Bonfim Danielle C, Dias Rhayra B, Fortuna-Costa Anneliese, Chicaybam Leonardo, Lopes Daiana V, Dutra Hélio S, Borojevic Radovan, Bonamino Martin, Mermelstein Claudia, Rossi Maria Isabel D
Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Institute of Medical Biochemistry, National Institute of Cancer, Rio de Janeiro, RJ, Brazil.
Stem Cells Int. 2016;2016:3865315. doi: 10.1155/2016/3865315. Epub 2016 Dec 8.
Bone marrow stromal cells (BMSCs) are considered a promising tool for bone bioengineering. However, the mechanisms controlling osteoblastic commitment are still unclear. Osteogenic differentiation of BMSCs requires the activation of -catenin signaling, classically known to be regulated by the canonical Wnt pathway. However, BMSCs treatment with canonical Wnts does not always result in osteogenic differentiation and evidence indicates that a more complex signaling pathway, involving cadherins, would be required to induce -catenin signaling in these cells. Here we showed that Wnt3a alone did not induce TCF activation in BMSCs, maintaining the cells at a proliferative state. On the other hand, we verified that, upon BMSCs osteoinduction with dexamethasone, cadherins were cleaved by the PS1/-secretase complex at the plasma membrane, and this event was associated with an enhanced -catenin translocation to the nucleus and signaling. When PS1/-secretase activity was inhibited, the osteogenic process was impaired. Altogether, we provide evidence that PS1/-secretase-mediated cadherin cleavage has as an important role in controlling -catenin signaling during the onset of BMSCs osteogenic differentiation, as part of a complex signaling pathway responsible for cell fate decision. A comprehensive map of these pathways might contribute to the development of strategies to improve bone repair.
骨髓基质细胞（BMSCs）被认为是骨生物工程中一种很有前景的工具。然而，控制成骨细胞定向分化的机制仍不清楚。BMSCs的成骨分化需要激活β-连环蛋白信号通路，传统上认为该信号通路受经典Wnt通路调控。然而，用经典Wnts处理BMSCs并不总是导致成骨分化，有证据表明，在这些细胞中诱导β-连环蛋白信号通路需要一个更复杂的信号通路，该通路涉及钙黏蛋白。在这里，我们表明单独的Wnt3a不会在BMSCs中诱导TCF激活，从而使细胞维持在增殖状态。另一方面，我们证实了，在用地塞米松对BMSCs进行骨诱导时，钙黏蛋白在质膜上被PS1/γ-分泌酶复合物切割，这一事件与增强的β-连环蛋白向细胞核的转位及信号传导相关。当PS1/γ-分泌酶活性被抑制时，成骨过程受损。总之，我们提供的证据表明，作为负责细胞命运决定的复杂信号通路的一部分，PS1/γ-分泌酶介导的钙黏蛋白切割在BMSCs成骨分化起始过程中控制β-连环蛋白信号传导方面具有重要作用。这些信号通路的全面图谱可能有助于开发改善骨修复的策略。
