Skip to main content

Advertisement

SpringerLink
Log in

The influence of geranylgeraniol on microvessel sprouting after bisphosphonate substitution in an in vitro 3D-angiogenesis assay

  • Original Article
  • Published:
Clinical Oral Investigations Aims and scope Submit manuscript

Abstract

Objectives

Recent studies focused on angiogenesis in the pathophysiology of bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ) and identified geranylgeraniol (GGOH) as a feasible option for BP-ONJ therapy. This study investigated the influence of GGOH on microvessel sprouting after BP-incubation in vitro.

Materials and methods

Ten experimental set-ups were randomly designed in an in vitro 3D-angiogenesis assay. Two groups included HUVEC cell spheroids with and without (±) GGOH substitution as controls and eight groups pairwise contained either clodronate or the nitrogen-containing bisphosphonates (N-BP) ibandronate, pamidronate, and zoledronate ± GGOH. The size of the cell spheroids including the outbranching sprouts (SpS) as well as the density (SpD) and length of the sprouts (SpL) were analyzed by a grid system after 0, 24, 48, and 72 h.

Results

For controls and NN-BP clodronate, no significant differences at any tested parameter and any point of measurement could be detected within the experimental set-ups ± GGOH (p each ≥0.05). For N-BP ibandronate, the experimental set-ups +GGOH showed a significantly increased SpS, SpD, and SpL after 48 and 72 h (p each ≤0.002) compared to the experimental set-ups −GGOH. For N-BPs pamidronate and zoledronate, the experimental set-ups + GGOH demonstrated a significantly increased SpS, SpD, and SpL after 24, 48, and 72 h (p each ≤0.001) compared to the experimental set-ups −GGOH.

Conclusions

The strong negative influence of N-BPs on microvessel sprouting could be significantly reversed by GGOH.

Clinical relevance

Since supportive therapeutic options for BP-ONJ are lacking, GGOH might be a promising substitute for BP-ONJ prevention and therapy.

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

  1. Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61:1115–1117

    Article  PubMed  Google Scholar 

  2. Walter C, Sagheb K, Bitzer J, Rahimi-Nedjat R, Taylor KJ (2014) Analysis of reasons for osteonecrosis of the jaws. Clin Oral Investig 18:2221–2226

    Article  PubMed  Google Scholar 

  3. Vyas S, Hameed S, Murugaraj V (2014) Denosumab-associated osteonecrosis of the jaw—a case report. Dent Update 41:449–450

    PubMed  Google Scholar 

  4. Van Poznak C (2010) Osteonecrosis of the jaw and bevacizumab therapy. Breast Cancer Res Treat 122:189–191

    Article  PubMed  PubMed Central  Google Scholar 

  5. Koch FP, Walter C, Hansen T, Jäger E, Wagner W (2011) Osteonecrosis of the jaw related to sunitinib. Oral Maxillofac Surg 15:63–66

    Article  PubMed  Google Scholar 

  6. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O’ Ryan F (2014) American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw-2014 update. J Oral Maxillofac Surg 72:1938–1956

    Article  PubMed  Google Scholar 

  7. Walter C, Klein MO, Pabst A, Al-Nawas B, Duschner H, Ziebart T (2010) Influence of bisphosphonates on endothelial cells, fibroblasts, and osteogenic cells. Clin Oral Investig 14:35–41

    Article  PubMed  Google Scholar 

  8. Walter C, Pabst A, Ziebart T, Klein MO, Al-Nawas B (2011) Bisphosphonates affect migration ability and cell viability of HUVEC, fibroblasts and osteoblasts in vitro. Oral Dis 17:194–199

    Article  PubMed  Google Scholar 

  9. Pabst AM, Ziebart T, Koch FP, Taylor KY, Al-Nawas B, Walter C (2012) The influence of bisphosphonates on viability, migration, and apoptosis of human oral keratinocytes—in vitro study. Clin Oral Investig 16:87–93

    Article  PubMed  Google Scholar 

  10. Hagelauer N, Pabst AM, Ziebart T, Ulbrich H, Walter C (2015) In vitro effects of bisphosphonates on chemotaxis, phagocytosis, and oxidative burst of neutrophil granulocytes. Clin Oral Investig 19:139–148

    Article  PubMed  Google Scholar 

  11. Ziebart T, Pabst A, Klein MO, Kaemmerer P, Gauss L, Brüllmann D, Al-Nawas B, Walter C (2011) Bisphosphonates: restrictions for vasculogenesis and angiogenesis: inhibition of cell function of endothelial progenitor cells and mature endothelial cells in vitro. Clin Oral Investig 15:105–111

