Targeting chondrocytes for arresting bony fusion in ankylosing spondylitis
Abstract Bony fusion caused by pathological new bone formation manifests the clinical feature of ankylosing spondylitis (AS). However, the underlying mechanism remains elusive. Here we discovered spontaneous kyphosis, arthritis and bony fusion in mature CD4-Cre;Ptpn11 f/f mice, which present the pat...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-021-26750-6 |
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| author | Fenli Shao Qianqian Liu Yuyu Zhu Zhidan Fan Wenjun Chen Shijia Liu Xiaohui Li Wenjie Guo Gen-Sheng Feng Haiguo Yu Qiang Xu Yang Sun |
| author_facet | Fenli Shao Qianqian Liu Yuyu Zhu Zhidan Fan Wenjun Chen Shijia Liu Xiaohui Li Wenjie Guo Gen-Sheng Feng Haiguo Yu Qiang Xu Yang Sun |
| author_sort | Fenli Shao |
| collection | DOAJ |
| description | Abstract Bony fusion caused by pathological new bone formation manifests the clinical feature of ankylosing spondylitis (AS). However, the underlying mechanism remains elusive. Here we discovered spontaneous kyphosis, arthritis and bony fusion in mature CD4-Cre;Ptpn11 f/f mice, which present the pathophysiological features of AS. A population of CD4-Cre-expressing proliferating chondrocytes was SHP2 deficient, which could differentiate into pre-hypertrophic and hypertrophic chondrocytes. Functionally, SHP2 deficiency in chondrocytes impeded the fusion of epiphyseal plate and promoted chondrogenesis in joint cavity and enthesis. Mechanistically, aberrant chondrocytes promoted ectopic new bone formation through BMP6/pSmad1/5 signaling. It is worth emphasizing that such pathological thickness of growth plates was evident in adolescent humans with enthesitis-related arthritis, which could progress to AS in adulthood. Targeting dysfunctional chondrogenesis with Smo inhibitor sonidegib significantly alleviated the AS-like bone disease in mice. These findings suggest that blockade of chondrogenesis by sonidegib would be a drug repurposing strategy for AS treatment. |
| format | Article |
| id | doaj-art-12886a3b76044df8b6656dcdbe796a6e |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2021-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-12886a3b76044df8b6656dcdbe796a6e2025-02-09T12:46:32ZengNature PortfolioNature Communications2041-17232021-11-0112111410.1038/s41467-021-26750-6Targeting chondrocytes for arresting bony fusion in ankylosing spondylitisFenli Shao0Qianqian Liu1Yuyu Zhu2Zhidan Fan3Wenjun Chen4Shijia Liu5Xiaohui Li6Wenjie Guo7Gen-Sheng Feng8Haiguo Yu9Qiang Xu10Yang Sun11State Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing UniversityDepartment of Rheumatology and Immunology, Children’s Hospital of Nanjing Medical UniversityAffiliated Hospital of Nanjing University of Chinese MedicineAffiliated Hospital of Nanjing University of Chinese MedicineDepartment of Radiology, Children’s Hospital of Nanjing Medical UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing UniversityDepartment of Pathology, and Division of Biological Sciences, University of California San DiegoDepartment of Rheumatology and Immunology, Children’s Hospital of Nanjing Medical UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing UniversityAbstract Bony fusion caused by pathological new bone formation manifests the clinical feature of ankylosing spondylitis (AS). However, the underlying mechanism remains elusive. Here we discovered spontaneous kyphosis, arthritis and bony fusion in mature CD4-Cre;Ptpn11 f/f mice, which present the pathophysiological features of AS. A population of CD4-Cre-expressing proliferating chondrocytes was SHP2 deficient, which could differentiate into pre-hypertrophic and hypertrophic chondrocytes. Functionally, SHP2 deficiency in chondrocytes impeded the fusion of epiphyseal plate and promoted chondrogenesis in joint cavity and enthesis. Mechanistically, aberrant chondrocytes promoted ectopic new bone formation through BMP6/pSmad1/5 signaling. It is worth emphasizing that such pathological thickness of growth plates was evident in adolescent humans with enthesitis-related arthritis, which could progress to AS in adulthood. Targeting dysfunctional chondrogenesis with Smo inhibitor sonidegib significantly alleviated the AS-like bone disease in mice. These findings suggest that blockade of chondrogenesis by sonidegib would be a drug repurposing strategy for AS treatment.https://doi.org/10.1038/s41467-021-26750-6 |
| spellingShingle | Fenli Shao Qianqian Liu Yuyu Zhu Zhidan Fan Wenjun Chen Shijia Liu Xiaohui Li Wenjie Guo Gen-Sheng Feng Haiguo Yu Qiang Xu Yang Sun Targeting chondrocytes for arresting bony fusion in ankylosing spondylitis Nature Communications |
| title | Targeting chondrocytes for arresting bony fusion in ankylosing spondylitis |
| title_full | Targeting chondrocytes for arresting bony fusion in ankylosing spondylitis |
| title_fullStr | Targeting chondrocytes for arresting bony fusion in ankylosing spondylitis |
| title_full_unstemmed | Targeting chondrocytes for arresting bony fusion in ankylosing spondylitis |
| title_short | Targeting chondrocytes for arresting bony fusion in ankylosing spondylitis |
| title_sort | targeting chondrocytes for arresting bony fusion in ankylosing spondylitis |
| url | https://doi.org/10.1038/s41467-021-26750-6 |
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