MicroRNA-488 regulates zinc transporter SLC39A8/ZIP8 during pathogenesis of osteoarthritis

Abstract

BackgroundEven though osteoarthritis (OA) is the most common musculoskeletal dysfunction, there are no effective pharmacological treatments to treat OA due to lack of understanding in OA pathology. To better understand the mechanism in OA pathogenesis and investigate its effective target, we analyzed miRNA profiles during OA pathogenesis and verify the role and its functional targets of miR-488.ResultsHuman articular chondrocytes were obtained from cartilage of OA patients undergoing knee replacement surgery and biopsy samples of normal cartilage and the expression profile of miRNA was analyzed. From expression profile, most potent miR was selected and its target and functional role in OA pathogenesis were investigated using target validation system and OA animal model system. Among miRNAs tested, miR-488 was significantly decreased in OA chondrocytes Furthermore, we found that exposure of IL-1β was also suppressed whereas exposure of TGF-β3 induced the induction of miR-488 in human articular chondrocytes isolated from biopsy samples of normal cartilages. Target validation study showed that miR-488 targets ZIP8 and suppression of ZIP8 in OA animal model showed the reduced cartilage degradation. Target validation study showed that miR-488 targets ZIP8 and suppression of ZIP8 in OA animal model showed the reduced cartilage degradation.ConclusionsmiR-488 acts as a positive role for chondrocyte differentiation/cartilage development by inhibiting MMP-13 activity through targeting ZIP-8.

microRNAs in Cartilage Development, Homeostasis, and Disease

“…miRNA profiling of patient-derived osteoarthritic chondrocytes has demonstrated downregulation of miR-140 in chondrocytes of osteoarthritic cartilage compared with normal human cartilage [35–37], although some studies also show increased miR-140 expression in OA cartilage [38, 39]. A recent study also reported that the expression level of miR-140 in the knee joint synovial fluid was inversely correlated with the severity of OA in patients [40].…”

MicroRNAs and post-transcriptional regulation of skeletal development

“…Numerous miRNAs have been shown to be regulated by IL1b action (Miyaki et al 2009, Dai et al 2012, Matsukawa et al 2013. MMP13 is regulated directly by miR-27b and miR-127-5p (Akhtar et al 2010 or indirectly by miR-27a, miR-9, miR-488, or miR-22 (Iliopoulos et al 2008, Jones et al 2009, Tardif et al 2009, Song et al 2013b, among others.…”

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

“…Ectopic expression of ZIP8 in cartilage tissue causes cartilage destruction, while surgically induced osteoarthritis pathogenesis is suppressed in chondrocyte-specific conditional Zip8-KO mice (212). MiR-488 has been shown to regulate ZIP8 expression during pathogenesis of osteoarthritis (381). ZIP8 plays indispensable roles in both multiple-organ organogenesis and hematopoiesis during early embryogenesis, because hypomorphic Zip8 mice show hypoplasia of multiple organs, such as the spleen, liver, kidney, and lung, and defects in hematopoiesis (118).…”