Local intra‑articular injection of vascular endothelial growth factor accelerates articular cartilage degeneration in rat osteoarthritis model

Deng,Shuang; Zhou,Jian‑Lin; Peng,Hao; Fang,Hong‑Song; Liu,Feng; Weng,Jin‑Qing

doi:10.3892/mmr.2018.8652

Local intra‑articular injection of vascular endothelial growth factor accelerates articular cartilage degeneration in rat osteoarthritis model

Authors:
- Shuang Deng
- Jian‑Lin Zhou
- Hao Peng
- Hong‑Song Fang
- Feng Liu
- Jin‑Qing Weng
View Affiliations

Affiliations: Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
Published online on: February 28, 2018 https://doi.org/10.3892/mmr.2018.8652
Pages: 6311-6318
Copyright: © Deng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

In the pathophysiology of osteoarthritis (OA), articular cartilage degeneration exhibits a significant role. Vascular endothelial growth factor (VEGF) is considered to be an effective angiogenic factor and a crucial regulator of articular cartilage degeneration in the development of OA. Therefore, the present study aimed to investigate the underlying influences of exogenous VEGF on articular cartilage degeneration in OA model rat. A total of 24 male Sprague‑Dawley rats were randomly allocated into 3 groups. In the normal saline (NS) and VEGF groups, animals received bilateral anterior cruciate ligament (ACL) transection to establish the OA model; at 4 weeks post‑surgery, the rats received local intra‑articular injections of 100 µl NS or VEGF solution, respectively, every week for 4 weeks. The Control group received neither surgery nor injections. All animals were sacrificed at 12 weeks following surgery. Prominent cartilage degeneration was observed in rats in the NS‑ and VEGF‑injected groups. The extent and the grade of cartilage damage in the VEGF‑injected group were notably more severe compared with those in the NS‑treated group. Western blotting results demonstrated that the expression levels of aggrecan and type II collagen were significantly reduced in OA model rats that were treated with VEGF. In addition, the expression levels of matrix metalloproteinase (MMP)‑3, MMP‑9, MMP‑13, a disintegrin and metalloproteinase with thrombospondin motifs (a disintegrin and metalloproteinase; ADAMTS)‑4, ‑5 and ‑12, type III collagen and transforming growth factor‑β1 were significantly increased following VEGF administration. Results from the present study indicated that VEGF may exhibit a promoting role in the development of OA by destroying articular cartilage matrix.

