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Journal of Orthopaedic Surgery and Research
Published in: Journal of Orthopaedic Surgery and Research 1/2016

Open Access 01-12-2016 | Research article

Reduction of intraarticular adhesion of knee by local application of rapamycin in rabbits via inhibition of fibroblast proliferation and collagen synthesis

Authors: Shuai Zhao, Yu Sun, Xiaolei Li, Jingcheng Wang, Lianqi Yan, Hui Chen, Daxin Wang, Jihang Dai, Jun He

Published in: Journal of Orthopaedic Surgery and Research | Issue 1/2016

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Abstract

Background

The formation of intraarticular adhesion is a common complication after total knee arthroplasty or anterior cruciate ligament reconstruction. Previously, little research was reported regarding whether the local application of rapamycin (RAPA) could reduce intraarticular adhesion following knee surgery. In our present study, we determined the therapeutic effect of RAPA by local application on the reduction of intraarticular adhesion following knee surgery in rabbits.

Methods

In this study, we built the model of knee surgery according to a previous study. The decorticated areas of the cortical bone were exposed and covered with cotton pads soaked with different concentrations of RAPA or physiological saline for 10 min. All of the rabbits were euthanized 4 weeks after the surgery. Macroscopic evaluation of the hydroxyproline content, the histological morphological analysis and collagen density and fibroblast density were used to evaluate the effect of RAPA on reducing intraarticular adhesion.

Results

The results shown that RAPA could significantly inhibit the proliferation of fibroblasts and reduce collagen synthesis; in the rabbit model of knee surgery, there were weak scar tissues around the decorticated areas in the 0.2 mg/ml RAPA group; moderate scar tissues were found in the 0.1 mg/ml RAPA group. However, severe fibrous adhesions were found in the 0.05 mg/ml RAPA group and the control group. The hydroxyproline content and the fibroblast density in the 0.2 mg/ml and 0.1 mg/ml RAPA groups were significantly less than those of the control group.

