Skip to main content

Advertisement

SpringerLink
Log in

BMP-7 inhibits cartilage degeneration through suppression of inflammation in rat zymosan-induced arthritis

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Bone morphogenetic protein-7 (BMP-7) regulates cartilage metabolism and promotes matrix synthesis. However, the effect of BMP-7 on inflammatory arthritis remains unknown. We investigated the effect and mechanism of exogenous BMP-7 on cartilage and synovium in vivo in rat zymosan-induced arthritis. Zymosan was injected into the left knees of Wistar rats. Phosphate-buffered saline or BMP-7 at 10, 100, or 1000 ng per joint was injected into the left knee every 2 days. Normal joints acted as normal controls. The knee joints were analyzed histologically and immunohistologically at 14 days. Joint swelling was evaluated by measuring the transverse diameter of the knee joints. Synovial lysates were collected, and the concentrations of interleukin-1β (IL-1β), IL-6, and IL-10 were measured by enzyme-linked immunosorbent assay. Intra-articular injection of zymosan resulted in acute inflammation and was followed by cartilage degeneration. Local administrations of BMP-7 inhibited this loss of cartilage matrix in a dose-dependent manner. Immunohistochemical analysis demonstrated enhanced type II collagen levels in cartilage and enhanced BMP-7 levels in cartilage and synovium after exogenous BMP-7 treatment. Joint swelling and cell infiltration into synovium were significantly reduced by BMP-7 injections. Administration of BMP-7 decreased IL-1β production significantly and increased IL-10 production in the synovium. Thus, intra-articular injections of BMP-7 had a protective effect on cartilage degeneration in the inflammatory arthritis model by enhancing levels of BMP-7 in cartilage and suppressing the production of IL-1β in synovium.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Axelrad TW, Einhorn TA (2009) Bone morphogenetic proteins in orthopaedic surgery. Cytokine Growth Factor Rev 20:481–488

    Article  PubMed  CAS  Google Scholar 

  • Bartelds GM, Wijbrandts CA, Nurmohamed MT, Stapel S, Lems WF, Aarden L, Dijkmans BA, Tak PP, Wolbink GJ (2009) Anti-infliximab and anti-adalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-TNF naive patients: a cohort study. Ann Rheum Dis 69:817–821

    Article  PubMed  Google Scholar 

  • Bobacz K, Sunk IG, Hayer S, Amoyo L, Tohidast-Akrad M, Kollias G, Smolen JS, Schett G (2008) Differentially regulated expression of growth differentiation factor 5 and bone morphogenetic protein 7 in articular cartilage and synovium in murine chronic arthritis: potential importance for cartilage breakdown and synovial hypertrophy. Arthritis Rheum 58:109–118

    Article  PubMed  CAS  Google Scholar 

  • Brennan FM, McInnes IB (2008) Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest 118:3537–3545

    Article  PubMed  CAS  Google Scholar 

  • Chubinskaya S, Kuettner KE (2003) Regulation of osteogenic proteins by chondrocytes. Int J Biochem Cell Biol 35:1323–1340

    Article  PubMed  CAS  Google Scholar 

  • Chubinskaya S, Merrihew C, Cs-Szabo G, Mollenhauer J, McCartney J, Rueger DC, Kuettner KE (2000) Human articular chondrocytes express osteogenic protein-1. J Histochem Cytochem 48:239–250

    Article  PubMed  CAS  Google Scholar 

  • Chubinskaya S, Hurtig M, Rueger DC (2007a) OP-1/BMP-7 in cartilage repair. Int Orthop 31:773–781

    Article  PubMed  Google Scholar 

  • Chubinskaya S, Kawakami M, Rappoport L, Matsumoto T, Migita N, Rueger DC (2007b) Anti-catabolic effect of OP-1 in chronically compressed intervertebral discs. J Orthop Res 25:517–530

    Article  PubMed  CAS  Google Scholar 

  • Chubinskaya S, Segalite D, Pikovsky D, Hakimiyan AA, Rueger DC (2008) Effects induced by BMPS in cultures of human articular chondrocytes: comparative studies. Growth Factors 26:275–283

    Article  PubMed  CAS  Google Scholar 

  • Daans M, Lories RJ, Luyten FP (2008) Dynamic activation of bone morphogenetic protein signaling in collagen-induced arthritis supports their role in joint homeostasis and disease. Arthritis Res Ther 10:R115

