Cartilage Biology and Regenerative Medicine Laboratory, College of Dental Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Department of OB/GYN, Division of Reproductive Sciences, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
J Dent Res. 2020 Sep;99(10):1174-1181. doi: 10.1177/0022034520924656. Epub 2020 May 22.
The Notch pathway is critical for the development of the extracellular matrix in cartilage by regulating both anabolic and catabolic cellular activities. Similarly, Notch signaling plays a biphasic role in adult cartilage health and osteoarthritis by maintaining homeostasis and contributing to degeneration, respectively. The temporomandibular joint (TMJ) is the synovial joint of the craniofacial complex and is subject to injury and osteoarthritis. While Notch has been studied in axial skeletal joints, little is known about the role of Notch in TMJ development and disease. We identified fibrocartilage stem cells (FCSCs) localized within the TMJ condyle superficial zone niche that regenerate cartilage and repair joint injury. Here we investigate the role of Notch in regulating TMJ development and FCSC fate. Using a Notch reporter mouse, we discovered FCSCs localized within the TMJ superficial niche exhibit Notch activity during TMJ morphogenesis. We further showed that constitutively activating Notch promotes FCSC differentiation toward both cartilage and bone lineages, but inhibits adipogenesis. Using a TNF-α-induced TMJ inflammatory arthritis mouse model, we found that the expression of Notch receptors and ligands are upregulated and coupled with cells undergoing cartilage to bone transdifferentiation, which may contribute to TMJ pathogenesis. We also discovered that global Notch inhibition reduces osteogenic and chondrogenic differentiation of FCSCs. Together, these findings suggest that Notch is critical for FCSC fate specification and TMJ homeostasis, and reveal that inhibition of the Notch pathway may be a new therapeutic target for treating TMJ osteoarthritis.
Notch 通路通过调节细胞的合成代谢和分解代谢活动，对于软骨细胞外基质的发育至关重要。同样，Notch 信号通路在成体软骨健康和骨关节炎中发挥着双重作用，通过维持内稳态和促进退化分别发挥作用。颞下颌关节（TMJ）是颅面复合体的滑膜关节，易受到损伤和骨关节炎的影响。虽然 Notch 在轴性骨骼关节中已有研究，但对于 Notch 在 TMJ 发育和疾病中的作用知之甚少。我们鉴定了位于 TMJ 髁突浅区龛内的纤维软骨干细胞（FCSC），它们可以再生软骨并修复关节损伤。在这里，我们研究了 Notch 在调节 TMJ 发育和 FCSC 命运中的作用。使用 Notch 报告小鼠，我们发现 FCSC 位于 TMJ 浅区龛内，在 TMJ 形态发生过程中表现出 Notch 活性。我们进一步表明，持续激活 Notch 可促进 FCSC 向软骨和成骨谱系分化，但抑制脂肪生成。使用 TNF-α诱导的 TMJ 炎症性关节炎小鼠模型，我们发现 Notch 受体和配体的表达上调，并与发生软骨向骨转化的细胞相关，这可能有助于 TMJ 的发病机制。我们还发现，全局 Notch 抑制减少了 FCSC 的成骨和成软骨分化。总之，这些发现表明 Notch 对于 FCSC 命运特化和 TMJ 内稳态至关重要，并揭示了抑制 Notch 通路可能是治疗 TMJ 骨关节炎的新治疗靶点。
