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Regulation of MMP and TIMP expression in synovial fibroblasts from knee osteoarthritis with flexion contracture using adenovirus-mediated relaxin gene therapy

 Jae Han Ko  ;  Young Mi Kang  ;  Jae Ho Yang  ;  Ji Sup Kim  ;  Won Jai Lee  ;  Sang Ho Kim  ;  Ick Hwan Yang  ;  Seong Hwan Moon 
 KNEE, Vol.26(2) : 317-329, 2019 
Journal Title
Issue Date
Adenoviridae ; Blotting, Western ; Cells, Cultured ; Fibroblasts/metabolism* ; Fibroblasts/pathology ; Fibronectins ; Gene Expression Regulation* ; Genetic Therapy/methods* ; Humans ; Osteoarthritis, Knee/genetics* ; Osteoarthritis, Knee/metabolism ; Osteoarthritis, Knee/therapy ; RNA/genetics ; Relaxin/therapeutic use* ; Reverse Transcriptase Polymerase Chain Reaction ; Synovial Membrane/metabolism* ; Synovial Membrane/pathology ; Tissue Inhibitor of Metalloproteinases/biosynthesis ; Tissue Inhibitor of Metalloproteinases/genetics*
Fibrosis ; Matrix metalloproteinases ; Relaxin ; Total knee arthroplasty
PURPOSE: The aim of this study was to investigate the effects of relaxin (RLN) expression on fibrosis inhibition in synovial fibroblasts. MATERIALS AND METHODS: Tissue cells from patients with knee osteoarthritis and >30° flexion contractures were utilised. Synovial fibroblasts were activated by TGF-β1 (two nanograms per millilitre) and then exposed to Ad-RLN as a therapeutic gene, adenovirus-lacZ construct as a marker gene, and SB505124 as an inhibitor for TGF-β1 signal for 48 h. The mRNA expression levels of collagens and MMPs were analysed by reverse transcription-polymerase chain reaction. Also, fibronectin, phosphorylation of Smad2 and ERK1/2, alpha smooth muscle actin, TIMP-1, TIMP-2, MMP-1 and MMP-13 levels were estimated using western blotting, and the total collagen synthesis was assayed. RESULTS: Ad-RLN-transduced synovial fibroblasts demonstrated 17%, 13%, and 48% reduction in collagen I, III and IV mRNA expression levels, respectively, and a 40% decrease in MMP-3, MMP-8, 20% decrease in MMP-9, MMP-13 mRNA expression, compared to non-Ad-RLN-transduced cells. In protein expression, Ad-RLN-transduced synovial fibroblasts demonstrated 46% increase in MMP-1, 5% decrease in MMP-2, 51% increase in MMP-9, and 22% increase in MMP-13, compared to non-Ad-RLN-transduced cells. Ad-RLN-transduced synovial fibroblasts showed a 25% decrease in TIMP-1 and 65% decrease in TIMP-2 protein expression at 48h, compared to non-Ad-RLN-transduced cells. Ad-RLN-transduced synovial fibroblasts demonstrated a 45% inhibition of fibronectin in protein expression level and 38% decrease in total collagen synthesis at 48h, compared to non-Ad-RLN-transduced cells. CONCLUSION: Relaxin expression exerted anti-fibrogenic effects on synovial fibroblasts from patients with knee osteoarthritis and flexion contractures. Therefore, relaxin could be an alternative therapeutic agent during the initial stage of osteoarthritis with flexion contracture by exerting its anti-fibrogenic effects.
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Orthopedic Surgery (정형외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Plastic and Reconstructive Surgery (성형외과학교실) > 1. Journal Papers
Yonsei Authors
Ko, Jae Han(고재한)
Kim, Sang Ho(김상호) ORCID logo https://orcid.org/0000-0003-3936-1869
Moon, Seong Hwan(문성환)
Yang, Ick Hwan(양익환)
Yang, Jae Ho(양재호) ORCID logo https://orcid.org/0000-0001-7421-2805
Lee, Won Jai(이원재) ORCID logo https://orcid.org/0000-0003-3056-0503
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