Skip to main content
Top
Published in: Arthritis Research & Therapy 5/2010

Open Access 01-10-2010 | Research article

Intravenous administration of anti-vascular endothelial growth factor humanized monoclonal antibody bevacizumab improves articular cartilage repair

Authors: Toshihiro Nagai, Masato Sato, Toshiharu Kutsuna, Mami Kokubo, Goro Ebihara, Naoshi Ohta, Joji Mochida

Published in: Arthritis Research & Therapy | Issue 5/2010

Login to get access

Abstract

Introduction

In this study, we investigate the efficacy of repairing an osteochondral defect in rabbit knee joints by administering bevacizumab, a humanized monoclonal anti-vascular endothelial growth factor (VEGF) antibody.

Methods

An osteochondral defect was created on the patellar groove of 20 Japanese white rabbits that were classified into two recipient groups: group B, administration of bevacizumab (100-mg intravenous injection on the day of surgery and 2 weeks later), and a control group (defect only). Rabbits were killed 1 and 3 months postoperatively. Sections were stained with safranin O. Repair sites were evaluated using the modified O'Driscoll International Cartilage Repair Society grading system. The expression of chondromodulin (ChM)-I and VEGF was evaluated using immunohistochemical analyses.

Results

At 1 month postoperatively, the repair site in group B was filled with cartilaginous tissue. At 3 months, the repair site retained this cartilage phenotype. At 1 month in the controls, the defects were mainly filled with fibrous tissue. At 3 months, the defect was replaced by fibrous tissue and bone. Over the 3-month period, histological scores were significantly higher in group B than in the controls. At 1 month, group B showed intense positive results for ChM-I in the bottom of the repair tissue. VEGF was also identified in the same area. In the controls, no ChM-I was observed in the repair tissue. Conversely, the remodeling hypertrophic chondrocyte layer stained intensely for VEGF.

