骨芽細胞USP26経路の活性化はインスリン抵抗性を低下させることにより多臓器線維症を軽減する

Osteoblast dysfunction contributes to systemic metabolic disorders by inducing insulin resistance (IR), a key factor in metabolic-related fibrosis. Therefore, the axis of osteoblast dysfunction, IR, and multi-organ fibrosis represents a crucial pathological pathway. This study revealed that the deletion of Ubiquitin Specific Peptidase 26 (USP26) in osteoblasts leads to decreased bone formation along with multi-organ fibrosis associated with IR. Mechanistically, the loss of USP26 decreases histone H3 lysine 18 lactylation (H3K18LA) in the promoter region of KH-Type Splicing Regulatory Protein (KSRP), resulting in decreased expression of KSRP and decreased alternative splicing of follistatin-like protein 1 (FSTL1) mRNA by KSRP. Elevated FSTL1 expression causes IR and high blood glucose levels, which leads to advanced glycation end-product (AGE) accumulation in the blood and multi-organ fibrosis. Activation of the USP26 pathway, specifically in osteoblasts, through extracellular vesicle-based bone-targeting drugs or mechanical loading can effectively prevent multi-organ fibrosis induced by IR. This study uncovered a causal relationship between skeletal degeneration and metabolism-related fibrosis, and highlights osteoblastic USP26 as a promising therapeutic target for addressing multi-organ fibrosis associated with IR.