McKay Orthopaedic Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
FASEB J. 2024 Sep;38(17):e70050. doi: 10.1096/fj.202400151R.
Tendons enable locomotion by transmitting high tensile mechanical forces between muscle and bone via their dense extracellular matrix (ECM). The application of extrinsic mechanical stimuli via muscle contraction is necessary to regulate healthy tendon function. Specifically, applied physiological levels of mechanical loading elicit an anabolic tendon cell response, while decreased mechanical loading evokes a degradative tendon state. Although the tendon response to mechanical stimuli has implications in disease pathogenesis and clinical treatment strategies, the cell signaling mechanisms by which tendon cells sense and respond to mechanical stimuli within the native tendon ECM remain largely unknown. Therefore, we explored the role of cell-ECM adhesions in regulating tendon cell mechanotransduction by perturbing the genetic expression and signaling activity of focal adhesion kinase (FAK) through both in vitro and in vivo approaches. We determined that FAK regulates tendon cell spreading behavior and focal adhesion morphology, nuclear deformation in response to applied mechanical strain, and mechanosensitive gene expression. In addition, our data reveal that FAK signaling plays an essential role in in vivo tendon development and postnatal growth, as FAK-knockout mouse tendons demonstrated reduced tendon size, altered mechanical properties, differences in cellular composition, and reduced maturity of the deposited ECM. These data provide a foundational understanding of the role of FAK signaling as a critical regulator of in situ tendon cell mechanotransduction. Importantly, an increased understanding of tendon cell mechanotransductive mechanisms may inform clinical practice as well as lead to the discovery of diagnostic and/or therapeutic molecular targets.
肌腱通过其致密的细胞外基质 (ECM) 将肌肉和骨骼之间的高拉伸机械力传递，从而使运动成为可能。通过肌肉收缩施加外在机械刺激对于调节健康的肌腱功能是必要的。具体来说，施加生理水平的机械负荷会引起肌腱细胞的合成代谢反应，而减少机械负荷会引起肌腱的降解状态。尽管肌腱对机械刺激的反应与疾病发病机制和临床治疗策略有关，但肌腱细胞在天然肌腱 ECM 中感知和响应机械刺激的细胞信号机制在很大程度上仍不清楚。因此，我们通过体外和体内方法干扰粘着斑激酶 (FAK) 的基因表达和信号活性，探索了细胞-细胞外基质黏附在调节肌腱细胞机械转导中的作用。我们确定 FAK 调节肌腱细胞的铺展行为和粘着斑形态、对施加的机械应变的核变形以及机械敏感基因的表达。此外，我们的数据表明 FAK 信号在体内肌腱发育和出生后生长中起着至关重要的作用，因为 FAK 敲除小鼠的肌腱表现出肌腱尺寸减小、机械性能改变、细胞组成差异以及沉积 ECM 的成熟度降低。这些数据为 FAK 信号作为原位肌腱细胞机械转导的关键调节剂的作用提供了基础理解。重要的是，对肌腱细胞机械转导机制的深入了解可能为临床实践提供信息，并导致发现诊断和/或治疗的分子靶点。
