Fang Fei, Casserly Matthew, Robbins Julia, Thomopoulos Stavros
Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Orthopedic Surgery, Columbia University, New York, NY, USA.
NPJ Regen Med. 2025 Jan 20;10(1):3. doi: 10.1038/s41536-025-00392-4.
A high prevalence of rotator cuff tears presents a major clinical challenge. A better understanding of the molecular mechanisms underlying enthesis development and healing is needed for developing treatments. We recently identified hedgehog (Hh)-lineage cells critical for enthesis development and repair. This study revealed cell-cell communication within the Hh-lineage cell population. To further characterize the role of Hh signaling, we used mouse models to activate and inactivate the Hh pathway in enthesis progenitors. Activation of Hh target genes during enthesis development increased its mineralization and mechanical properties. Activation of Hh signaling at the injured mature enthesis promoted fibrocartilage formation, enhanced mineralization, and increased expression of chondrogenic and osteogenic markers, which implies that Hh signaling drives cell differentiation to regenerate the damaged enthesis. Conversely, deletion of Hh target genes impaired enthesis healing. In summary, this study revealed a new strategy for enthesis repair via activation of Hh signaling in endogenous cells.
肩袖撕裂的高发病率带来了重大的临床挑战。为了开发治疗方法，需要更好地了解起止点发育和愈合的分子机制。我们最近发现刺猬信号通路（Hh）谱系细胞对起止点的发育和修复至关重要。这项研究揭示了Hh谱系细胞群体内的细胞间通讯。为了进一步阐明Hh信号传导的作用，我们使用小鼠模型在起止点祖细胞中激活和失活Hh信号通路。在起止点发育过程中激活Hh靶基因可增加其矿化和力学性能。在受伤的成熟起止点激活Hh信号可促进纤维软骨形成，增强矿化，并增加软骨生成和成骨标志物的表达，这意味着Hh信号驱动细胞分化以再生受损的起止点。相反，删除Hh靶基因会损害起止点愈合。总之，本研究揭示了一种通过激活内源性细胞中的Hh信号来修复起止点的新策略。
