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Abstract Number: 1133

Microrna-128 Interference Mitigates the Progression of Keen Osteoarthritis By Regulating Sirtuin-1

Feng-Sheng Wang1, Yi-Chih Sun1, Yu-Shan Chen1 and Jih-Yang Ko2, 1Core Facility for Phenomics & Diagnostics, Department of Medical Research, Core Facility for Phenomics & Diagnostics, Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Taiwan, Kaohsiung, Taiwan, 2Department of Orthopedic Surgery, Department of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital, Taiwan, Kaohsiung, Taiwan

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: cartilage, MicroRNA, osteoarthritis and synovitis

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Session Information

Date: Monday, November 9, 2015

Title: Biology and Pathology of Bone and Joint Poster I: Osteoarthritis Pathogenesis

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:  MicroRNAs, non-coding small RNAs, reportedly regulate development, remodeling and pathogenesis activities in various tissues through silencing mRNA targets and protein translation. This study is undertaken to analyze comparative microRNA expression profiles, characterize the biological role of candidate microRNA-128 (miR-128) in articular cartilage integrity and investigate whether knockdown of miR-128 attenuated cartilage erosion, synovial remodeling, subchondral bone deterioration and osoteophyte accumulation during the pathogenesis of knee OA.

Methods:   Left knees of male Spargue-Dwley rats underwent medial parapatellar arthrotomy and anterior cruciate ligament transaction (ACLT) to induce OA. Arthrography of cartilage injury and synovitis were visualized by 9.4T μMRI. Articular cartilage damage was scored by OARSI scale. Subchondral bone microarchitecture and osteophyte formation were quantified by μCT. Comparative microRNA expression of injured joints was analyzed by Megaplex™ microRNA arrays and verified by quantitative RT-PCR and in situ hybridization. 

Results:   miR-128 expression was increased with intensive articular cartilage destruction and chondrocyte apoptosis in the development of knee OA. Intra-articular injection of lentivirus-mediated exogenous miR-128 led to intact knee joints progressively had severe chondrocyte loss and exacerbated cartilage breakdown that recapitulated OA histopathology. Of note, intra-articular administration of exogenous miR-128 antisense oligonucleotide (miR-128-AS) attenuated the ACLT-mediated chondrocyte apoptosis, proteinase expression (MMP3, MMP9 and ADAMTS5), cartilage matrix degradation and microstructure impediment. The miR-128-AS treatment lessened the provoking effects on synovial thickening, fibroblast activation, macrophage infiltration and inflammatory regulator expression (IL-1β, TNFα, CXCL-9 and COX-2). This administration also simultaneously ameliorated subchondral plate damage, trabecular microarchitecture loss and osteophyte deposition. miR-128 decreased sirtuin-1 (SIRT1) mRNA and protein expression through targeting the 3’-UTR of sirtuin-1 in chondrocytes. miR-128-AS treatment restored SIRT1 signaling and stabilized cartilage transcription factor SOX9 through regulating acetylation state of SOX9 in affected knee joints.

Conclusion:   miR-128 aggravated joint integrity in the pathogenesis of knee OA. Interruption of miR-128 maintained chondrocyte viability and metabolism through regulating SIRT1 signaling and thereby alleviated the pathogenesis of cartilage erosion, synovitis, subchondral plate damage and osteophyte development. This study sheds a new light on miR-128 deterioration of articular cartilage homeostasis and highlights the therapeutic potential of miR-128 interference for curtailing knee OA pathogenesis.

 


Disclosure: F. S. Wang, None; Y. C. Sun, None; Y. S. Chen, None; J. Y. Ko, None.

To cite this abstract in AMA style:

Wang FS, Sun YC, Chen YS, Ko JY. Microrna-128 Interference Mitigates the Progression of Keen Osteoarthritis By Regulating Sirtuin-1 [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/microrna-128-interference-mitigates-the-progression-of-keen-osteoarthritis-by-regulating-sirtuin-1/. Accessed .
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