Tnxb, encoding tenascin-X (TN-X), is an extracellular matrix protein. TN-X is involved in multiple biological processes. It can directly interact with TGF-β through its fibrinogen-like domain, interfering with TGF-β binding to its receptor, thus playing a role in the regulation of endothelial-to-mesenchymal transition (EndMT), endothelial inflammation and atherogenesis [1].

In endothelium-specific Tnxb knockout (EC-Tnxb-KO) mice, increased endothelial TGF-β signaling, as well as increased expression of EndMT and inflammatory marker genes were observed. When EC-Tnxb-KO mice were subjected to partial carotid artery ligation, there was increased vascular remodeling. Also, when crossed to low-density lipoprotein receptor-deficient mice and fed a high-fat diet, they showed advanced atherosclerotic lesions. Treatment with an anti-TGF-beta antibody or additional endothelial loss of TGF-beta receptors 1 and 2 normalized endothelial TGF-beta signaling and prevented EndMT [1]. In F8-/-mouse cartilage, loss of Tnxb augmented cartilage degeneration and subchondral bone loss in hemophilic arthropathy (HA), and Tnxb knockdown promoted chondrocyte apoptosis and inhibited phosphorylation of AKT [2].

In summary, Tnxb is crucial for regulating TGF-β-related signaling pathways, which is important in processes like preventing EndMT, endothelial inflammation, atherogenesis and maintaining cartilage homeostasis. The EC-Tnxb-KO and F8-/-mouse models with Tnxb loss-of-function have revealed its role in atherosclerosis and HA, providing insights into these disease mechanisms and potential treatment strategies.