Conclusions

Intravenous administration of bevacizumab contributes to better repair of articular cartilage in an osteochondral defect model. We suggest the possibility of facilitating articular cartilage repair with anti-VEGF antibody rather than using cultured cells or artificial scaffolds.
Appendix
Available only for authorised users
Literature
1.
go back to reference Paget J: Healing of cartilage. Clin Orthop Relat Res. 1969, 64: 7-8. Paget J: Healing of cartilage. Clin Orthop Relat Res. 1969, 64: 7-8.
2.
go back to reference Pridie KH: A method of resurfacing osteoarthritic knee joints. J Bone Joint Surg Br. 1959, 41: 618-619. Pridie KH: A method of resurfacing osteoarthritic knee joints. J Bone Joint Surg Br. 1959, 41: 618-619.
3.
go back to reference Muller B, Kohn D: Indication for and performance of articular cartilage drilling using the Pridie method. Orthopade. 1999, 28: 4-10. Muller B, Kohn D: Indication for and performance of articular cartilage drilling using the Pridie method. Orthopade. 1999, 28: 4-10.
4.
go back to reference Insall JN: Intra-articular surgery for degenerative arthritis of the knee. A report of the work of the late K. H. Pridie. J Bone Joint Surg Br. 1967, 49: 211-228. Insall JN: Intra-articular surgery for degenerative arthritis of the knee. A report of the work of the late K. H. Pridie. J Bone Joint Surg Br. 1967, 49: 211-228.
5.
go back to reference Insall J: The Pridie debridement operation for osteoarthritis of the knee. Clin Orthop. 1974, 101: 61-67. Insall J: The Pridie debridement operation for osteoarthritis of the knee. Clin Orthop. 1974, 101: 61-67.
6.
go back to reference Steadman J, Rodkey W, Briggs K, Rodrigo J: The microfracture technique in the management of complete cartilage defects in the knee joint. Orthopade. 1999, 28: 26-32. Steadman J, Rodkey W, Briggs K, Rodrigo J: The microfracture technique in the management of complete cartilage defects in the knee joint. Orthopade. 1999, 28: 26-32.
7.
go back to reference Steadman J, Rodkey W, Rodrigo J: Microfracture: surgical technique and rehabilitation to treat chondral defects. Clin Orthop Relat Res. 2001, S362-S369. 391 Suppl Steadman J, Rodkey W, Rodrigo J: Microfracture: surgical technique and rehabilitation to treat chondral defects. Clin Orthop Relat Res. 2001, S362-S369. 391 Suppl
8.
go back to reference Steadman J, Rodkey W, Briggs K: Microfracture to treat full-thickness chondral defects: surgical technique, rehabilitation, and outcomes. J Knee Surg. 2002, 15: 170-176. Steadman J, Rodkey W, Briggs K: Microfracture to treat full-thickness chondral defects: surgical technique, rehabilitation, and outcomes. J Knee Surg. 2002, 15: 170-176.
9.
go back to reference Mithoefer K, Williams RJ, Warren RF, Potter HG, Spock CR, Jones EC, Wickiewicz TL, Marx RG: Chondral resurfacing of articular cartilage defects in the knee with the microfracture technique: surgical technique. J Bone Joint Surg Am. 2006, 88: 294-304. 10.2106/JBJS.F.00292.CrossRef Mithoefer K, Williams RJ, Warren RF, Potter HG, Spock CR, Jones EC, Wickiewicz TL, Marx RG: Chondral resurfacing of articular cartilage defects in the knee with the microfracture technique: surgical technique. J Bone Joint Surg Am. 2006, 88: 294-304. 10.2106/JBJS.F.00292.CrossRef
10.
go back to reference Hangody L, Kish G, Karpati Z, Udvarhelyi I, Szerb I, Bely M: Autogenous osteochondral graft technique for replacing knee cartilage defects in dogs. Orthopedics. 1997, 5: 175-181. Hangody L, Kish G, Karpati Z, Udvarhelyi I, Szerb I, Bely M: Autogenous osteochondral graft technique for replacing knee cartilage defects in dogs. Orthopedics. 1997, 5: 175-181.
11.
go back to reference Hangody L, Feczko P, Bartha L, Bodo G, Kish G: Mosaicplasty for the treatment of articular defects of the knee and ankle. Clin Orthop Relat Res. 2001, S328-S336. 391 Suppl Hangody L, Feczko P, Bartha L, Bodo G, Kish G: Mosaicplasty for the treatment of articular defects of the knee and ankle. Clin Orthop Relat Res. 2001, S328-S336. 391 Suppl
