Extracellular Vesicles Derived from Ligament Tissue Transport Interleukin-17A to Mediate Ligament-To-Bone Crosstalk in Ankylosing Spondylitis

Pathological new bone formation is a critical feature of the progression of ankylosing spondylitis (AS), and spine ankylosis is a distinctive feature of this condition. Ligaments are the primary regions of pathological new bone formation in AS. Here, it is demonstrated that ligament tissue-derived extracellular vesicles (EVs) and their interleukin-17A (IL-17A) cargo mediate the communication between the tissue and other cells. The investigation revealed that IL-17A in EVs can activate the JAK-STAT3 pathway, thereby stimulating the expression of MMP14 in AS ligament. Overexpression of MMP14 can lead to changes in the cytoskeleton and mechanical signaling of mesenchymal stem cells and other cells. These alterations in cellular cytoskeleton and mechanical signaling at ligament sites in patients with AS or in stem cells treated with EVs can result in pathological new bone formation. Finally, inhibiting IL-17A activity and EV endocytosis effectively controlled inflammation and pathological new bone formation. Overall, these data suggest that ligament-derived EVs and the enclosed IL-17A have a potential role in driving pathological new bone formation in AS, and targeting EVs may therefore emerge as a novel approach to delaying ectopic ossification in AS. Extracellular vesicles (EVs) derived from ligament tissue mediate inter-tissue communication between ligament and bone in ankylosing spondylitis (AS). EVs carrying interleukin-17A promote osteogenic differentiation of AS mesenchymal stem cells by altering the cellular cytoskeleton and mechanical signaling. This study provides the first evidence of tissue EVs contributing to pathological ossification in AS, offering potential avenues for targeted therapies. image