    Article  PubMed  Google Scholar 

  12. Pabst AM, Ziebart T, Ackermann M, Konerding MA, Walter C (2014) Bisphosphonates’ antiangiogenic potency in the development of bisphosphonate-associated osteonecrosis of the jaws: influence on microvessel sprouting in an in vivo 3D matrigel assay. Clin Oral Investig 18:1015–1022

    Article  PubMed  Google Scholar 

  13. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B (2009) American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaw—2009 update. Aust Endod J 35:119–130

    Article  PubMed  Google Scholar 

  14. Freiberger JJ, Padilla-Burgos R, Chhoeu AH, Kraft KH, Boneta O, Moon RE, Piantadosi CA (2007) Hyperbaric oxygen treatment and bisphosphonate-induced osteonecrosis of the jaw: a case series. J Oral Maxillofac Surg 65:1321–1327

    Article  PubMed  Google Scholar 

  15. Freiberger JJ (2009) Utility of hyperbaric oxygen in treatment of bisphosphonate related osteonecrosis of the jaws. J Oral Maxillofac Surg 67:96–106

    Article  PubMed  Google Scholar 

  16. Vescovi P, Manfredi M, Merigo E, Meleti M, Fornaini C, Rocca JP, Nammour S (2010) Surgical approach with Er:YAG laser on osteonecrosis of the jaws (ONJ) in patients under bisphosphonate therapy (BPT). Lasers Med Sci 25:101–113

    Article  PubMed  Google Scholar 

  17. Pabst AM, Krüger M, Ziebart T, Jacobs C, Sagheb K, Walter C (2015) The influence of geranylgeraniol on human oral keratinocytes after bisphosphonate treatment: an in vitro study. J Craniomaxillofac Surg 43:688–695

    Article  PubMed  Google Scholar 

  18. Assaf AT, Zrnc TA, Riecke B, Wikner J, Zustin J, Friedrich RE, Heiland M, Smeets R, Grobe A (2014) Intraoperative efficiency of fluorescence imaging by Visually Enhanced Lesion Scope (VELscope) in patients with bisphosphonate related osteonecrosis of the jaw (BRONJ). J Oral Maxillofac Surg 42:157–164

    Google Scholar 

  19. Belcher R, Boyette J, Pierson T, Siegel E, Bartel TB, Aniasse E, Stack B Jr (2014) What is the role of positron emission tomography in osteonecrosis of the jaws? J Oral Maxillofac Surg 72:306–310

    Article  PubMed  Google Scholar 

  20. Hamada H, Matsuo A, Koizumi T, Satomi T, Chikazu D (2014) A simple evaluation method for early detection of bisphosphonate-related osteonecrosis of the mandible using computed tomography. J Craniomaxillofac Surg 42:924–929

    Article  PubMed  Google Scholar 

  21. Blus C, Szmukler-Moncler C, Giannelli G, Denotti G, Orru G (2013) Use of ultrasonic bone surgery (Piezosurgery) to surgically treat bisphosphonate-related osteonecrosis of the jaws (BRONJ). A case series report with at least 1 year follow-up. Open Dent J 7:94–101

    Article  PubMed  PubMed Central  Google Scholar 

  22. Soydan SS, Uckan S (2014) Management of bisphosphonate-related osteonecrosis of the jaw with a platelet-rich fibrin membrane: technical report. J Oral Maxillofac Surg 72:322–326

    Article  PubMed  Google Scholar 

  23. Ersan N, van Ruijven LJ, Bronckers AL, Olgaç V, Ilgüy D, Everts V (2014) Teriparatide and the treatment of bisphosphonate-related osteonecrosis of the jaw: a rat model. Dentomaxillofac Radiol 43:20130144

    Article  PubMed  Google Scholar 

  24. Draenert GF, Huetzen DO, Kämmerer PW, Palarie V, Nacu V, Wagner W (2012) Dexrazoxane shows cytoprotective effects in zoledronic acid-treated human cells in vitro and in the rabbit tibia model in vivo. J Craniomaxillofac Surg 40:369–374

    Article  Google Scholar 

  25. Marcuzzi A, Tommasini A, Crovella S, Pontillo A (2010) Natural isoprenoids inhibit LPS induced production of cytokines and nitric oxide in aminobisphosphonate-treated monocytes. Int Immunopharmacol 10:639–642

    Article  PubMed  Google Scholar 

  26. Ziebart T, Koch F, Klein MO, Guth J, Adler J, Pabst A, Al-Nawas B, Walter C (2011) Geranylgeraniol—a new potential therapeutic approach to bisphosphonate associated osteonecrosis of the jaw. Oral Oncol 47:195–201

