ADSC-derived exosomes inhibit cbl-cathepsin K-dependent osteoclast activation in inflammatory arthritis

Abstract Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes joint inflammation and bone destruction due to increased osteoclast differentiation and activity. Adipose-derived stem cells (ADSCs) are used to treat tissue injury because they are easy to harvest and exhibit immunomodulatory and regenerative capacity. Previous studies demonstrated that ADSC-derived exosomes (ADSC-Exo) protect articular cartilage from damage and exert anti-inflammation effects. Thus, we investigated the underlying mechanisms of ADSC-Exo in regulating osteoclast activation in inflammatory arthritis. RANKL is a TNF-family cytokine that binds to the RANK required for mature osteoclasts. However, whether ADSC-Exo is functionally involved in the inhibition of osteoclast formation via regulating RANK-mediated signaling in these pathological conditions is unclear. Our data revealed that ADSC-Exo ameliorated the RA severity and bone loss in vivo and inhibited osteoclast differentiation, RANK downstream signaling, NFATc1, cathepsin K, and cbl-b. Moreover, ADSC-Exo could significantly suppress the population of RANKL-expressing TH17 cells. In brief, ADSC-Exo protects articular cartilage and bone destruction from damage and ameliorates gait abnormality in CIA rats, which may be related to the inhibition of the RANK-signaling pathway in osteoclasts. As it is relatively feasible to obtain human adipose tissue, ADSC-Exo may be a potential therapy for RA. This study could comprehensively understand the immunomodulatory effects of ADSC-Exo on suppressing osteoclastogenesis. This finding is critical for understanding the bone homeostasis modulated by MSC-Exo and provides biological evidence of ADSC-Exo in inflammatory arthritis. Supported by grants from the Ministry of Science and Technology (111-2321-B-418-002, 111-2314-B-418-004), FEMH (2022-C-042 and 2022-C-123), NYCU-FEMH Cooperation grants (111DN12, 111DN22), NTUH-FEMH Cooperation (111-FTN0012).