12.
go back to reference Szerb I, Hangody L, Duska Z, Kaposi NP: Mosaicplasty: long-term follow-up. Bull Hosp Jt Dis. 2005, 63: 54-62. Szerb I, Hangody L, Duska Z, Kaposi NP: Mosaicplasty: long-term follow-up. Bull Hosp Jt Dis. 2005, 63: 54-62.
13.
go back to reference Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L: Treatment of deep cartilage defects knee with autologus chondrocyte transplantation. N Engl J Med. 1994, 331: 889-895. 10.1056/NEJM199410063311401.CrossRef Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L: Treatment of deep cartilage defects knee with autologus chondrocyte transplantation. N Engl J Med. 1994, 331: 889-895. 10.1056/NEJM199410063311401.CrossRef
14.
go back to reference Peterson L, Minas T, Brittberg M, Lindahl A: Treatment of osteochondritis dissecans of the knee with autologouschondrocyte transplantation: results at two to ten years. J Bone Joint Surg Am. 2003, 85-A Suppl 2: 17-24. Peterson L, Minas T, Brittberg M, Lindahl A: Treatment of osteochondritis dissecans of the knee with autologouschondrocyte transplantation: results at two to ten years. J Bone Joint Surg Am. 2003, 85-A Suppl 2: 17-24.
15.
go back to reference Zaslav K, Cole B, Brewster R, DeBerardino T, Farr J, Fowler P, Nissen C, STAR Study Principal Investigators: A prospective study of autologous chondrocyte implantation in patients with failed prior treatment for articular cartilage defects of the knee: results of the Study of the Treatment of Articular Repair (STAR) clinical trial. Am J Sports Med. 2009, 37: 42-55. 10.1177/0363546508322897.CrossRef Zaslav K, Cole B, Brewster R, DeBerardino T, Farr J, Fowler P, Nissen C, STAR Study Principal Investigators: A prospective study of autologous chondrocyte implantation in patients with failed prior treatment for articular cartilage defects of the knee: results of the Study of the Treatment of Articular Repair (STAR) clinical trial. Am J Sports Med. 2009, 37: 42-55. 10.1177/0363546508322897.CrossRef
16.
go back to reference Moseley JB, Anderson AF, Browne JE, Mandelbaum BR, Micheli LJ, Fu F, Erggelet C: Long-term durability of autologus chondrocyte implantation: a multicenter, observational study in US patients. Am J Sports Med. 2010, 38: 238-46. 10.1177/0363546509348000.CrossRef Moseley JB, Anderson AF, Browne JE, Mandelbaum BR, Micheli LJ, Fu F, Erggelet C: Long-term durability of autologus chondrocyte implantation: a multicenter, observational study in US patients. Am J Sports Med. 2010, 38: 238-46. 10.1177/0363546509348000.CrossRef
17.
go back to reference Darling EM, Athanasiou KA: Articular cartilage bioreactor and bioprocess. Tissue Eng. 2003, 9: 9-26. 10.1089/107632703762687492.CrossRef Darling EM, Athanasiou KA: Articular cartilage bioreactor and bioprocess. Tissue Eng. 2003, 9: 9-26. 10.1089/107632703762687492.CrossRef
18.
go back to reference Backwalter JA, Lohmander S: Operative treatment of osteoarthrosis. Current practice and future development. J Bone Joint Surg Am. 1994, 76: 1405-1418. Backwalter JA, Lohmander S: Operative treatment of osteoarthrosis. Current practice and future development. J Bone Joint Surg Am. 1994, 76: 1405-1418.
19.
go back to reference Freed LE, Grande DA, Lingbin Z, Emmanual J, Marquis JC, Langer R: Joint resurfacing using allograft chondrocytes and synthetic biodegradable polymer scaffolds. J Biomed Mater Res. 1994, 28: 891-899. 10.1002/jbm.820280808.CrossRef Freed LE, Grande DA, Lingbin Z, Emmanual J, Marquis JC, Langer R: Joint resurfacing using allograft chondrocytes and synthetic biodegradable polymer scaffolds. J Biomed Mater Res. 1994, 28: 891-899. 10.1002/jbm.820280808.CrossRef
20.
go back to reference Hunziker EB: Articular cartilage repair: basic science and clinical progress. A review of the current status and prospects. Osteoarthritis Cartilage. 2002, 10: 432-463. 10.1053/joca.2002.0801.CrossRef Hunziker EB: Articular cartilage repair: basic science and clinical progress. A review of the current status and prospects. Osteoarthritis Cartilage. 2002, 10: 432-463. 10.1053/joca.2002.0801.CrossRef