    Article  PubMed  Google Scholar 

  27. Hagelauer N, Ziebart T, Pabst AM, Walter C (2015) Bisphosphonates inhibit cell functions of HUVECs, fibroblasts and osteogenic cells via inhibition of protein geranylgeranylation. Clin Oral Investig 19:1079–1091

    Article  PubMed  Google Scholar 

  28. Pabst AM, Krüger M, Ziebart T, Jacobs C, Walter C (2015) Isoprenoid geranylgeraniol: the influence on cell characteristics of endothelial progenitor cells after bisphosphonate therapy in vitro. Clin Oral Investig 19:1625–1633

    Article  PubMed  Google Scholar 

  29. Weibel ER, Kistler GS, Scherle WF (1966) Practical stereological methods for morphometric cytology. J Cell Biol 30:23–38

    Article  PubMed  PubMed Central  Google Scholar 

  30. Favia G, Piattelli A, Sportelli P, Capodiferro S, Iezzi G (2011) Osteonecrosis of the posterior mandible after implant insertion: a clinical and histological case report. Clin Implant Dent Relat Res 13:58–63

  31. Staton CA, Reed MW, Brown NJ (2009) A critical analysis of current in vitro and in vivo angiogenesis assays. Int J Exp Pathol 90:195–221

    Article  PubMed  PubMed Central  Google Scholar 

  32. Voss PJ, Stoddart M, Ziebart T, Zeiter S, Nelson K, Bittermann G, Schmelzeisen R, Poxleitner P (2015) Zoledronate induces osteonecrosis of the jaw in sheep. J Craniomaxillofac Surg 43:1133–1138

    Article  PubMed  Google Scholar 

  33. Voss PJ, Stoddart MJ, Bernstein A, Schmelzeisen R, Nelson K, Stadelmann V, Ziebart T, Poxleitner PJ (2016) Zoledronate induces bisphosphonate-related osteonecrosis of the jaw in osteopenic sheep. Clin Oral Investig 20:31–38

    Article  PubMed  Google Scholar 

  34. Conway EM, Collen D, Carmeliet P (2001) Molecular mechanisms of blood vessel growth. Cardiovasc Res 49:507–521

    Article  PubMed  Google Scholar 

  35. Burri PH, Djonov V (2002) Intussusceptive angiogenesis—the alternative to capillary sprouting. Mol Asp Med 23:1–27

    Article  Google Scholar 

  36. Ackermann M, Wolloscheck T, Wellmann A, Li VW, Li WW, Konerding MA (2011) Priming with a combination of proangiogenic growth factors improves wound healing in normoglycemic mice. Int J Mol Med 27:647–653

    PubMed  PubMed Central  Google Scholar 

  37. Ackermann M, Houdek JP, Gibney BC, Ysasi A, Wagner W, Belle J, Schittny JC, Enzmann F, Tsuda A, Mentzer SJ, Konerding MA (2014) Sprouting and intussusceptive angiogenesis in postpneumonectomy lung growth: mechanisms of alveolar neovascularization. Angiogenesis 17:541–551

    Article  PubMed  Google Scholar 

  38. Konerding MA, Turhan A, Ravnic DJ, Lin M, Fuchs C, Secomb TW, Tsuda A, Mentzer SJ (2010) Inflammation-induced intussusceptive angiogenesis in murine colitis. Anat Rec (Hoboken) 293:849–857

    Article  Google Scholar 

  39. Ackermann M, Morse BA, Delventhal V, Carvajal IM, Konerding MA (2012) Anti-VEGFR2 and anti-IGF-1R-Adnectins inhibit Ewing’s sarcoma A673-xenograft growth and normalize tumor vascular architecture. Angiogenesis 15:685–695

    Article  PubMed  Google Scholar 

  40. Wehrhan F, Hyckel P, Ries J, Stockmann P, Nkenke E, Schlegel KA, Neukam FW, Amann K (2010) Expression of Msx-1 is suppressed in bisphosphonate associated osteonecrosis related jaw tissue-etiopathology considerations respecting jaw developmental biology-related unique features. J Transl Med 8:96

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wehrhan F, Stockmann P, Nkenke E, Schlegel KA, Guentsch A, Wehrhan T, Neukam FW, Amann K (2011) Differential impairment of vascularization and angiogenesis in bisphosphonate-associated osteonecrosis of the jaw-related mucoperiosteal tissue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 112:216–221

