Research Article of International Journal of Dental Research and Reviews
Selection of Angiogenic Markers that Predict the Transition from Bisphosphonate Exposure to MRONJ in a Rat Model
Sonoko Nakasato1, Joshua Sanchez1, Katherine Chapman1, Michael Benichou1, Sadanand Fulzele2, Jeffrey A. Elo1, Shirley Y. Kang1, Carlos Guerra1, James L. Borke1
1College of Dental Medicine, Western University of Health Sciences, Pomona, California, UNITED STATES;
2Orthopedic Surgery, Augusta University, Augusta, Georgia, UNITED STATES
Medication related osteonecrosis of the jaw (MRONJ) is a disorder characterized by loss of blood supply to the jaws and death to the bone. In our previous work, we created a rat model of MRONJ by two injections of 60ug/Kg zoledronic acid (a powerful bisphosphonate abbreviated as ZA) via tail vein followed by extraction of a single first molar. We have shown in this model (ZA-treated rats plus molar extraction) a decrease in the vasculature of the jaws and a delay in bone healing beyond 4 weeks. Purpose: The current study identified angiogenic factors from the jaws of our MRONJ model where expression was altered independent of exposure to ZA alone. Methods: Using RT-PCR arrays containing 84 different gene sequences related to angiogenesis, we screened RNA isolated from the jaws of Control, ZA-treated rats, and our MRONJ rat model (ZA-treated plus first molar extraction), 3 and 6 weeks after extraction. Heat maps of gene expression were analyzed to identify genes where expression was either maximal or lost in MRONJ rats relative to ZA-treated rats without extraction. Results: Our study demonstrates the loss or gain of expression for 22 genes in the MRONJ rat model relative to rats treated with ZA alone. In MRONJ rats, the loss of expression was seen for 10 genes after 3 weeks and 3 additional genes (13 total) after 6 weeks where maximal expression was seen in rats treated with ZA-alone. This study also identified 5 genes that were maximally expressed in MRONJ rats after 3 weeks and an additional 4 genes (9 total) after 6 weeks that were not expressed in rats treated with ZA alone. Conclusions: Our study identifies genes that predict the transition from asymptomatic bisphosphonate exposure to MRONJ.
Keywords: Osteonecrosis; MRONJ; BRONJ; animal model; bisphosphonate; markers
How to cite this article:
Sonoko Nakasato, Joshua Sanchez, Katherine Chapman, Michael Benichou, Sadanand Fulzele, Jeffrey A. Elo, Shirley Y. Kang, Carlos Guerra, James L. Borke. Selection of Angiogenic Markers that Predict the Transition from Bisphosphonate Exposure to MRONJ in a Rat Model. International Journal of Dental Research and Reviews, 2018,1:6. DOI: 10.28933/ijdrr-2018-10-1801
1. Ruggiero SL, Drew SJ. Osteonecrosis of the jaw and bisphosphonate therapy. J Dent Res, 2007; 86:1013-1021.
2. Woo S, Hellstin J, Kalmar J. Systematic review: Bisphosphonates in osteonecrosis of the jaw. Ann Intern Med, 2006; 144:753-761.
3. Marx RE, Sawatari Y, Firtin M, Broumand V. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention and treatment. J Oral Maxilofac Surg, 2005; 63:1567-1575.
4. Stresing V, Fournier PG, Bellahcène A, Benzaïd I, Mönkkönen H, Colombel M, Ebetino FH, Castronovo V, Clézardin P. Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase. Bone, 2011; 48(2):259-66.
5. Guevarra CS, Borke JL, Stevens MR, Bisch FC, Zakhary I,Messer R, Gerlach RC, Elsalanty ME. Vascular Alterations in the Sprague-Dawley Rat Mandible during Intravenous Bisphosphonate Therapy. J. Oral Implantology, 2015; Apr;41(2):e24-9.
6. Wood J, Bonjean K, Ruetz S, Bellahcène A, Devy L, Foidart JM, Castronovo V, Green JR. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther, 2002; Sep;302(3):1055-61.
7. Fournier P, Boissier S, Filleur S, Guglielmi J, Cabon F, Colombel M, Clézardin P. Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res, 2002; Nov 15;62(22):6538-44.
