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Adenovirus-mediated osteoprotegerin ameliorates cartilage destruction by inhibiting proteoglycan loss and chondrocyte apoptosis in rats with collagen-induced arthritis

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Abstract

Our aim is to elucidate the effects of osteoproteogerin (OPG) on cartilage destruction in rats as a model of collagen-induced arthritis (CIA). To establish the CIA model, Sprague Dawley rats were injected with bovine type II collagen solution subcutaneously via the tails. Adenovirus-mediated OPG (Ad-OPG) was then injected intra-articularly either at the beginning of CIA (early OPG treatment) or one week after CIA establishment (late OPG treatment); vehicle or Ad-green fluorescent protein were injected as controls. The rats were killed 4 weeks after treatment. Ankle-joint sections were obtained for histology. Serum samples were collected for enzyme-linked immunosorbent assay. Safranin O staining showed that proteoglycan loss was inhibited in the early and late Ad-OPG groups. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining revealed that both early and late Ad-OPG treatments significantly prevented chondrocyte apoptosis in CIA rats. Furthermore, disintegrin and metalloproteinase with thrombospondin motif−5 expression decreased remarkably in the early and late OPG treatment groups. However, the cartilage destruction score, cartilage oligomeric matrix protein level and caspase-3 expression were only decreased in the early Ad-OPG treatment group. Additionally, ankle-joint swelling and the interleukin-1β expression level in CIA rats were not notably altered by Ad-OPG treatment. Taken together, our results suggest that early Ad-OPG treatment has potent protective effects against cartilage destruction during rheumatoid arthritis progression, mainly by reducing proteoglycan loss and chondrocyte apoptosis.

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Acknowledgments

This study was supported by the Natural Science Fund of the Ningbo Science and Technology Bureau (No. 201101A6110108).

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The authors declare no competing interests.

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    Authors and Affiliations

    1. Spine Lab, Department of Orthopedic Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China, 310003

      Zhi-yun Feng & Zhong Chen

    2. Department of Orthopedics, Beilun People’s Hospital, No. 1288, Lu shan Road, Ningbo, Zhejiang Province, People’s Republic of China, 315806

      Zhen-nian He, Bin Zhang, Jian Guo, Yuan-lin Xu & Ming-yuan Han

    3. Department of Laboratory Center, Beilun People’s Hospital, No. 1288, Lu shan Road, Ningbo, Zhejiang Province, People’s Republic of China, 315806

      Yi-qiao Li

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    Fig. S1

    Expression level of OPG was significantly higher in chondrocytes infected with adenovirus-OPG than in those infected with adenovirus-GFP (9.2-fold). Glyceraldehyde-3-phosphate dehydrogenate (GAPDH) was used as an internal control. (GIF 7 kb)

    High resolution image (TIFF 72 kb)

    Fig. S2

    Another 15 collagen-induced arthritis (CIA) rats were established. Each group of three was killed after 1, 7, 14, 21 and 28 days. Sections were stained with Fast Green-safranin O and TUNEL (terminal dUTP nick end-labeling) to show the state of proteoglycan loss and chondrocyte apoptosis in the evolution of CIA. As shown, compared with the normal control, a significant loss of proteoglycan can be observed at the onset of CIA (day 1, a) and becomes severe at day 7 (b). Cartilage destruction, such as the irregularity of articular surface and thinning of cartilage, was initially noted at day 14 (c). The integrity of the cartilage is compromised on day 21 and 28, with the formation of large fissures and focals (d,). At the same time, sparse safarain O staining on the cartilage occurs at day 14 and later (c–e). The number of TUNEL-positive chondrocytes at the beginning of arthritis (28.0%, f, k) was comparable with the normal control (24.1%), became more prevalent at day 7 (52.1%, g, l) and mounted by day 14 (h, m) and day 21 (i, n). Finally, it became overwhelming at day 28 (j, o). Quantitative data showed that the proteoglycan loss score was 1.6 (mild to severe) at the onset of arthritis and increased to 2.3 (severe) after 7 days (p). The cartilage destruction score was higher than 2 at day 14 (q), indicating structural changes of cartilage according to the modified criterion. Magnification: ×100 (a-j), ×400 (k-o, box in f-j). (GIF 269 kb)

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    Feng, Zy., He, Zn., Zhang, B. et al. Adenovirus-mediated osteoprotegerin ameliorates cartilage destruction by inhibiting proteoglycan loss and chondrocyte apoptosis in rats with collagen-induced arthritis. Cell Tissue Res 362, 187–199 (2015). https://doi.org/10.1007/s00441-015-2194-8

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