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. 2013 May 20;20(1):31.
doi: 10.1186/1423-0127-20-31.

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

Jinsoo Song  1 , Dongkyun Kim, Chang Hoon Lee, Myeung Su Lee, Churl-Hong Chun, Eun-Jung Jin
Affiliations

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

Jinsoo Song et al. J Biomed Sci. .

Abstract

Background: Even 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.

Results: Human 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.

Conclusions: miR-488 acts as a positive role for chondrocyte differentiation/cartilage development by inhibiting MMP-13 activity through targeting ZIP-8.

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Figures

Figure 1
Figure 1
Expression profile of miRNAs in OA chondrocytes. (A) Images of human articular chondrocytes isolated form OA cartilages (upper panel) and safranin O staining of OA cartilage (lower panel). (B) Changes in miRNA level were determined by real-time PCR. *, statistically different from control cells (P < 0.005).
Figure 2
Figure 2
MiR-488 is involved in degeneration of human articular chondrocytes. (A) Human articular chondrocytes isolated from autopsy normal cartilage were treated with 10 ng/ml IL-1β in the presence of miR-488 or miR-488 inhibitor (anti-miR-488), stained with phalloidin (left panel), and expression level of type II collagen was analyzed (right panel). (B) Human articular chondrocytes isolated from autopsy normal cartilage were treated with 10 ng/ml IL-1β or 5 ng/ml TGF-β3, stained with phalloidin (left panel), and expression level of type II collagen and miR-488 were analyzed by real-time PCR (right panel). *, statistically different from control cells (p < 0.001). The error bars represent average of data from each human sample.
Figure 3
Figure 3
MiR-488 targets ZIP8. Human articular chondrocytes isolated from autopsy normal cartilage were isolated as described in Material and Method. (A) Articular chondrocytes were treated 2.5, 5, or 10 ng/ml IL-1β and expression level of MMP-13 was examined by real-time PCR (left panel). Cells were treated with 10 ng/ml of IL-1β, expression level was analyzed at indicated time points by real-time PCR (right upper panel), and activation of MMP-13 was analyzed and zymography (Zymo, right lower panel) and immunoblotting (IB, right lower panel), respectively. (B) Expression levels of ZIPs were analyzed by real-time PCR. (C) Human articular chondrocytes isolated from autopsy normal cartilage were treated with 10 ng/ml IL-1β in the presence of miR-488 or miR-488 inhibitor (anti-miR-488) and expression levels of ZIP2, -7, -8 were examined by real-time PCR. (D) Luciferase reporter gene assays of cells expressing the construct containing the human ZIP2, -7, -8 3’-UTR in the absence or presence of miR-488. The expression level of ZIP-8 was analyzed by immunoblotting in normal and OA chondrocytes.
Figure 4
Figure 4
Suppression of ZIP8 protects DMM-induced cartilage degradation. (A) OA chondrocytes were infected with si-ZIP-8 virus and the expression level of MMP-13, type II collagen was examined by immunoblotting. (B) Mouse cartilages with OA induced by destabilization of the medial meniscus (DMM) were stained with Safranin O. Sham-operated (Sham) cartilage was used as control.
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