纤维软骨
刺猬信号通路
刺猬
肌腱
祖细胞
平滑
刺激
解剖
医学
细胞生物学
癌症研究
信号转导
生物
内科学
干细胞
病理
骨关节炎
替代医学
关节软骨
作者
Timur Kamalitdinov,Keitaro Fujino,Sinaia Keith Lang,Xi Jiang,Rashad Madi,Mary Kate Evans,Miltiadis H. Zgonis,Andrew F. Kuntz,Nathaniel A. Dyment
标识
DOI:10.1016/j.joca.2023.04.013
摘要
While the role of hedgehog (Hh) signaling in promoting zonal fibrocartilage production during development is well-established, whether this pathway can be leveraged to improve tendon-to-bone repair in adults is unknown. Our objective was to genetically and pharmacologically stimulate the Hh pathway in cells that give rise to zonal fibrocartilaginous attachments to promote tendon-to-bone integration.Hh signaling was stimulated genetically via constitutive Smo (SmoM2 construct) activation of bone marrow stromal cells or pharmacologically via systemic agonist delivery to mice following anterior cruciate ligament reconstruction (ACLR). To assess tunnel integration, we measured mineralized fibrocartilage (MFC) formation in these mice 28 days post-surgery and performed tunnel pullout testing.Hh pathway-related genes increased in cells forming the zonal attachments in wild-type mice. Both genetic and pharmacologic stimulation of the Hh pathway increased MFC formation and integration strength 28 days post-surgery. We next conducted studies to define the role of Hh in specific stages of the tunnel integration process. We found Hh agonist treatment increased the proliferation of the progenitor pool in the first week post-surgery. Additionally, genetic stimulation led to continued MFC production in the later stages of the integration process. These results indicate that Hh signaling plays an important biphasic role in cell proliferation and differentiation towards fibrochondrocytes following ACLR.This study reveals a biphasic role for Hh signaling during the tendon-to-bone integration process after ACLR. In addition, the Hh pathway is a promising therapeutic target to improve tendon-to-bone repair outcomes.
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