Conclusions

We concluded that the local application of RAPA could reduce intraarticular adhesion after knee surgery in the rabbit model; this effect was mediated by inhibition of fibroblast proliferation and collagen synthesis, which may provide a new method for reducing intraarticular adhesion after clinical knee surgery.
Literature
1.
Fukui N, Tashiro T, Hiraoka H, Oda H, Nakamura K. Adhesion formation can be reduced by the suppression of transforming growth factor-β activity. J Orthop Res. 2000;18(2):212–9.CrossRefPubMed
2.
Hayashi M, Sekiya H, Takatoku K, Kariya Y, Hoshino Y. Experimental model of knee contracture in extension: its prevention using a sheet made from hyaluronic acid and carboxymethylcellulose. Knee Surg Sport Tr A. 2004;12(6):545–51.CrossRef
3.
Eakin CL. Knee arthrofibrosis: prevention and management of a potentially devastating condition. Phys Sportsmed. 2001;29(3):31–42.CrossRefPubMed
4.
Mayr HO, St O, Hr A. Arthroscopic treatment of arthrofibrosis after ACL reconstruction. Local and generalized arthrofibrosis. Oper Orthop Traumato. 2014;26(1):7–18.CrossRef
5.
Monument MJ, Hart DA, Befus AD, Salo PT, Zhang M, Hildebrand KA. The mast cell stabilizer ketotifen reduces joint capsule fibrosis in a rabbit model of post-traumatic joint contractures. Inflamm Res. 2012;61(4):285–92.CrossRefPubMedPubMedCentral
6.
Ortved K, Wagner B, Calcedo R, Wilson J, Schaefer D, Nixon A. Humoral and cell-mediated immune response, and growth factor synthesis after direct intraarticular injection of rAAV2-IGF-I and rAAV5-IGF-I in the equine middle carpal joint. Hum Gene Ther. 2015;26(3):161–71.CrossRefPubMedPubMedCentral
7.
Fukui N, Nakajima K, Tashiro T, Oda H, Nakamura K. Neutralization of fibroblast growth factor-2 reduces intraarticular adhesions. Clin Orthop Relat R. 2001;383:250–8.CrossRef
8.
Lee Y, Shao H, Wang J, Liu H, Hou S, Young T. Hyaluronic acid modulates gene expression of connective tissue growth factor (CTGF), transforming growth factor-β (TGF-β), and vascular endothelial growth factor (VEGF) in human fibroblast-like synovial cells from advanced-stage osteoarthritis in vitro. J Orthop Res. 2010;28(4):492–6.CrossRefPubMed
9.
Murakami S, Muneta T, Ezura Y, Furuya K, Yamamoto H. Quantitative analysis of synovial fibrosis in the infrapatellar fat pad before and after anterior cruciate ligament reconstruction. Am J Sport Med. 1997;25(1):29–34.CrossRef
10.
Zeichen J, Van Griensven M, Albers I, Lobenhoffer P, Bosch U. Immunohistochemical localization of collagen VI in arthrofibrosis. Arch Orthop Traum Su. 1999;119(5–6):315–8.CrossRef
11.
Watarai A, Schirmer L, Th O, Nes S, Freudenberg U, Werner C, Simon JC, et al. TGFβ functionalized starPEG-heparin hydrogels modulate human dermal fibroblast growth and differentiation. Acta Biomater. 2015;25:65–75.CrossRefPubMed
12.
13.
Jerosch J, Aldawoudy AM. Arthroscopic treatment of patients with moderate arthrofibrosis after total knee replacement. Knee Surg Sport Tr A. 2007;15(1):71–7.CrossRef
14.
Li X, Yan L, Wang J, Sun Y, Wang Q, Lu Z, et al. Comparison of the effects of mitomycin C and 10-hydroxycamptothecin on an experimental intraarticular adhesion model in rabbits. Eur J Pharmacol. 2013;703(1):42–5.PubMed
15.
Bal A, Eksioglu E, Gulec B, Aydog E, Gurcay E, Cakci A. Effectiveness of corticosteroid injection in adhesive capsulitis. Clin Rehabil. 2008;22(6):503–12.CrossRefPubMed
16.
Namazi H, Torabi S. Novel use of botulinum toxin to ameliorate arthrofibrosis: an experimental study in rabbits. Toxicol Pathol. 2007;35(5):715–8.CrossRefPubMed
17.
Olsen TW, Benegas NM, Joplin AC, Evangelista T, Mindrup EA, Holland EJ. Rapamycin inhibits corneal allograft rejection and neovascularization. Arch Ophthalmol. 1994;112(11):1471–5.CrossRefPubMed
18.
Chen H, Fong T, Hsu P, Chiu W. Multifaceted effects of rapamycin on functional recovery after spinal cord injury in rats through autophagy promotion, anti-inflammation, and neuroprotection. J Surg Res. 2013;179(1):e203–10.CrossRefPubMed
19.
Schachner T, Zou Y, Oberhuber A, Tzankov A, Mairinger T, Laufer GUN, et al. Local application of rapamycin inhibits neointimal hyperplasia in experimental vein grafts. Ann Thorac Surg. 2004;77(5):1580–5.CrossRefPubMed
20.
Zou J, Zhang X, Yang H, Zhu Y, Ma H, Wang S. Rapamycin-loaded nanoparticles for inhibition of neointimal hyperplasia in experimental vein grafts. J Cardiothorac Surg. 2011;6(1):69.CrossRefPubMedPubMedCentral
21.
Wang B, Ding W, Zhang M, Li H, Gu Y. Rapamycin attenuates aldosterone-induced tubulointerstitial inflammation and fibrosis. Cell Physiol Biochem. 2015;35(1):116–25.CrossRefPubMed
22.
Korfhagen TR, Le Cras TD, Davidson CR, Schmidt SM, Ikegami M, Whitsett JA, et al. Rapamycin prevents transforming growth factor-α--induced pulmonary fibrosis. Am J Resp Cell Mol. 2009;41(5):562–72.CrossRef