View Figures

View References

1	Goldring MB: Anticytokine therapy for osteoarthritis. Expert Opin Biol Ther. 1:817–829. 2001. View Article : Google Scholar : PubMed/NCBI
2	Zhang LZ, Zheng HA, Jiang Y, Tu YH, Jiang PH and Yang AL: Mechanical and biologic link between cartilage and subchondral bone in osteoarthritis. Arthritis Care Res. 64:960–967. 2012. View Article : Google Scholar
3	Pufe T, Petersen W, Tillmann B and Mentlein R: The splice variants VEGF121 and VEGF189 of the angiogenic peptide vascular endothelial growth factor are expressed in osteoarthritic cartilage. Arthritis Rheum. 44:1082–1088. 2001. View Article : Google Scholar : PubMed/NCBI
4	Horner A, Bord S, Kelsall AW, Coleman N and Compston JE: Tie2 ligands angiopoietin-1 and angiopoietin-2 are coexpressed with vascular endothelial cell growth factor in growing human bone. Bone. 28:65–71. 2001. View Article : Google Scholar : PubMed/NCBI
5	Pfander D, Kortje D, Zimmermann R, Weseloh G, Kirsch T, Gesslein M, Cramer T and Swoboda B: Vascular endothelial growth factor in articular cartilage of healthy and osteoarthritic human knee joints. Ann Rheum Dis. 60:1070–1073. 2001. View Article : Google Scholar : PubMed/NCBI
6	Inoue K, Masuko-Hongo K, Okamoto M and Nishioka K: Induction of vascular endothelial growth factor and matrix metalloproteinase-3 (stromelysin) by interleukin-1 in human articular chondrocytes and synoviocytes. Rheum Int. 26:93–98. 2005. View Article : Google Scholar
7	Kim WU, Kang SS, Yoo SA, Hong KH, Bae DG, Lee MS, Hong SW, Chae CB and Cho CS: Interaction of vascular endothelial growth factor 165 with neuropilin-1 protects rheumatoid synoviocytes from apoptotic death by regulating Bcl-2 expression and Bax translocation. J Immunol. 177:5727–5735. 2006. View Article : Google Scholar : PubMed/NCBI
8	Gerber HP, Vu TH, Ryan AM, Kowalski J, Werb Z and Ferrara N: VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med. 5:623–628. 1999. View Article : Google Scholar : PubMed/NCBI
9	Pufe T, Harde V, Petersen W, Goldring MB, Tillmann B and Mentlein R: Vascular endothelial growth factor (VEGF) induces matrix metalloproteinase expression in immortalized chondrocytes. J Pathol. 202:367–374. 2004. View Article : Google Scholar : PubMed/NCBI
10	Enomoto H, Inoki I, Komiya K, Shiomi T, Ikeda E, Obata K, Matsumoto H, Toyama Y and Okada Y: Vascular endothelial growth factor isoforms and their receptors are expressed in human osteoarthritic cartilage. Am J Pathol. 162:171–181. 2003. View Article : Google Scholar : PubMed/NCBI
11	Ludin A, Sela JJ, Schroeder A, Samuni Y, Nitzan DW and Amir G: Injection of vascular endothelial growth factor into knee joints induces osteoarthritis in mice. Osteoarthritis Cartilage. 21:491–497. 2013. View Article : Google Scholar : PubMed/NCBI
12	Zhou JL, Liu SQ, Qiu B, Hu QJ, Ming JH and Peng H: Effects of hyaluronan on vascular endothelial growth factor and receptor-2 expression in a rabbit osteoarthritis model. J Orthop Sci. 14:313–319. 2009. View Article : Google Scholar : PubMed/NCBI
13	Li Y, Zhang Y, Chen C, Zhang H, Ma C and Xia Y: Establishment of a rabbit model to study the influence of advanced glycation end products accumulation on osteoarthritis and the protective effect of pioglitazone. Osteoarthritis Cartilage. 24:307–314. 2016. View Article : Google Scholar : PubMed/NCBI
14	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
15	Ko JY, Lee MS, Lian WS, Weng WT, Sun YC, Chen YS and Wang FS: MicroRNA-29a counteracts synovitis in knee osteoarthritis pathogenesis by targeting VEGF. Sci Rep. 7:35842017. View Article : Google Scholar : PubMed/NCBI
16	Wimsey S, Lien CF, Sharma S, Brennan PA, Roach HI, Harper GD and Górecki DC: Changes in immunolocalisation of beta-dystroglycan and specific degradative enzymes in the osteoarthritic synovium. Osteoarthritis Cartilage. 14:1181–1188. 2006. View Article : Google Scholar : PubMed/NCBI
17	Yik JH, Hu Z, Kumari R, Christiansen BA and Haudenschild DR: Cyclin-dependent kinase 9 inhibition protects cartilage from the catabolic effects of proinflammatory cytokines. Arthritis Rheumatol. 66:1537–1546. 2014. View Article : Google Scholar : PubMed/NCBI
