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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.[/vc_column_text][vc_column_text]
In this study, severe immunodeficient NCG mice (strain ID, T001475) were intravenously transferred with purified CD3+ T cells to explore whether SHP2-deficient T cell is critical for AS-like bone disease.
Learn more about GemPharmatech’s immunodeficient mouse model, NCG, and its next generation NCG strains.
https://doi.org/10.1038/s41467-021-26750-6[/vc_column_text][/vc_column][/vc_row][vc_row][vc_column][vc_column_text]
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