    Article  PubMed  Google Scholar 

  • de Hooge AS, van de Loo FA, Koenders MI, Bennink MB, Arntz OJ, Kolbe T, van den Berg WB (2004) Local activation of STAT-1 and STAT-3 in the inflamed synovium during zymosan-induced arthritis: exacerbation of joint inflammation in STAT-1 gene-knockout mice. Arthritis Rheum 50:2014–2023

    Article  PubMed  Google Scholar 

  • de Hooge ASK, van de Loo FAJ, Arntz OJ, van den Berg WB (2000) Involvement of IL-6, apart from its role in immunity, in mediating a chronic response during experimental arthritis. Am J Pathol 157:2081–2091

    Article  PubMed  Google Scholar 

  • den Boer FC, Bramer JA, Blokhuis TJ, Van Soest EJ, Jenner JM, Patka P, Bakker FC, Burger EH, Haarman HJ (2002) Effect of recombinant human osteogenic protein-1 on the healing of a freshly closed diaphyseal fracture. Bone 31:158–164

    Article  Google Scholar 

  • Drexler SK, Kong PL, Wales J, Foxwell BM (2008) Cell signalling in macrophages, the principal innate immune effector cells of rheumatoid arthritis. Arthritis Res Ther 10:216

    Article  PubMed  Google Scholar 

  • Elshaier AM, Hakimiyan AA, Rappoport L, Rueger DC, Chubinskaya S (2009) Effect of interleukin-1beta on osteogenic protein 1-induced signaling in adult human articular chondrocytes. Arthritis Rheum 60:143–154

    Article  PubMed  CAS  Google Scholar 

  • Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Nature 423:356–361

    Article  PubMed  CAS  Google Scholar 

  • Fonseca JE, Santos MJ, Canhao H, Choy E (2009) Interleukin-6 as a key player in systemic inflammation and joint destruction. Autoimmun Rev 8:538–542

    Article  PubMed  CAS  Google Scholar 

  • Gegout P, Gillet P, Chevrier D, Guingamp C, Terlain B, Netter P (1994) Characterization of zymosan-induced arthritis in the rat: effects on joint inflammation and cartilage metabolism. Life Sci 55:PL321–PL326

    Article  PubMed  CAS  Google Scholar 

  • Glansbeek HL, van Beuningen HM, Vitters EL, van der Kraan PM, van den Berg WB (1998) Stimulation of articular cartilage repair in established arthritis by local administration of transforming growth factor-beta into murine knee joints. Lab Invest 78:133–142

    PubMed  CAS  Google Scholar 

  • Hayashi M, Muneta T, Ju Y, Mochizuki T, Sekiya I (2008) Weekly intra-articular injections of bone morphogenetic protein-7 inhibits osteoarthritis progression. Arthritis Res Ther 10:R118

    Article  PubMed  Google Scholar 

  • Hermann J, Walmsley M, Brennan FM (1998) Cytokine therapy in rheumatoid arthritis. Springer Semin Immunopathol 20:275–288

    Article  PubMed  CAS  Google Scholar 

  • Huch K, Wilbrink B, Flechtenmacher J, Koepp HE, Aydelotte MB, Sampath TK, Kuettner KE, Mollenhauer J, Thonar EJ (1997) Effects of recombinant human osteogenic protein 1 on the production of proteoglycan, prostaglandin E2, and interleukin-1 receptor antagonist by human articular chondrocytes cultured in the presence of interleukin-1beta. Arthritis Rheum 40:2157–2161

    Article  PubMed  CAS  Google Scholar 

  • Hyc A, Osiecka-Iwan A, Dziunycz P, Moskalewski S (2007) Preparation of rat synovial membrane for studies of cytokine secretion. Folia Histochem Cytobiol 45:57–60

    PubMed  CAS  Google Scholar 

  • Jelic M, Pecina M, Haspl M, Kos J, Taylor K, Maticic D, McCartney J, Yin S, Rueger D, Vukicevic S (2001) Regeneration of articular cartilage chondral defects by osteogenic protein-1 (bone morphogenetic protein-7) in sheep. Growth Factors 19:101–113

    Article  PubMed  CAS  Google Scholar 

  • Keystone EC, Schorlemmer HU, Pope C, Allison AC (1977) Zymosan-induced arthritis: a model of chronic proliferative arthritis following activation of the alternative pathway of complement. Arthritis Rheum 20:1396–1401

    Article  PubMed  CAS  Google Scholar 

  • Le Buanec H, Delavallee L, Bessis N, Paturance S, Bizzini B, Gallo R, Zagury D, Boissier MC (2006) TNFalpha kinoid vaccination-induced neutralizing antibodies to TNFalpha protect mice from autologous TNFalpha-driven chronic and acute inflammation. Proc Natl Acad Sci USA 103:19442–19447

