Targeting chondrocytes for arresting bony fusion in ankylosing spondylitis

Fenli Shao, Qianqian Liu, Yuyu Zhu, Zhidan Fan, Wenjun Chen, Shijia Liu, Xiaohui Li, Wenjie Guo, Gen-Sheng Feng, Haiguo Yu (), Qiang Xu () and Yang Sun ()
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Fenli Shao: Nanjing University
Qianqian Liu: Nanjing University
Yuyu Zhu: Nanjing University
Zhidan Fan: Children’s Hospital of Nanjing Medical University
Wenjun Chen: Affiliated Hospital of Nanjing University of Chinese Medicine
Shijia Liu: Affiliated Hospital of Nanjing University of Chinese Medicine
Xiaohui Li: Children’s Hospital of Nanjing Medical University
Wenjie Guo: Nanjing University
Gen-Sheng Feng: University of California San Diego
Haiguo Yu: Children’s Hospital of Nanjing Medical University
Qiang Xu: Nanjing University
Yang Sun: Nanjing University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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;Ptpn11f/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.

Date: 2021
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DOI: 10.1038/s41467-021-26750-6

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