21.
go back to reference Marcacci M, Berruto M, Brocchetta D, Delcogliano A, Ghinelli D, Gobbi A, Kon E, Pederzini L, Rosa D, Sacchetti GL, Stefani G, Zanasi S: Articular cartilage engineeiring with Hyalograft C: 3-year clinical results. Clin Orthop Relat Res. 2005, 435: 96-105. 10.1097/01.blo.0000165737.87628.5b.CrossRef Marcacci M, Berruto M, Brocchetta D, Delcogliano A, Ghinelli D, Gobbi A, Kon E, Pederzini L, Rosa D, Sacchetti GL, Stefani G, Zanasi S: Articular cartilage engineeiring with Hyalograft C: 3-year clinical results. Clin Orthop Relat Res. 2005, 435: 96-105. 10.1097/01.blo.0000165737.87628.5b.CrossRef
22.
go back to reference Crawford DC, Heveran CM, Cannon WD, Foo LF, Potter HG: An autologus cartilage tissue implant NeoCart for treatment of grade III chondral injury to the distal femur: prospective clinical safety trial at 2 years. Am J Sports Med. 2009, 37: 1334-1343. 10.1177/0363546509333011.CrossRef Crawford DC, Heveran CM, Cannon WD, Foo LF, Potter HG: An autologus cartilage tissue implant NeoCart for treatment of grade III chondral injury to the distal femur: prospective clinical safety trial at 2 years. Am J Sports Med. 2009, 37: 1334-1343. 10.1177/0363546509333011.CrossRef
23.
go back to reference Nagai T, Sato M, Furukawa KS, Kutsuna T, Ohta N, Ushida T, Mochida J: Optimization of allograft implantation using scaffold-free chondrocyte plates. Tissue Eng Part A. 2008, 14: 1225-1235. 10.1089/ten.tea.2007.0225.CrossRef Nagai T, Sato M, Furukawa KS, Kutsuna T, Ohta N, Ushida T, Mochida J: Optimization of allograft implantation using scaffold-free chondrocyte plates. Tissue Eng Part A. 2008, 14: 1225-1235. 10.1089/ten.tea.2007.0225.CrossRef
24.
go back to reference Nagai T, Furukawa KS, Sato M, Ushida T, Mochida J: Characteristics of a scaffold-free articular chondrocyte plate grown in rotational culture. Tissue Eng Part A. 2008, 14: 1183-1193. 10.1089/ten.tea.2007.0114.CrossRef Nagai T, Furukawa KS, Sato M, Ushida T, Mochida J: Characteristics of a scaffold-free articular chondrocyte plate grown in rotational culture. Tissue Eng Part A. 2008, 14: 1183-1193. 10.1089/ten.tea.2007.0114.CrossRef
25.
go back to reference Mainil-Varlet P, Rieser F, Grogan S, Mueller W, Saager C, Jakob RP: Articular cartilage repair using a tissue-engineered cartilage-like implant: an animal study. Osteoarthritis Cartilage. 2001, 9 Suppl A: S6-S15. 10.1053/joca.2001.0438.CrossRef Mainil-Varlet P, Rieser F, Grogan S, Mueller W, Saager C, Jakob RP: Articular cartilage repair using a tissue-engineered cartilage-like implant: an animal study. Osteoarthritis Cartilage. 2001, 9 Suppl A: S6-S15. 10.1053/joca.2001.0438.CrossRef
26.
go back to reference Brehm W, Aklin B, Yamashita T, Rieser F, Trub T, Jakob RP, Mainil-Varlet P: Repair of superficial osteochondral defects with an autologous scaffold-free cartilage construct in a caprine model: implantation method and short-term results. Osteoarthritis Cartilage. 2006, 14: 1214-1226. 10.1016/j.joca.2006.05.002.CrossRef Brehm W, Aklin B, Yamashita T, Rieser F, Trub T, Jakob RP, Mainil-Varlet P: Repair of superficial osteochondral defects with an autologous scaffold-free cartilage construct in a caprine model: implantation method and short-term results. Osteoarthritis Cartilage. 2006, 14: 1214-1226. 10.1016/j.joca.2006.05.002.CrossRef
27.
go back to reference Park K, Huang J, Azar F, Jin RL, Min BH, Han DK, Hasty K: Scaffold-free, engineered porcine cartilage construct for cartilage defect repair: in vitro and in vivo study. Artif Organs. 2006, 30: 586-596. 10.1111/j.1525-1594.2006.00267.x.CrossRef Park K, Huang J, Azar F, Jin RL, Min BH, Han DK, Hasty K: Scaffold-free, engineered porcine cartilage construct for cartilage defect repair: in vitro and in vivo study. Artif Organs. 2006, 30: 586-596. 10.1111/j.1525-1594.2006.00267.x.CrossRef
28.