    Article  PubMed  Google Scholar 

  42. Agarwala S, Sule A, Pai BU, Joshi VR (2002) Alendronate in the treatment of avascular necrosis of the hip. Rheumatology 41:346–347

    Article  PubMed  Google Scholar 

  43. Matos MA, Araujo FP, Paixao FB (2007) The effect of zoledronate on bone remodeling during the healing process. Acta Cir Bras 22:115–119

    PubMed  Google Scholar 

  44. Amanat N, McDonald M, Godfrey C, Bilston L, Little D (2007) Optimal timing of a single dose of zoledronic acid to increase strength in rat fracture repair. J Bone Miner Res 22:867–876

    Article  PubMed  Google Scholar 

  45. Wehrhan F, Hyckel P, Amann K, Ries J, Stockmann P, Schlegel K, Neukam F, Nkenke E (2011) Msx-1 is suppressed in bisphosphonate-exposed jaw bone analysis of bone turnover-related cell signalling after bisphosphonate treatment. Oral Dis 17:433–442

    Article  PubMed  Google Scholar 

  46. Marcuzzi A, Zanin V, Piscianz E, Tricarico PM, Vuch J, Girardelli M, Monasta L, Bianco AM, Crovella S (2012) Lovastatin-induced apoptosis in modulated by geranylgeraniol in a neuroblastoma cell line. Int J Dev Neurosci 30:451–456

    Article  PubMed  Google Scholar 

  47. Tricarico PM, Marcuzzi A, Piscianz E, Monasta L, Crovella S, Kleiner G (2013) Mevalonate kinase deficiency and neuroinflammation: balance between apoptosis and pyroptosis. Int J Mol Sci 14:23274–23288

    Article  PubMed  PubMed Central  Google Scholar 

  48. Tricarico PM, Kleiner G, Valencic E, Campisciano G, Girardelli M, Crovella S, Knowles A, Marcuzzi A (2014) Block of the mevalonate pathway triggers oxidative and inflammatory molecular mechanisms modulated by exogenous isoprenoid compounds. Int J Mol Sci 15:6843–6856

    Article  PubMed  PubMed Central  Google Scholar 

  49. Tricarico PM, Girardelli M, Kleiner G, Knowles A, Valencic E, Crovella S, Marcuzzi A (2015) Alendronate, a double-edged sword acting in the mevalonate pathway. Mol Med Rep 12:4238–4242

    PubMed  PubMed Central  Google Scholar 

  50. Zanin V, Marcuzzi A, Piscianz E, Vuch J, Bianco AM, Monesta L, Decorti G, Crovella S (2012) The effect of clodronate on a mevalonate kinase deficiency cellular model. Inflamm Res 61:1363–1367

    Article  PubMed  Google Scholar 

  51. Marcuzzi A, Decorti G, Pontillo A, Ventura A, Tommasini A (2010) Decreased cholesterol levels reflect a consumption of anti-inflammatory isoprenoids associated with an impaired control of inflammation in a mouse model of mevalonate kinase deficiency. Inflamm Res 59:335–338

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors give special thanks to Kathy Taylor for proof-reading and language checking.

Author information

Authors and Affiliations

  1. Department of Oral and Maxillofacial Surgery, Federal Armed Forces Hospital, Rübenacherstr, 170, 56072, Koblenz, Germany

    A. M. Pabst

  2. Department of Oral and Maxillofacial Surgery, University Medical Center, Augustusplatz 2, 55131, Mainz, Germany

    A. M. Pabst, M. Krüger, K. Sagheb, S. Blatt, E. Goetze & C. Walter

  3. Department of Oral and Maxillofacial Surgery, University Clinic, Georg-Voigt-Straße 3, 35039, Marburg, Germany

    T. Ziebart

  4. Department of Orthodontics, University Medical Center, Augustusplatz 2, 55131, Mainz, Germany

    C. Jacobs

Authors
  1. A. M. Pabst
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Krüger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. Sagheb
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T. Ziebart
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. Jacobs
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. Blatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E. Goetze
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C. Walter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. M. Pabst.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Funding

No fundings were received for this study. The work was supported by the Department of Oral and Maxillofacial Surgery, University Medical Center, Augustusplatz 2, 55131 Mainz, Germany.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study, formal consent is not required.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pabst, A.M., Krüger, M., Sagheb, K. et al. The influence of geranylgeraniol on microvessel sprouting after bisphosphonate substitution in an in vitro 3D-angiogenesis assay. Clin Oral Invest 21, 771–778 (2017). https://doi.org/10.1007/s00784-016-1842-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00784-016-1842-z

Keywords

Search

Navigation