Julius Wolff Institute, Berlin Institute of Health at Charité, Berlin, Germany.
BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité, Berlin, Germany.
Commun Biol. 2024 Aug 30;7(1):1064. doi: 10.1038/s42003-024-06753-x.
Biophysical cues have the ability to enhance cellular signaling response to Bone Morphogenetic Proteins, an essential growth factor during bone development and regeneration. Yet, therapeutic application of Bone Morphogenetic Protein 2 (BMP2) is restricted due to uncontrolled side effects. An understanding of the temporal characteristics of mechanically regulated signaling events and underlying mechanism is lacking. Using a 3D bioreactor system in combination with a soft macroporous biomaterial substrate, we mimic the in vivo environment that BMP2 is acting in. We show that the intensity and duration of BMP2 signaling increases with increasing loading frequency in synchrony with the number and size of focal adhesions. Long-term mechanical stimulation increases the expression of BMP receptor type 1B, specific integrin subtypes and integrin clustering. Together, this triggered a short-lived mechanical echo that enhanced BMP2 signaling even when BMP2 is administered directly after mechanical stimulation, but not when it is applied after a resting period of ≥30 min. Interfering with cytoskeletal remodeling hinders focal adhesion remodeling verifying its critical role in shifting cells into a state of high BMP2 responsiveness. The design of biomaterials that exploit this potential locally at the site of injury will help to overcome current limitations of clinical growth factor treatment.
生物物理线索能够增强细胞对骨形态发生蛋白（Bone Morphogenetic Protein，BMP）的信号反应，BMP 是骨发育和再生过程中的关键生长因子。然而，由于无法控制的副作用，骨形态发生蛋白 2（BMP2）的治疗应用受到限制。目前对于机械调节信号事件的时间特征和潜在机制还缺乏了解。本研究使用 3D 生物反应器系统结合软大孔生物材料基质，模拟 BMP2 作用的体内环境。研究表明，BMP2 信号的强度和持续时间随加载频率的增加而增加，与粘着斑的数量和大小同步增加。长期机械刺激会增加 BMP 受体 1B 型、特定整合素亚型和整合素聚集的表达。总的来说，这引发了短暂的机械回声，即使在机械刺激后直接给予 BMP2，甚至在休息期≥30 分钟后给予 BMP2，也能增强 BMP2 信号。干扰细胞骨架重塑会阻碍粘着斑重塑，这验证了其在将细胞转变为高 BMP2 反应状态中的关键作用。设计能够在损伤部位局部利用这种潜力的生物材料将有助于克服当前临床生长因子治疗的局限性。