    Article  PubMed  Google Scholar 

  • Lee MJ, Yang CW, Jin DC, Chang YS, Bang BK, Kim YS (2003) Bone morphogenetic protein-7 inhibits constitutive and interleukin-1 beta-induced monocyte chemoattractant protein-1 expression in human mesangial cells: role for JNK/AP-1 pathway. J Immunol 170:2557–2563

    PubMed  CAS  Google Scholar 

  • Lories RJ, Derese I, Ceuppens JL, Luyten FP (2003) Bone morphogenetic proteins 2 and 6, expressed in arthritic synovium, are regulated by proinflammatory cytokines and differentially modulate fibroblast-like synoviocyte apoptosis. Arthritis Rheum 48:2807–2818

    Article  PubMed  CAS  Google Scholar 

  • Lubberts E, Joosten LA, Helsen MM, van den Berg WB (1998) Regulatory role of interleukin 10 in joint inflammation and cartilage destruction in murine streptococcal cell wall (SCW) arthritis. More therapeutic benefit with IL-4/IL-10 combination therapy than with IL-10 treatment alone. Cytokine 10:361–369

    Article  PubMed  CAS  Google Scholar 

  • Maric I, Poljak L, Zoricic S, Bobinac D, Bosukonda D, Sampath KT, Vukicevic S (2003) Bone morphogenetic protein-7 reduces the severity of colon tissue damage and accelerates the healing of inflammatory bowel disease in rats. J Cell Physiol 196:258–264

    Article  PubMed  CAS  Google Scholar 

  • Moghaddam A, Elleser C, Biglari B, Wentzensen A, Zimmermann G (2009) Clinical application of BMP 7 in long bone non-unions. Arch Orthop Trauma Surg 130:71-76

    Article  PubMed  Google Scholar 

  • Muehleman C, Kuettner KE, Rueger DC, Ten Dijke P, Chubinskaya S (2002) Immunohistochemical localization of osteogenetic protein (OP-1) and its receptors in rabbit articular cartilage. J Histochem Cytochem 50:1341–1350

    Article  PubMed  CAS  Google Scholar 

  • Nakagawa T, Akagi M, Hoshikawa H, Chen M, Yasuda T, Mukai S, Ohsawa K, Masaki T, Nakamura T, Sawamura T (2002) Lectin-like oxidized low-density lipoprotein receptor 1 mediates leukocyte infiltration and articular cartilage destruction in rat zymosan-induced arthritis. Arthritis Rheum 46:2486–2494

    Article  PubMed  CAS  Google Scholar 

  • Pileri SA, Roncador G, Ceccarelli C, Piccioli M, Briskomatis A, Sabattini E, Ascani S, Santini D, Piccaluga PP, Leone O, Damiani S, Ercolessi C, Sandri F, Pieri F, Leoncini L, Falini B (1997) Antigen retrieval techniques in immunohistochemistry: comparison of different methods. J Pathol 183:116–123

    Article  PubMed  CAS  Google Scholar 

  • Pohlers D, Siegling A, Buchner E, Schmidt-Weber CB, Palombo-Kinne E, Emmrich F, Bräuer R, Kinne RW (2005) Expression of cytokine mRNA and protein in joints and lymphoid organs during the course of rat antigen-induced arthritis. Arthritis Res Ther 7:R445-R457

    Article  PubMed  CAS  Google Scholar 

  • Saas J, Haag J, Rueger D, Chubinskaya S, Sohler F, Zimmer R, Bartnik E, Aigner T (2006) IL-1beta, but not BMP-7 leads to a dramatic change in the gene expression pattern of human adult articular chondrocytes—portraying the gene expression pattern in two donors. Cytokine 36:90–99

    Article  PubMed  CAS  Google Scholar 

  • Sato M, Sano H, Iwaki D, Kudo K, Konishi M, Takahashi H, Takahashi T, Imaizumi H, Asai Y, Kuroki Y (2003) Direct binding of Toll-like receptor 2 to zymosan, and zymosan-induced NF-kappa B activation and TNF-alpha secretion are down-regulated by lung collectin surfactant protein A. J Immunol 171:417–425

    PubMed  CAS  Google Scholar 

  • Sekiya I, Tang T, Hayashi M, Morito T, Ju YJ, Mochizuki T, Muneta T (2009) Periodic knee injections of BMP-7 delay cartilage degeneration induced by excessive running in rats. J Orthop Res 27:1088–1092