go back to reference Caplan AI, Elyaderani M, Mochizuki Y, Wakitani S, Goldberg VM: Principles of cartilage repair and regeneration. Clin Orthop Relat Res. 1997, 342: 254-272. 10.1097/00003086-199709000-00033.CrossRef Caplan AI, Elyaderani M, Mochizuki Y, Wakitani S, Goldberg VM: Principles of cartilage repair and regeneration. Clin Orthop Relat Res. 1997, 342: 254-272. 10.1097/00003086-199709000-00033.CrossRef
29.
go back to reference Nagai T, Sato M, Furukawa KS, Kutsuna T, Ohta N, Ushida T, Mochida J: Repair of total thickness defect of articular cartilage with scaffold-free chondrocyte plate. Proceedings of 55th Annual Meeting, Orthopaedic Research Society, 22-25 February. 2009, Las Vegas, NV, USA Nagai T, Sato M, Furukawa KS, Kutsuna T, Ohta N, Ushida T, Mochida J: Repair of total thickness defect of articular cartilage with scaffold-free chondrocyte plate. Proceedings of 55th Annual Meeting, Orthopaedic Research Society, 22-25 February. 2009, Las Vegas, NV, USA
30.
go back to reference Herbert H, Louis F, William N, Thomas C, John H, William H, Jordan B, Ari B, Susan G, Eric H, Napoleone F, Gwen F, Beth R, Robert R, Fairooz K: Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for metastatic colorectal cancer. N Engl J Med. 2004, 350: 2335-2342. 10.1056/NEJMoa032691.CrossRef Herbert H, Louis F, William N, Thomas C, John H, William H, Jordan B, Ari B, Susan G, Eric H, Napoleone F, Gwen F, Beth R, Robert R, Fairooz K: Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for metastatic colorectal cancer. N Engl J Med. 2004, 350: 2335-2342. 10.1056/NEJMoa032691.CrossRef
31.
go back to reference Jain RK: Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001, 7: 987-989. 10.1038/nm0901-987.CrossRef Jain RK: Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001, 7: 987-989. 10.1038/nm0901-987.CrossRef
32.
go back to reference Willet CG, Boucher Y, Di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV, Mino M, Cohen KS, Scadden DT, Hartford AC, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Chen HX, Shellito PC, Lauwers GY, Jain RK: Direct evidence the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004, 10: 145-147. 10.1038/nm988.CrossRef Willet CG, Boucher Y, Di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV, Mino M, Cohen KS, Scadden DT, Hartford AC, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Chen HX, Shellito PC, Lauwers GY, Jain RK: Direct evidence the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004, 10: 145-147. 10.1038/nm988.CrossRef
33.
go back to reference Hayami T, Funaki H, Yaoeda K, Mitui K, Yamagiwa H, Tokunaga K, Hatano H, Kondo J, Hiraki Y, Yamamoto T, Duong le T, Endo N: Expression of the cartilage derived anti-angiogenic factor chondromodulin-I decreases in the early stage of experimental osteoarthritis. J Rheumatol. 2003, 30: 2207-2217. Hayami T, Funaki H, Yaoeda K, Mitui K, Yamagiwa H, Tokunaga K, Hatano H, Kondo J, Hiraki Y, Yamamoto T, Duong le T, Endo N: Expression of the cartilage derived anti-angiogenic factor chondromodulin-I decreases in the early stage of experimental osteoarthritis. J Rheumatol. 2003, 30: 2207-2217.
34.
go back to reference O'Driscoll SW, Keeley FW, Salter RB: Durability of regenerated articular cartilage produced by free autogenous periosteal grafts in major full-thickness defects in joint surfaces under the influence of continuous passive motion: a follow-up report at one year. J Bone Joint Surg Am. 1998, 70: 595-606. O'Driscoll SW, Keeley FW, Salter RB: Durability of regenerated articular cartilage produced by free autogenous periosteal grafts in major full-thickness defects in joint surfaces under the influence of continuous passive motion: a follow-up report at one year. J Bone Joint Surg Am. 1998, 70: 595-606.
35.
go back to reference Eskens FA: Angiogenesis inhibitors in clinical development. Br J Cancer. 2004, 90: 1-7. 10.1038/sj.bjc.6601401.CrossRef Eskens FA: Angiogenesis inhibitors in clinical development. Br J Cancer. 2004, 90: 1-7. 10.1038/sj.bjc.6601401.CrossRef
36.
