Suppression of ABCD2 dysregulates lipid metabolism via dysregulation of miR‐141:ACSL4 in human osteoarthritis

Abstract

Even though increasing evidence indicates the importance of peroxisomal lipid metabolism in regulating biological and pathological events, its involvement in cartilage development has not been well studied. Here, we identified the importance of peroxisomal function, particularly the functional integrity of ABCD2, in the pathogenesis of osteoarthritis (OA). Knockdown of ABCD2 in OA chondrocytes induced the accumulation of very long chain fatty acids (VLCFAs) and apoptotic cell death. Moreover, knockdown of ABCD2 altered profiles of miRNAs that affect the expression level of ACSL4, a known direct regulator of lipid metabolism. Suppression of ACSL4 in human chondrocytes‐induced VLCFA accumulation, MMP‐13 expression, and apoptotic cell death. In vivo morph‐down of the ACSL4 homologue in zebrafish resulted in significant defects in cartilage development and in vivo knockdown of ACSL4 in cartilage tissue of an OA model mice promoted severe cartilage degradation. In summary, to the best of our knowledge, this is the first report suggesting that the regulatory network among peroxisomal ABCD2:ACSL4:VLCFA serves as a novel regulator of cartilage homeostasis, and these data may provide novel insights into the role of peroxisomal fatty acid metabolism in pathogenesis of human OA. Significance of the study Our study indicates that peroxisomal dysfunction is closely related to OA pathogenesis. Particularly, the functional integrity of ABCD2 may play an important role in OA pathogenesis via the accumulation of VLCFAs and stimulation of apoptotic death through altering profiles of miRNAs that target ACSL4. Our findings suggest that targeting the regulatory network among the peroxisomal ABCD2:ACSL4:VLCFA axis may provide a new potential therapeutic strategy for OA pathogenesis.

Identification of Novel Genes in Osteoarthritic Fibroblast-Like Synoviocytes Using Next-Generation Sequencing and Bioinformatics Approaches

“…One recent study by Park et al . reported the dysregulated miR-141-3p through ATP‐binding cassette transporter in human OA chondrocytes participated in altered lipid metabolism and suggested a novel insight into understanding the pathogenesis of OA 49. In view of inflammatory conditions, miR-141 seemed to play dual roles in regulating inflammation-related signaling pathways.…”

Network Pharmacology Identifies the Mechanisms of Action of Shaoyao Gancao Decoction in the Treatment of Osteoarthritis

“…Also, lipid metabolism is a chemical reaction involving lipids, which are compounds soluble in organic solvents [66]. Park et al showed that the functional integrity of ABCD2 in modulating lipid metabolism was through the dysregulation of miR-141, and through ACSL4 in OA [67].…”

A pilot study of peripheral blood DNA methylation models as predictors of knee osteoarthritis radiographic progression: data from the Osteoarthritis Initiative (OAI)

“…Among the topstream regulators identified in our ontology analysis was PITX2, a component of the Wnt signaling pathway key to mensenchymal stem cell function which is altered in OA patients 50 . MicroRNA-141 is dysregulated in human OA and contributes to pathogenesis by augmentation of lipid metabolism 51 , and is important in maintaining the appropriate expression of key osteoblast differentiation proteins including Runx2, Sclerostin, ALP, and Dlx5 52 . MicroRNA-9 has been shown to directly augment the expression of the key catabolic enzyme matrix metalloproteinase-13 (MMP13) in OA patients 53 and animal models 54 .…”