Exosomes derived from diabetic serum accelerate the progression of osteoarthritis.

ABSTRACT

Diabetes mellitus (DM) has been demonstrated to accelerate the progression of osteoarthritis (OA) by largely unknown mechanisms. Studies have shown that DM dysfunctional adipocyte-derived exosomes play a crucial role in the pathogenesis of remote organ functions. The present study aimed to clarify whether and how diabetic adipocyte-derived exosomes mediate the pathological regulation of OA. We found that intraarticular injection of DM serum exosomes in the non-diabetic mice significantly exacerbated OA injury as evidenced by a rough and fractured cartilage surface as well as increased chondrocyte apoptosis, decreased mitochondrial membrane potential (△Ψ) and increased expression of cleaved caspase-3. Mechanistic investigation identified that miR-130b-3p was significantly increased in circulating exosomes derived from DM mice and exosomes derived from HG-treated normal adipocytes, and we demonstrated that transfection of miR-130b-3p mimics significantly exacerbated the mitochondrial function of chondrocytes. Our data also indicated that miR-130b-3p impaired the △Ψ, increased cleaved caspase-3 levels, and decreased the expression of 5'-adenosine monophosphate-activated protein kinase α1 (AMPKα1), Silent mating-type information regulation 2 homolog 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in chondrocytes. Pharmacologic activation of AMPKα1 using AICAR reversed the â–³Ψ and catabolic responses in chondrocytes transfected with miR-130b-3p mimics. Moreover, AICAR decreased the effects of miR-130b-3p mimics on chondrocytes transfected with SIRT1-siRNA or PGC-1α-siRNA. The current study demonstrated that adipocyte-derived exosomal miR-130b-3p under DM conditions suppresses mitochondrial function in chondrocytes through targeting the AMPKα1/SIRT1/PGC1-α pathway, thus exacerbating OA injury.