23.
Gao Y, Xu X, Ding K, Liang Y, Jiang D, Dai H. Rapamycin inhibits transforming growth factor β-induced fibrogenesis in primary human lung fibroblasts. Yonsei Med J. 2013;54(2):437–44.CrossRefPubMedPubMedCentral
24.
Tamaki Z, Asano Y, Kubo M, Ihn H, Tada Y, Sugaya M, et al. Effects of the immunosuppressant rapamycin on the expression of human α (I) collagen and matrix metalloproteinase 1 genes in scleroderma dermal fibroblasts. J Dermatol Sci. 2014;74(3):251–9.CrossRefPubMed
25.
26.
Milani BY, Milani FY, Park D, Namavari A, Shah J, Amirjamshidi H, et al. Rapamycin inhibits the production of myofibroblasts and reduces corneal scarring after photorefractive keratectomy. Invest Ophth Vis Sci. 2013;54(12):7424–30.CrossRef
27.
Yan L, Sun Y, Wang J, Dai S, Feng X, Jiang B, et al. The effect of mitomycin C in reducing intraarticular adhesion after knee surgery in rabbits. Eur J Pharmacol. 2010;643(1):1–5.CrossRefPubMed
28.
Rothkopf DM, Webb S, Szabo RM, Gelberman RH, May JW. An experimental model for the study of canine flexor tendon adhesions. J Hand Surg. 1991;16(4):694–700.CrossRef
29.
Woessner JF. The determination of hydroxyproline in tissue and protein samples containing small proportions of this imino acid. Arch Biochem Biophys. 1961;93(2):440–7.CrossRefPubMed
30.
Liang Y, Sun Y, Li X, Yan L, Wang J, Hu J, et al. The optimal concentration of topical hydroxycamptothecin in preventing intraarticular scar adhesion. Sci Rep. 2014;4:6405.CrossRefPubMedPubMedCentral
31.
Sun Y, Liang Y, Hu J, Wang J, Wang D, Li X, et al. Reduction of intraarticular adhesion by topical application of colchicine following knee surgery in rabbits. Sci Rep. 2014;4:6405.CrossRefPubMedPubMedCentral
32.
Fukui N, Fukuda A, Kojima K, Nakajima K, Oda H, Nakamura K. Suppression of fibrous adhesion by proteoglycan decorin. J Orthop Res. 2001;19(3):456–62.CrossRefPubMed
33.
Shelbourne KD, Patel DV, Martini DJ. Classification and management of arthrofibrosis of the knee after anterior cruciate ligament reconstruction. Am J Sport Med. 1996;24(6):857–62.CrossRef
34.
Cosgarea AJ, DeHaven KE, Lovelock JE. The surgical treatment of arthrofibrosis of the knee. Am J Sport Med. 1994;22(2):184–91.CrossRef
35.
Jingcheng W, Lianqi Y, Yu S, Daxin W, Shanhe D, Tangyun Y, et al. A comparative study of the preventive effects of mitomycin C and chitosan on intraarticular adhesion after knee surgery in rabbits. Cell Biochem Biophys. 2012;62(1):101–5.CrossRef
36.
Geissler EK, Schlitt HJ. The potential benefits of rapamycin on renal function, tolerance, fibrosis, and malignancy following transplantation. Kidney Int. 2010;78(11):1075–9.CrossRefPubMed
37.
Wu MJ, Wen MC, Chiu YT, Chiou YY, Shu KH, Tang M. Rapamycin attenuates unilateral ureteral obstruction-induced renal fibrosis. Kidney Int. 2006;69(11):2029–36.CrossRefPubMed
38.
Abdulrahman BA, Khweek AA, Akhter A, Caution K, Kotrange S, Abdelaziz DH, et al. Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis. Autophagy. 2011;7(11):1359–70.CrossRefPubMedPubMedCentral
39.
Kim YJ, Lee ES, Kim SH, Lee HY, Noh SM, Kang DY, et al. Inhibitory effects of rapamycin on the different stages of hepatic fibrosis. World J Gastroentero. 2014;20(23):7452.CrossRef
40.
Ong CT, Khoo YT, Mukhopadhyay A, Do DV, Lim IJ, Aalami O, et al. mTOR as a potential therapeutic target for treatment of keloids and excessive scars. Exp Dermatol. 2007;16(5):394–404.CrossRefPubMed
41.
Andreoli A, Ruf MT, Itin P, Pluschke G, Schmid P. Phosphorylation of the ribosomal protein S6, a marker of mTOR (mammalian target of rapamycin) pathway activation, is strongly increased in hypertrophic scars and keloids. Brit J Dermatol. 2015;172(5):1415–7.CrossRef
42.
Mitra A, Luna JI, Marusina AI, Merleev A, Kundu-Raychaudhuri S, Fiorentino D, et al. Dual mTOR inhibition is required to prevent TGF-β-mediated fibrosis: implications for scleroderma. J Invest Dermatol. 2015;135(11):2873–6.CrossRefPubMedPubMedCentral
43.
Poulalhon N, Farge D, Roos N, Tacheau C, Neuzillet C, Michel L, et al. Modulation of collagen and MMP-1 gene expression in fibroblasts by the immunosuppressive drug rapamycin. A direct role as an antifibrotic agent? J Biol Chem. 2006;281(44):33045–52.CrossRefPubMed
Metadata
Title
Reduction of intraarticular adhesion of knee by local application of rapamycin in rabbits via inhibition of fibroblast proliferation and collagen synthesis
Authors
Shuai Zhao
Yu Sun
Xiaolei Li
Jingcheng Wang
Lianqi Yan
Hui Chen
Daxin Wang
Jihang Dai
Jun He
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Orthopaedic Surgery and Research / Issue 1/2016
Electronic ISSN: 1749-799X
DOI
https://doi.org/10.1186/s13018-016-0375-0

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