Prx1-expressing cells contributing to fracture repair require primary cilia for complete healing in mice.
Prx1-expressing cells contributing to fracture repair require primary cilia for complete healing in mice.
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Prx1表达细胞有助于骨折修复，需要初级纤毛才能使小鼠完全愈合。
DOI：
10.1016/j.bone.2020.115738
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发表时间：
2021-03
期刊：
影响因子：
4.1
通讯作者：
Yang Y
中科院分区：
文献类型：
--
作者：
Moore ER;Mathews OA;Yao Y;Yang Y
骨是一种动态器官，在发育、负荷诱导适应和骨折修复过程中不断发生变化。了解自然骨折愈合的细胞和分子机制可以导致提高新形成组织的质量，提高愈合速度或取代侵入性手术的治疗方法。认为骨膜中的Prx1表达细胞提供骨折骨痂中的大多数成骨细胞和软骨细胞，但这种行为的确切机制尚不清楚。初级纤毛是一种感觉细胞器，已知其介导参与骨折愈合的几种信号传导途径，并且是Prx1表达细胞促进幼年骨发育和成年负荷诱导骨形成所需的。因此，我们研究了Prx1表达细胞的初级纤毛在骨折修复中的作用，通过开发一种小鼠模型，使我们能够同时跟踪Prx1谱系细胞的命运和破坏Prx1表达细胞的初级纤毛在体内。纤毛KO小鼠表现出异常大的老茧，骨形成显著减少和持续的软骨结节。早期软骨痂中mRNA表达的分析揭示了成骨、Hh信号传导和Wnt信号传导的下调，以及软骨形成和血管生成的上调。突变小鼠硬骨痂中Osx和Periostin蛋白表达降低，αSMA蛋白表达增加。我们进一步使用了Gli1LacZ报告基因，发现Hh信号在愈合后期的突变愈伤组织中显著上调。有趣的是，改变的蛋白质表达和Hh信号并不与标记的Prx1谱系细胞，表明纤毛的损失改变Hh信号非自主。总的来说，纤毛KO小鼠表现出严重延迟和不完全的骨折愈合，我们的研究结果表明，Prx1表达细胞的初级纤毛是必要的，以调整Hh信号传导适当的骨折修复。
Bone is a dynamic organ that is continuously modified during development, load-induced adaptation, and fracture repair. Understanding the cellular and molecular mechanisms for natural fracture healing can lead to therapeutics that enhance the quality of newly formed tissue, advance the rate of healing, or replace the need for invasive surgical procedures. Prx1-expressing cells in the periosteum are thought to supply the majority of osteoblasts and chondrocytes in the fracture callus, but the exact mechanisms for this behavior are unknown. The primary cilium is a sensory organelle that is known to mediate several signaling pathways involved in fracture healing and required for Prx1-expressing cells to contribute to juvenile bone development and adult load-induced bone formation. We therefore investigated the role of Prx1-expressing cell primary cilia in fracture repair by developing a mouse model that enabled us to simultaneously track Prx1 lineage cell fate and disrupt Prx1-expressing cell primary cilia in vivo. The cilium KO mice exhibited abnormally large calluses with significantly decreased bone formation and persistent cartilage nodules. Analysis of mRNA expression in the early soft callus revealed downregulation of osteogenesis, Hh signaling, and Wnt signaling, and upregulation of chondrogenesis and angiogenesis. The mutant mice also exhibited decreased Osx and Periostin but increased αSMA protein expression in the hard callus. We further used a Gli1LacZ reporter and found that Hh signaling was significantly upregulated in the mutant callus at later stages of healing. Interestingly, altered protein expression and Hh signaling did not correlate with labeled Prx1-lineage cells, suggesting loss of cilia altered Hh signaling non-autonomously. Overall, cilium KO mice demonstrated severely delayed and incomplete fracture healing, and our findings suggest Prx1-expressing cell primary cilia are necessary to tune Hh signaling for proper fracture repair.
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影响因子：
--
作者：
Lee KL;Guevarra MD;Nguyen AM;Chua MC;Wang Y;Jacobs CR
通讯作者：
Jacobs CR
影响因子：
4.1
作者：
Bonnet, Nicolas;Garnero, Patrick;Ferrari, Serge
通讯作者：
Ferrari, Serge
影响因子：
4.3
作者：
Castro-Silva, Igor Iuco;Zambuzzi, Willian Fernando;Granjeiro, Jose Mauro
通讯作者：
Granjeiro, Jose Mauro
影响因子：
4.8
作者：
Chen, Julia C.;Hoey, David A.;Jacobs, Christopher R.
通讯作者：
Jacobs, Christopher R.
DOI：
10.1073/pnas.0504750102
发表时间：
2005-10-11
影响因子：
11.1
作者：
Akiyama, H;Kim, JE;de Crombrugghe, B
通讯作者：
de Crombrugghe, B