go back to reference Branavan S, Lorraine EH, Ewa MP: Modulation angiogenesis. JAMA. 2004, 292: 972-977. 10.1001/jama.292.8.972.CrossRef Branavan S, Lorraine EH, Ewa MP: Modulation angiogenesis. JAMA. 2004, 292: 972-977. 10.1001/jama.292.8.972.CrossRef
37.
go back to reference Solchaga LA, Yoo JU, Lundberg M, Dennis JE, Huibregtse BA, Goldberg VM, Caplan AI: Hyaluronan-based polymers in the treatment of osteochondral defects. J Orthop Res. 2000, 18: 773-780. 10.1002/jor.1100180515.CrossRef Solchaga LA, Yoo JU, Lundberg M, Dennis JE, Huibregtse BA, Goldberg VM, Caplan AI: Hyaluronan-based polymers in the treatment of osteochondral defects. J Orthop Res. 2000, 18: 773-780. 10.1002/jor.1100180515.CrossRef
38.
go back to reference Shapiro F, Koide S, Glimcher MJ: Cell origin and differentiation in the repair of full-thickness defects of articular cartilage. J Bone Joint Surg Am. 1993, 75: 532-553. Shapiro F, Koide S, Glimcher MJ: Cell origin and differentiation in the repair of full-thickness defects of articular cartilage. J Bone Joint Surg Am. 1993, 75: 532-553.
39.
go back to reference Kubo S, Cooper GM, Matsumoto T, Phillippi JA, Corsi KA, Usas A, Li G, Fu FH, Huard J: Blocking vascular endothelial growth factor with soluble Flt-1 improves the chondrogenic potential of mouse skeletal muscle-derived stem cells. Arthritis Rheum. 2009, 60: 155-165. 10.1002/art.24153.CrossRef Kubo S, Cooper GM, Matsumoto T, Phillippi JA, Corsi KA, Usas A, Li G, Fu FH, Huard J: Blocking vascular endothelial growth factor with soluble Flt-1 improves the chondrogenic potential of mouse skeletal muscle-derived stem cells. Arthritis Rheum. 2009, 60: 155-165. 10.1002/art.24153.CrossRef
40.
go back to reference Hashimoto S, Ochs RL, Komiya S, Lotz M: Linkage of chondrocyte apoptosis and cartilage degradation in human osteoarthritis. Arthritis Rheum. 1998, 41: 1632-1638. 10.1002/1529-0131(199809)41:9<1632::AID-ART14>3.0.CO;2-A.CrossRef Hashimoto S, Ochs RL, Komiya S, Lotz M: Linkage of chondrocyte apoptosis and cartilage degradation in human osteoarthritis. Arthritis Rheum. 1998, 41: 1632-1638. 10.1002/1529-0131(199809)41:9<1632::AID-ART14>3.0.CO;2-A.CrossRef
41.
go back to reference Hashimoto S, Creighton-Achermann L, Takahashi K, Amiel D, Coutts RD, Lotz M: Development and regulation of osteophyte formation during experimental osteoarthritis. Osteoarthritis Cartilage. 2002, 10: 180-187. 10.1053/joca.2001.0505.CrossRef Hashimoto S, Creighton-Achermann L, Takahashi K, Amiel D, Coutts RD, Lotz M: Development and regulation of osteophyte formation during experimental osteoarthritis. Osteoarthritis Cartilage. 2002, 10: 180-187. 10.1053/joca.2001.0505.CrossRef
42.
go back to reference Enomoto H, Inoki I, Komiya K, Shiomi T, Ikeda E, Obata K, Matsumoto H, Toyama Y, Okada Y: Vascular endothelial growth factor isoforms and their receptors are expressed in human osteoarthritic cartilage. Am J Pathol. 2003, 162: 171-181.CrossRef Enomoto H, Inoki I, Komiya K, Shiomi T, Ikeda E, Obata K, Matsumoto H, Toyama Y, Okada Y: Vascular endothelial growth factor isoforms and their receptors are expressed in human osteoarthritic cartilage. Am J Pathol. 2003, 162: 171-181.CrossRef
43.
go back to reference Tanaka E, Aoyama J, Miyauchi M, Takata T, Hanaoka K, Iwabe T, Tanne K: Vascular endothelial growth factor plays an important autocrine/paracrine role in the progression of osteoarthritis. Histochem Cell Biol. 2005, 123: 275-281. 10.1007/s00418-005-0773-6.CrossRef Tanaka E, Aoyama J, Miyauchi M, Takata T, Hanaoka K, Iwabe T, Tanne K: Vascular endothelial growth factor plays an important autocrine/paracrine role in the progression of osteoarthritis. Histochem Cell Biol. 2005, 123: 275-281. 10.1007/s00418-005-0773-6.CrossRef
44.