    Article  PubMed  CAS  Google Scholar 

  • van de Loo FA, Arntz OJ, van Enckevort FH, Lent PL van, van den Berg WB (1998) Reduced cartilage proteoglycan loss during zymosan-induced gonarthritis in NOS2-deficient mice and in anti-interleukin-1-treated wild-type mice with unabated joint inflammation. Arthritis Rheum 41:634–646

    Article  PubMed  Google Scholar 

  • van de Loo FA, Joosten LA, van Lent PL, Arntz OJ, van den Berg WB (1995) Role of interleukin-1, tumor necrosis factor alpha, and interleukin-6 in cartilage proteoglycan metabolism and destruction. Effect of in situ blocking in murine antigen- and zymosan-induced arthritis. Arthritis Rheum 38:164–172

    Article  PubMed  Google Scholar 

  • van den Berg WB (1998) Joint inflammation and cartilage destruction may occur uncoupled. Springer Semin Immunopathol 20:149–164

    Article  PubMed  Google Scholar 

  • Vukicevic S, Basic V, Rogic D, Basic N, Shih MS, Shepard A, Jin D, Dattatreyamurty B, Jones W, Dorai H, Ryan S, Griffiths D, Maliakal J, Jelic M, Pastorcic M, Stavljenic A, Sampath TK (1998) Osteogenic protein-1 (bone morphogenetic protein-7) reduces severity of injury after ischemic acute renal failure in rat. J Clin Invest 102:202–214

    Article  PubMed  CAS  Google Scholar 

  • Wang S, Chen Q, Simon TC, Strebeck F, Chaudhary L, Morrissey J, Liapis H, Klahr S, Hruska KA (2003) Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy. Kidney Int 63:2037–2049

    Article  PubMed  CAS  Google Scholar 

  • White AP, Vaccaro AR, Hall JA, Whang PG, Friel BC, McKee MD (2007) Clinical applications of BMP-7/OP-1 in fractures, nonunions and spinal fusion. Int Orthop 31:735–741

    Article  PubMed  Google Scholar 

  • Yasukawa H, Ohishi M, Mori H, Murakami M, Chinen T, Aki D, Hanada T, Takeda K, Akira S, Hoshijima M, Hirano T, Chien KR, Yoshimura A (2003) IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat Immunol 4:551–556

    Article  PubMed  CAS  Google Scholar 

  • Yimin KM, Minagawa T (2003) Up-regulation of granulomatous inflammation in interleukin-6 knockout mice infected with Rhodococcus aurantiacus. Immunology 110:501–506

    Article  PubMed  CAS  Google Scholar 

  • Zeisberg M (2006) Bone morphogenic protein-7 and the kidney: current concepts and open questions. Nephrol Dial Transplant 21:568–573

    Article  PubMed  CAS  Google Scholar 

  • Zeisberg M, Bottiglio C, Kumar N, Maeshima Y, Strutz F, Muller GA, Kalluri R (2003) Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models. Am J Physiol Renal Physiol 285:F1060–F1067

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

BMP-7 was kindly provided by Stryker Biotech. The authors thank Miyoko Ojima for expert help with the histology.

Author information

Authors and Affiliations

  1. Section of Orthopedic Surgery, Division of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113–8519, Japan

    Toru Takahashi, Takeshi Muneta & Ichiro Sekiya

  2. Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, Tokyo, Japan

    Takeshi Muneta & Kunikazu Tsuji

  3. Section of Cartilage Regeneration, Graduate School, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, 113–8519, Japan

    Ichiro Sekiya

Authors
  1. Toru Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takeshi Muneta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kunikazu Tsuji
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ichiro Sekiya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ichiro Sekiya.

Additional information

This study was supported by the Japan Society for the Promotion of Science (21591937 to T.M.; 21591914 to I.S.), by the Japanese Ministry of Education, by the Global Center of Excellence (GCOE) Program, and by the International Research Center for Molecular Science in Tooth and Bone Diseases (to T.M.).

T.T. carried out the animal experiments, analyzed the results, and drafted the manuscript. T.M. designed the initial plan for the study. K.T. gave advice regarding the manuscript. I.S. conducted the experiments, participated in the evaluation of the results, and completed the final manuscript. All authors read and approved the final manuscript.

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Takahashi, T., Muneta, T., Tsuji, K. et al. BMP-7 inhibits cartilage degeneration through suppression of inflammation in rat zymosan-induced arthritis. Cell Tissue Res 344, 321–332 (2011). https://doi.org/10.1007/s00441-011-1154-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-011-1154-1

Keywords

Search

Navigation