8. Vincenzi B, Napolitano A, Zoccoli A, Iuliani M, Pantano F, Papapietro N, Denaro V, Santini D, Tonini G. Serum VEGF levels as predictive marker of bisphosphonate-related osteonecrosis of the jaw. J Hematol Oncol, 2012; 5: 56.
9. Thumbigere-Math V, Michalowicz BS, Hughes PJ, Basi DL, Tsai ML, Swenson KK, Rockwell L, Gopalakrishnan R. Serum Markers of Bone Turnover and Angiogenesis in Bisphosphonate-related Osteonecrosis of the Jaw Patients Following Discontinuation of Long-term Intravenous Bisphosphonate Therapy. J Oral Maxillofac Surg, 2016; Apr; 74(4): 738–746.
10. Ma S, Goh EL, Jin A, Bhattacharya R, Boughton OR, Patel B, Karunaratne A, Vo NT, Atwood R, Cobb JP, Hansen U, Abel RL. Long-term effects of bisphosphonate therapy: perforations, microcracks and mechanical properties. Sci Rep, 2017; 7: 43399
11. Manzano-Moreno FJ, Ramos-Torrecillas J, Melguizo-Rodríguez L, Illescas-Montes R, RuizC, García-Martínez O. Bisphosphonate Modulation of the Gene Expression of Different Markers Involved in Osteoblast Physiology: Possible Implications in Bisphosphonate-Related Osteonecrosis of the Jaw. Int J Med Sci, 2018; 15(4): 359–367.
12. Marino KL, Zakhary I, Abdelsayed RA, Carter JA, O’Neill JC, Khashaba RM, Elsalanty M, Stevens MR, Borke JL. Development of a rat model of bisphosphonate-related osteonecrosis of the jaw (BRONJ). J Oral Implantol, 2012, 38(S1):511-518.
13. Schulte D. Küppers V, Dartsch N, Broermann A, Li H, Zarbock A, Kamenyeva O, Kiefer F, Khandoga A, Massberg S, Vestweber D. Stabilizing the VE-cadherin-catenin complex blocks leukocyte extravasation and vascular permeability. EMBO J, 2011; 30, 4157–4170.
14. Muller WA, Weigl SA, Deng X, Phillips DM. PECAM-1 is required for transendothelial migration of leukocytes. J Exp Med, 1993; 178 (2):449-460.
15. Duque GA, Descoteaux A. Macrophage Cytokines: Involvement in Immunity and Infectious Diseases Front Immunol, 2014; 5:(491) e1-12.
16. Sheikh F, Dickensheets H, Gamero AM, Vogel SN, Donnelly RP. An essential role for IFN-β in the induction of IFN-stimulated gene expression by LPS in macrophages. J Leukoc Biol, 2014; 96(4):591-600.
17. Farberov S, Meidan R. Functions and transcriptional regulation of thrombospondins and their interrelationship with fibroblast growth factor-2 in bovine luteal cells. Biol Reprod, 2014; 91(3):1-10
18. Ruohola JK, Valve EM, Vainikka S, Alitalo K, Härkönen PL. Androgen and fibroblast growth factor (FGF) regulation of FGF receptors in S115 mouse mammary tumor cells. Endocrinology, 1995; 136(5):2179-88
19. Suehiro A, Hirano S, Kishimoto Y, Tateya I, Rousseau B, Ito J. Effects of basic fibroblast growth factor on rat vocal fold fibroblasts. Ann Otol Rhinol Laryngo, 2010; 119(10):690-6
20. Pons S, Torres-Aleman I. Basic fibroblast growth factor modulates insulin-like growth factor-I, its receptor, and its binding proteins in hypothalamic cell cultures. Endocrinology, 1992; 131(5):2271-8
21. Lucerna M, Mechtcheriakova D, Kadl A, Schabbauer G, Schäfer R, Gruber F, Koshelnick Y, Müller HD, Issbrücker K, Clauss M, Binder BR, Hofer E. NAB2, a corepressor of EGR-1, inhibits vascular endothelial growth factor-mediated gene induction and angiogenic responses of endothelial cells. J Biol Chem, 2003; Mar 28;278(13):11433-40.