go back to reference Pufe T, Petersen W, Tillmann B, Mentlein R: The splice variants VEGF121 and VEGF189 of the angiogenic peptide vascular endothelial growth factor are expressed in osteoarthritic cartilage. Arthritis Rheum. 2001, 44: 1082-1088. 10.1002/1529-0131(200105)44:5<1082::AID-ANR188>3.0.CO;2-X.CrossRef Pufe T, Petersen W, Tillmann B, Mentlein R: The splice variants VEGF121 and VEGF189 of the angiogenic peptide vascular endothelial growth factor are expressed in osteoarthritic cartilage. Arthritis Rheum. 2001, 44: 1082-1088. 10.1002/1529-0131(200105)44:5<1082::AID-ANR188>3.0.CO;2-X.CrossRef
45.
go back to reference Pufe T, Harde V, Petersen W, Goldring MB, Tillmann B, Mentlein R: Vascular endothelial growth factor (VEGF) induces matrix metalloproteinase expression in immortalized chondrocytes. J Pathol. 2004, 202: 367-374. 10.1002/path.1527.CrossRef Pufe T, Harde V, Petersen W, Goldring MB, Tillmann B, Mentlein R: Vascular endothelial growth factor (VEGF) induces matrix metalloproteinase expression in immortalized chondrocytes. J Pathol. 2004, 202: 367-374. 10.1002/path.1527.CrossRef
46.
go back to reference Pufe T, Lemke A, Kurz B, Petersen W, Tillmann B, Grodzinsky AJ, Mentlein R: Mechanical overload induces VEGF in cartilage discs via hypoxia-inducible factor. Am J Pathol. 2004, 164: 185-192.CrossRef Pufe T, Lemke A, Kurz B, Petersen W, Tillmann B, Grodzinsky AJ, Mentlein R: Mechanical overload induces VEGF in cartilage discs via hypoxia-inducible factor. Am J Pathol. 2004, 164: 185-192.CrossRef
47.
go back to reference Murakami M, Iwai S, Hiratsuka S, Yamauchi M, Nakamura K, Iwakura Y, Shibuya M: Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocytes/macrophages. Blood. 2006, 108: 1849-1856. 10.1182/blood-2006-04-016030.CrossRef Murakami M, Iwai S, Hiratsuka S, Yamauchi M, Nakamura K, Iwakura Y, Shibuya M: Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocytes/macrophages. Blood. 2006, 108: 1849-1856. 10.1182/blood-2006-04-016030.CrossRef
48.
go back to reference Afuwape AO, Kiriakidis S, Paleolog EM: The role of the angiogenic molecule VEGF in the pathogenesis of rheumatoid arthritis. Histol Histopathol. 2002, 17: 961-972. Afuwape AO, Kiriakidis S, Paleolog EM: The role of the angiogenic molecule VEGF in the pathogenesis of rheumatoid arthritis. Histol Histopathol. 2002, 17: 961-972.
49.
go back to reference Gerber HP, Vu TH, Ryan AM, Kowalski J, Werb Z, Ferrara N: VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med. 1999, 5: 623-628. 10.1038/9467.CrossRef Gerber HP, Vu TH, Ryan AM, Kowalski J, Werb Z, Ferrara N: VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med. 1999, 5: 623-628. 10.1038/9467.CrossRef
50.
go back to reference Carlevaro MF, Cermelli S, Cancedda R, Descalzi Cancedda F: Vascular endothelial growth factor (VEGF) in cartilage neovascularization and chondrocyte differentiation: auto-paracrine role during endochondral bone formation. J Cell Sci. 2000, 113: 59-69. Carlevaro MF, Cermelli S, Cancedda R, Descalzi Cancedda F: Vascular endothelial growth factor (VEGF) in cartilage neovascularization and chondrocyte differentiation: auto-paracrine role during endochondral bone formation. J Cell Sci. 2000, 113: 59-69.
51.
go back to reference Yin M, Pacifici M: Vascular regression is required for mesenchymal condensation and chondrogenesis in the developing limb. Dev Dyn. 2001, 222: 522-533. 10.1002/dvdy.1212.CrossRef Yin M, Pacifici M: Vascular regression is required for mesenchymal condensation and chondrogenesis in the developing limb. Dev Dyn. 2001, 222: 522-533. 10.1002/dvdy.1212.CrossRef
52.
go back to reference Hiraki Y, Inoue H, Iyama K, Kamizono A, Ochiai M, Shukunami C, Iijima S, Suzuki F, Kondo J: Identification of chondromodulin I as a novel endothelial cell inhibitor: purification and its localization in the avascular zone of epiphyseal cartilage. J Biol Chem. 1997, 272: 32419-32426. 10.1074/jbc.272.51.32419.CrossRef Hiraki Y, Inoue H, Iyama K, Kamizono A, Ochiai M, Shukunami C, Iijima S, Suzuki F, Kondo J: Identification of chondromodulin I as a novel endothelial cell inhibitor: purification and its localization in the avascular zone of epiphyseal cartilage. J Biol Chem. 1997, 272: 32419-32426. 10.1074/jbc.272.51.32419.CrossRef
53.
