Intervertebral disc-intrinsic Hedgehog signaling maintains disc cell phenotypes and prevents disc degeneration through both cell autonomous and non-autonomous mechanisms

被引:5
|
作者
Zhang, Lei [1 ,2 ]
Hu, Siyuan [2 ]
Xiu, Chunmei [1 ]
Li, Meng [2 ]
Zheng, Yixin [2 ]
Zhang, Rui [2 ]
Li, Bin [1 ,2 ]
Chen, Jianquan [1 ,2 ]
机构
[1] Hangzhou City Univ, Sch Med, Dept Clin Med, Key Lab Novel Targets & Drug Study Neural Repair Z, Hangzhou 310015, Zhejiang, Peoples R China
[2] Soochow Univ, Orthoped Inst, Suzhou Med Coll, Suzhou 215006, Jiangsu, Peoples R China
基金
中国国家自然科学基金;
关键词
Low back pain; Shh signaling; Intervertebral disc homeostasis; Gli3; repressor; Dis cell differentiation; Chondrocyte-like cells; ACTIVATION; GROWTH; MICE; GLI3; SHH; AGE;
D O I
10.1007/s00018-023-05106-x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Intervertebral disc degeneration is closely related to abnormal phenotypic changes in disc cells. However, the mechanism by which disc cell phenotypes are maintained remains poorly understood. Here, Hedgehog-responsive cells were found to be specifically localized in the inner annulus fibrosus and cartilaginous endplate of postnatal discs, likely activated by Indian Hedgehog. Global inhibition of Hedgehog signaling using a pharmacological inhibitor or Agc1-CreERT2-mediated deletion of Smo in disc cells of juvenile mice led to spontaneous degenerative changes in annulus fibrosus and cartilaginous endplate accompanied by aberrant disc cell differentiation in adult mice. In contrast, Krt19-CreER-mediated deletion of Smo specifically in nucleus pulposus cells led to healthy discs and normal disc cell phenotypes. Similarly, age-related degeneration of nucleus pulposus was accelerated by genetic inactivation of Hedgehog signaling in all disc cells, but not in nucleus pulposus cells. Furthermore, inactivation of Gli2 in disc cells resulted in partial loss of the vertebral growth plate but otherwise healthy discs, whereas deletion of Gli3 in disc cells largely corrected disc defects caused by Smo ablation in mice. Taken together, our findings not only revealed for the first time a direct role of Hedgehog-Gli3 signaling in maintaining homeostasis and cell phenotypes of annuls fibrosus and cartilaginous endplate, but also identified disc-intrinsic Hedgehog signaling as a novel non-cell-autonomous mechanism to regulate nucleus pulposus cell phenotype and protect mice from age-dependent nucleus pulposus degeneration. Thus, targeting Hedgehog signaling may represent a potential therapeutic strategy for the prevention and treatment of intervertebral disc degeneration.
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页数:23
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