The loss of Ubiquitin Specific Peptidase 26 (USP26) in osteoblasts results in decreased bone formation, as well as multi-organ fibrosis associated with insulin resistance (IR). Mechanistically, the absence of USP26 reduces glycolysis and lactate accumulation, leading to decreased histone H3 lysine 18 lactylation (H3K18LA) in the promoter region of KH-type splicing regulatory protein (KSRP). This results in lower transcription of KSRP and diminished alternative splicing of follistatin-like protein 1 (FSTL1) mRNA by KSRP. Consequently, the elevated FSTL1 contributes to IR and elevated blood glucose levels. This results in the accumulation of advanced glycation end products (AGEs) in the blood, ultimately leading to multi-organ fibrosis. Furthermore, activating the USP26 pathway specifically in osteoblasts through extracellular vesicle (EV)-based bone-targeting drug or compression loading can effectively prevent multi-organ fibrosis induced by IR.
ABSTRACT
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.
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