go back to reference Kitahara H, Hayami T, Tokunaga K, Endo N, Funaki H, Yoshida Y, Yaoita E, Yamamoto T: Chondromodulin-I expression in rat articular cartilage. Arch Histol Cytol. 2003, 66: 221-228. 10.1679/aohc.66.221.CrossRef Kitahara H, Hayami T, Tokunaga K, Endo N, Funaki H, Yoshida Y, Yaoita E, Yamamoto T: Chondromodulin-I expression in rat articular cartilage. Arch Histol Cytol. 2003, 66: 221-228. 10.1679/aohc.66.221.CrossRef
54.
go back to reference Gonzalez AM, Buscaglia M, Ong M, Baird A: Distribution of basic fibroblast growth factor in the 18-day rat fetus: localization in the basement membranes of diverse tissues. J Cell Biol. 1990, 110: 753-765. 10.1083/jcb.110.3.753.CrossRef Gonzalez AM, Buscaglia M, Ong M, Baird A: Distribution of basic fibroblast growth factor in the 18-day rat fetus: localization in the basement membranes of diverse tissues. J Cell Biol. 1990, 110: 753-765. 10.1083/jcb.110.3.753.CrossRef
55.
go back to reference Gelb DE, Rosier RN, Puzas JE: The production of transforming growth factor-beta by chick growth plate chondrocytes in short term monolayer culture. Endocrinology. 1990, 127: 1941-1947. 10.1210/endo-127-4-1941.CrossRef Gelb DE, Rosier RN, Puzas JE: The production of transforming growth factor-beta by chick growth plate chondrocytes in short term monolayer culture. Endocrinology. 1990, 127: 1941-1947. 10.1210/endo-127-4-1941.CrossRef
56.
go back to reference Thiennu HV, Shipley JM, Bergers G, Burger JE, Helms JA, Hanahan D, Shapiro SD, Senior RM, Werb Z: MMP-9/Gelatinase B is a key regulator of growth plate angiogenesis and apoptosis. Cell. 1998, 93: 411-422. 10.1016/S0092-8674(00)81169-1.CrossRef Thiennu HV, Shipley JM, Bergers G, Burger JE, Helms JA, Hanahan D, Shapiro SD, Senior RM, Werb Z: MMP-9/Gelatinase B is a key regulator of growth plate angiogenesis and apoptosis. Cell. 1998, 93: 411-422. 10.1016/S0092-8674(00)81169-1.CrossRef
57.
go back to reference Zelzer E, Mamluk R, Ferrara N, Johnson RS, Schipani E, Olsen BR: VEGFA is necessary for chondrocyte survival during bone development. Development. 2004, 131: 2161-2171. 10.1242/dev.01053.CrossRef Zelzer E, Mamluk R, Ferrara N, Johnson RS, Schipani E, Olsen BR: VEGFA is necessary for chondrocyte survival during bone development. Development. 2004, 131: 2161-2171. 10.1242/dev.01053.CrossRef
58.
go back to reference Haigh JJ, Gerber HP, Ferrara N, Wagner EF: Conditional inactivation of VEGF-A in areas of collagen2a1 expression results in embryonic lethality in the heterozygous state. Development. 2000, 127: 1445-1453. Haigh JJ, Gerber HP, Ferrara N, Wagner EF: Conditional inactivation of VEGF-A in areas of collagen2a1 expression results in embryonic lethality in the heterozygous state. Development. 2000, 127: 1445-1453.
59.
go back to reference Van der Flier M, Coenjaerts FE, Mwinzi PN, Rijkers E, Ruyken M, Scharringa J, Kimpen JLL, Hoepelman AIM, Geelen SPM: Antibody neutralization of vascular endothelial growth factor (VEGF) fails to attenuate vascular permeability and brain edema in experimental pneumococcal meningitis. J Neuroimmunol. 2005, 160: 170-177. 10.1016/j.jneuroim.2004.11.013.CrossRef Van der Flier M, Coenjaerts FE, Mwinzi PN, Rijkers E, Ruyken M, Scharringa J, Kimpen JLL, Hoepelman AIM, Geelen SPM: Antibody neutralization of vascular endothelial growth factor (VEGF) fails to attenuate vascular permeability and brain edema in experimental pneumococcal meningitis. J Neuroimmunol. 2005, 160: 170-177. 10.1016/j.jneuroim.2004.11.013.CrossRef
Metadata
Title
Intravenous administration of anti-vascular endothelial growth factor humanized monoclonal antibody bevacizumab improves articular cartilage repair
Authors
Toshihiro Nagai
Masato Sato
Toshiharu Kutsuna
Mami Kokubo
Goro Ebihara
Naoshi Ohta
Joji Mochida
Publication date
01-10-2010
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 5/2010
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar3142

Other articles of this Issue 5/2010

Arthritis Research & Therapy 5/2010 Go to the issue