22. Borghese C, Casagrande N, Pivetta E, Colombatti A, Boccellino M, Amler E, Normanno N, Caraglia M, De Rosa G, Aldinucci D. Self-assembling nanoparticles encapsulating zoledronic acid inhibit mesenchymal stromal cells differentiation, migration and secretion of proangiogenic factors and their interactions with prostate cancer cells. Oncotarget, 2017; 8(26):42926-42938.
23. Lin C, McGough R, Aswad B, Block JA, Terek R. Hypoxia induces HIF-1alpha and VEGF expression in chondrosarcoma cells and chondrocytes. J Orthop Res, 2004; 22(6):1175-81.
24. Belotti D, Paganoni P, Manenti L, Garofalo A, Marchini S, Taraboletti G, Giavazzi R. Matrix Metalloproteinases (MMP9 and MMP2) Induce the Release of Vascular Endothelial Growth Factor (VEGF) by Ovarian Carcinoma Cells: implications for ascites formation. Cancer Res, 2003; 1;63(17):5224-9.
25. Kuyvenhoven JP, Molenaar IQ, Verspaget HW, Veldman MG, Palareti G, Legnani C, Moolenburgh SE, Terpstra OT, Lamers CB, van Hoek B, Porte RJ. Plasma MMP-2 and MMP-9 and their inhibitors TIMP-1 and TIMP-2 during human orthotopic liver transplantation. The effect of aprotinin and the relation to ischemia/reperfusion injury. Thromb Haemost, 2004; Mar;91(3):506-13.
26. Potiron VA, Sharma G, Nasarre P, Clarhaut JA, Augustin HG, Gemmill RM, Roche J, Drabkin HA. Sempahorin SEMA3F Affects Multiple Signaling Pathways in Lung Cancer Cells. Cancer Res, 2007; Sep 15;67(18):8708-15.
27. Zucker S, Mirza H, Conner CE, Lorenz AF, Drews MH, Bahou WF, Jesty J. Vascular endothelial growth factor induces tissue factor and matrix metalloproteinase production in endothelial cells: conversion of prothrombin to thrombin results in progelatinase A activation and cell proliferation. Int J Cancer, 1998; Mar 2;75(5):780-6.
28. Long J, Wang Y, Wang W, Chang BH, Danesh FR. Identification of MicroRNA-93 as a Novel Regulator of Vascular Endothelial Growth Factor in Hyperglycemic Conditions. J Biol Chem, 2010;. Jul 23;285(30):23457-65.
29. Rugani P, Walter C, Kirnbauer B, Acham S, Begus-Nahrman Y, Jakse N. Prevalence of Medication-Related Osteonecrosis of the Jaw in Patients with Breast Cancer, Prostate Cancer, and Multiple Myeloma. Dent. J (Basel), 2016; 4(4): 32; doi:10.3390/dj4040032.
30. Ohnishi Y, Ito K, Kitamura R, Funayama S, Hori K, Inoue M. Importance of Professional Oral Hygiene in Preventing Medication-related Osteonecrosis of the Jaw. Int J Oral-Med Sci, 2017; 15(3)(4):85-92.
31. Dimopoulos MA, Kastritis E, Bamia C, Melakopoulos I, Gika D, Roussou M, Migkou M, Eleftherakis-Papaiakovou E, Christoulas D, Terpos E, Bamias A. Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol, 2009; 20: 117-120,
32. Lawler J. Thrombospondin-1 as an endogenous inhibitor of angiogenesis and tumor growth. Cell Mol Med, 2002; Jan-Mar;6(1):1-12.
33. Grothey A, Galanis E. Targeting angiogenesis: progress with anti-VEGF treatment with large molecules. Nat Rev Clin Oncol, 2009; 6: 507-518.
34. Madan A, Varma S, Cohen HJ. Co-Transfection of the 3’ Erythropoietin Hypoxia Inducible Enhancer by HIF-1 Protein. Blood Cells, Molecules, and Diseases, 1997; 23(10) May 31: 169–176.
35. Bekisz J, Baron S, Balinsky C, Morrow A, Zoon KC. Antiproliferative Properties of Type I and Type II Interferon. Pharmaceuticals, 2010; 3(4), 994-1015.
This work and its PDF file(s) are licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.