation in mesenchymal progenitors. Using several different approaches, including inhibitor, neutralizing antibody, and siRNA, we demonstrate that PTH increases the release of amphiregulin from osteoblastic cells, which acts on the EGFRs expressed on mesenchymal progenitors to stimulate the Akt and p38MAPK pathways and subsequently promote their migration in vitro. Furthermore, inactivation of EGFR signaling specifically in osteoprogenitors/osteoblasts attenuated the anabolic actions of PTH on bone formation. Taken together, these results suggest a novel mechanism for the therapeutic effect of PTH on osteoporosis and an important role of EGFR signaling in mediating PTH's anabolic actions on bone.
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