18	Tsarouhas A, Soufla G, Katonis P, Pasku D, Vakis A and Spandidos DA: Transcript levels of major MMPs and ADAMTS-4 in relation to the clinicopathological profile of patients with lumbar disc herniation. Eur Spine. 20:781–790. 2011. View Article : Google Scholar
19	Yu J, Liang F, Huang H, Pirttiniemi P and Yu D: Effects of loading on chondrocyte hypoxia, HIF-1α and VEGF in the mandibular condylar cartilage of young rats. Orthod Craniofac Res. 2017.(Epub ahead of print).
20	Fay J, Varoga D, Wruck CJ, Kurz B, Goldring MB and Pufe T: Reactive oxygen species induce expression of vascular endothelial growth factor in chondrocytes and human articular cartilage explants. Arthritis Res Ther. 8:R1892006. View Article : Google Scholar : PubMed/NCBI
21	Lingaraj K, Poh CK and Wang W: Vascular endothelial growth factor (VEGF) is expressed during articular cartilage growth and re-expressed in osteoarthritis. Ann Acad Med. 39:399–403. 2010.
22	Nagai T, Sato M, Kobayashi M, Yokoyama M, Tani Y and Mochida J: Bevacizumab, an anti-vascular endothelial growth factor antibody, inhibits osteoarthritis. Arthritis Res Ther. 16:4272014. View Article : Google Scholar : PubMed/NCBI
23	Neve A, Cantatore FP, Corrado A, Gaudio A, Ruggieri S and Ribatti D: In vitro and in vivo angiogenic activity of osteoarthritic and osteoporotic osteoblasts is modulated by VEGF and vitamin D3 treatment. Regul Pept. 184:81–84. 2013. View Article : Google Scholar : PubMed/NCBI
24	Chen XY, Hao YR, Wang Z, Zhou JL, Jia QX and Qiu B: The effect of vascular endothelial growth factor on aggrecan and type II collagen expression in rat articular chondrocytes. Rheumatol Int. 32:3359–3364. 2012. View Article : Google Scholar : PubMed/NCBI
25	Jian-lin Z, Hong-song F, Hao P, Shuang D, Shen C, Jian-ping L, Bo Q, Jin-qing W and Feng L: The relationship between HIF-2α and VEGF with radiographic severity in the primary osteoarthritic knee. Yonsei Med J. 57:735–740. 2016. View Article : Google Scholar : PubMed/NCBI
26	Jackson JR, Minton JA, Ho ML, Wei N and Winkler JD: Expression of vascular endothelial growth factor in synovial fibroblasts is induced by hypoxia and interleukin 1beta. J Rheumatol. 24:1253–1259. 1997.PubMed/NCBI
27	Harada S, Nagy JA, Sullivan KA, Thomas KA, Endo N, Rodan GA and Rodan SB: Induction of vascular endothelial growth factor expression by prostaglandin E2 and E1 in osteoblasts. J Clin Invest. 93:2490–2496. 1994. View Article : Google Scholar : PubMed/NCBI
28	Distler JH, Wenger RH, Gassmann M, Kurowska M, Hirth A, Gay S and Distler O: Physiologic responses to hypoxia and implications for hypoxia-inducible factors in the pathogenesis of rheumatoid arthritis. Arthritis Rheum. 50:10–23. 2004. View Article : Google Scholar : PubMed/NCBI
29	Van der Rest M and Garrone R: Collagen family of proteins. FASEB J. 5:2814–2823. 1991. View Article : Google Scholar : PubMed/NCBI
30	Hardingham T: Proteoglycans: Their structure, interactions and molecular organization in cartilage. Biochem Soc Trans. 9:489–497. 1981. View Article : Google Scholar : PubMed/NCBI
31	Honorati MC, Cattini L and Facchini A: VEGF production by osteoarthritic chondrocytes cultured in micromass and stimulated by IL-17 and TNF-alpha. Connect Tissue Res. 48:239–245. 2007. View Article : Google Scholar : PubMed/NCBI
32	Shen P, Jiao Z, Zheng JS, Xu WF, Zhang SY, Qin A and Yang C: Injecting vascular endothelial growth factor into the temporomandibular joint induces osteoarthritis in mice. Sci Rep. 5:162442015. View Article : Google Scholar : PubMed/NCBI
33	Rose BJ and Kooyman DL: A tale of two joints: The role of matrix metalloproteases in cartilage biology. Dis Markers. 2016:48950502016. View Article : Google Scholar : PubMed/NCBI
34	Oh JS, Youm YS, Cho SD, Choi SW and Cho YJ: The expression of vascular endothelial growth factor and Syndecan-4 in cartilage from osteoarthritic knees. Bone Joint J. 96-B:1319–1324. 2014. View Article : Google Scholar : PubMed/NCBI