Growth factors and mechanical cues synergistically affect cellular functions, triggering a variety of signaling pathways. The molecular levels of such cooperative interactions are not fully understood. Due to its role in osteogenesis, the growth factor bone morphogenetic protein 2 (BMP‐2) is of tremendous interest for bone regenerative medicine, osteoporosis therapeutics, and beyond. Here, contribution of BMP‐2 signaling and extracellular mechanical cues to the osteogenic commitment of C2C12 cells is investigated. It is revealed that these two distinct pathways are integrated at the transcriptional level to provide multifactorial control of cell differentiation. The activation of osteogenic genes requires the cooperation of BMP‐2 pathway‐associated Smad1/5/8 heteromeric complexes and mechanosensitive YAP/TAZ translocation. It is further demonstrated that the Smad complexes remain bound onto and active on target genes, even after BMP‐2 removal, suggesting that they act as a “molecular memory unit.” Thus, synergistic stimulation with BMP‐2 and mechanical cues drives osteogenic differentiation in a programmable fashion.

中文翻译：

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BMP-2 信号传导和机械转导通过 YAP/TAZ 协同驱动成骨分化。

生长因子和机械信号协同影响细胞功能，触发多种信号通路。这种合作相互作用的分子水平尚不完全清楚。由于其在成骨中的作用，生长因子骨形态发生蛋白 2 (BMP-2) 在骨再生医学、骨质疏松症治疗等领域引起了极大的兴趣。在此，研究了 BMP-2 信号传导和细胞外机械信号对 C2C12 细胞成骨承诺的贡献。研究表明，这两种不同的途径在转录水平上整合，以提供细胞分化的多因素控制。成骨基因的激活需要 BMP-2 通路相关的 Smad1/5/8 异聚复合物和机械敏感的 YAP/TAZ 易位的配合。进一步证明，即使在 BMP-2 去除后，Smad 复合物仍然与靶基因结合并保持活性，这表明它们充当“分子记忆单元”。因此，BMP-2 和机械信号的协同刺激以可编程方式驱动成骨分化。