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.
Highlights
Bony fusion caused by pathological new bone formation manifests the clinical feature of ankylosing spondylitis (AS)
Depending on the hypothesis that inflammation activates the repair process followed by new bone formation, the disability of anti-inflammation treatments would be attributable to that it is too late to prevent the formation of ectopic new bone in patients with AS, who conforms to the diagnostic criteria of enthesitis and definite radiographic sacroiliitis
CD4-Cre;Ptpn11f/f (CD4-CKO) mice were generated by crossing Ptpn11f/f (CD4-Ctrl) mice with mice expressing Cre driven by endogenous CD4 promoter
Summary
Bony fusion caused by pathological new bone formation manifests the clinical feature of ankylosing spondylitis (AS). 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. Ankylosing spondylitis (AS) is a chronic seronegative arthritis that primarily affects the axial skeleton[1] It is highly heritable (heritability > 90%) and has a strong association with human leukocyte antigen-B27 gene[2,3]. The mechanism of pathological new bone formation remains elusive at present. Increased osteoclasts were found on the bony surfaces of calcified cartilage and subchondral bone marrow in AS14,17 It suggests chondrogenesis and osteoclastogenesis participate in the progression of AS
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