Background/Purpose: Zinc Finger CCHC Domain Containing Protein 6 (ZCCHC6) or Terminal Uridylyltransferase 7 (TUT7) is a member of terminal uridylyltransferase family that mediate terminal uridylation of mRNA or miRNA modulating their expression, stability and biogenesis. Matrix metalloprotease 13 (MMP13) is one of the key protease responsible for the degradation of cartilage extracellular matrix and plays central role in the pathogenesis of osteoarthritis (OA). In the present study we investigated the effect of ZCCHC6 deletion on the expression of MMP13 in human and mouse chondrocytes in vitro. We used global zcchc6 knockout (zcchc6-/-) mice to determine the role of zcchc6 in OA pathogenesis and the regulation of MMP13 expression in vivo.

Methods: Human chondrocytes were used for ZCCHC6 knockdown and overexpression experiments. The mouse chondrocytes from zcchc6-/- mice and corresponding wild type (zcchc6+/+) littermate were used to determine the expression of MMP13 under pathological conditions (stimulation with IL-1β). The expression of MMP13 mRNA was determined by qPCR using gene specific TaqMan assays and the protein expression levels were determined using Western blotting and ELISA. The zcchc6-/- and the zcchc6+/+ control mice were subjected to destabilization of medial meniscus (DMM) surgery to determine the role of zcchc6 in OA pathogenesis. The extent of damage to mouse joints was determined by OARSI scoring system.

Results: The expression of ZCCHC6 was upregulated in human normal and OA chondrocytes as well as mouse chondrocytes under pathological conditions. Depletion of ZCCHC6 in human normal and OA chondrocytes resulted in decreased expression of MMP13 at mRNA and protein levels in the presence or absence of IL-1β. Overexpression of ZCCHC6 in human OA chondrocytes resulted in increased expression of MMP13. The expression of MMP13 was found to be downregulated in the mouse chondrocytes prepared from zcchc6-/- mice in comparison to zcchc6+/+ littermate. Transfection of zcchc6 in mouse chondrocytes derived from zcchc6-/- mice reversed the expression of MMP13. The severity of DMM-induced OA was significantly low in zcchc6-/- mice compared to zcchc6+/+ mice. Furthermore, the expression of MMP13 in zcchc6-/- mice joints with DMM surgery was significantly low in comparison to zcchc6+/+ mice.

Conclusion: In the present study, we demonstrate a novel role of ZCCHC6 in the regulation of MMP13 expression in human and mouse chondrocytes and cartilage. We show here that zcchc6 deletion has protective effect on the development of OA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-role-of-zcchc6-in-the-regulation-of-mmp13-in-experimental-osteoarthritis-in-mice/