Top

Published in:

01-02-2011 | Original Article

Bisphosphonates: restrictions for vasculogenesis and angiogenesis: inhibition of cell function of endothelial progenitor cells and mature endothelial cells in vitro

Authors: Thomas Ziebart, Andreas Pabst, Marcus Oliver Klein, Peer Kämmerer, Leonie Gauss, Dan Brüllmann, Bilal Al-Nawas, Christian Walter

Published in: Clinical Oral Investigations | Issue 1/2011

Abstract

Bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ) is one of the main side effects in patients treated with bisphosphonates for metastasis to the bone or osteoporosis. BP-ONJ usually occurs in patients treated with highly potent nitrogen-containing bisphosphonates. The exact mechanism of action and etiopathology is still unknown. In addition to inhibition of bone remodelling, an anti-angiogenetic effect has become the focus of research. The aim of these study was to investigate the effect of different bisphosphonates on human umbilicord vein endothelial cells (HUVEC) and endothelial progenitor cells (EPC), which play an important role in angiogenesis. Using varying concentrations, the impact of one non-nitrogen-containing bisphosphonate (clodronate) and three nitrogen-containing bisphosphonates (ibandronate, pamidronate and zoledronate) on HUVEC and EPC was analysed. The biologic behaviour of HUVEC after incubation with different bisphosphonates was measured in a Boyden migration assay as well as in a 3D angiogenesis assay. The number of apoptotic cells was measured by Tunnel assay. To underline the importance of neoangiogenesis in the context of BP-ONJ, we measured the EPC number after incubation with different bisphosphonates in vitro. HUVEC and EPC were significantly influenced by bisphosphonates at different concentrations compared with the non-treated control groups. The nitrogen-containing bisphosphonates pamidronate and zoledronate had the greatest impact on the cells, whereas clodronate followed by ibandronate was less distinct on cell function. These results underline the hypothesis that inhibited angiogenesis induced by bisphosphonates might be of relevance in the development and maintenance of BP-ONJ. The increased impact by highly potent bisphosphonates on HUVEC and EPC may explain the high prevalence of BP-ONJ in patients undergoing this treatment.

Diel IJ, Bergner R, Grotz KA (2007) Adverse effects of bisphosphonates: current issues. J Support Oncol 5(10):475–482PubMed

Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of jaws: a growing epidemic. J Oral Maxillofac Surg 61(9):1115–1117CrossRefPubMed

Walter C, Grotz KA, Kunkel M et al (2007) Prevalence of bisphosphonate associated osteonecrosis of the jaw within the field of osteonecrosis. Support Care Cancer 15(2):197–202CrossRefPubMed

Ruggiero SL, Dodson TB, Assael LA et al (2009) American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws—2009 update. J Oral Maxillofac Surg 67(5 Suppl):2–12PubMed

Hoff AO, Toth BB, Altundag K et al (2008) Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 23(6):826–836CrossRefPubMed

Boonyapakorn T, Schirmer I, Reichart PA et al (2008) Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol 44(9):857–869CrossRefPubMed

Walter C, Al-Nawas B, Grotz KA et al (2008) Prevalence and risk factors of bisphosphonate-associated osteonecrosis of the jaw in prostate cancer patients with advanced disease treated with zoledronate. Eur Urol 54(5):1066–1072CrossRefPubMed

Abu-Id MH, Warnke PH, Gottschalk J et al (2008) “Bis-phossy jaws”—high and low risk factors for bisphosphonate-induced osteonecrosis of the jaw. J Craniomaxillofac Surg 36(2):95–103PubMed

Lam DK, Sandor GK, Holmes HI et al (2007) A review of bisphosphonate-associated osteonecrosis of the jaws and its management. J Can Dent Assoc 73(5):417–422PubMed

10.

Landesberg R, Cozin M, Cremers S et al (2008) Inhibition of oral mucosal cell wound healing by bisphosphonates. J Oral Maxillofac Surg 66(5):839–847CrossRefPubMed

11.

Simon MJ, Niehoff P, Kimmig B et al. (2009) Expression profile and synthesis of different collagen types I, II, III, and V of human gingival fibroblasts, osteoblasts, and SaOS-2 cells after bisphosphonate treatment. Clin Oral Investig. In press

12.

Gerber HP, Ferrara N (2000) Angiogenesis and bone growth. Trends Cardiovasc Med 10(5):223–228CrossRefPubMed

13.

Asahara T, Masuda H, Takahashi T et al (1999) Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 85(3):221–228PubMed

14.

Asahara T, Murohara T, Sullivan A et al (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275(5302):964–967CrossRefPubMed

15.

Ziebart T, Yoon CH, Trepels T et al (2008) Sustained persistence of transplanted proangiogenic cells contributes to neovascularization and cardiac function after ischemia. Circ Res 103(11):1327–1334CrossRefPubMed

16.

Urbich C, Heeschen C, Aicher A et al (2005) Cathepsin L is required for endothelial progenitor cell-induced neovascularization. Nat Med 11(2):206–213CrossRefPubMed

17.

Allegra A, Oteri G, Nastro E et al (2007) Patients with bisphosphonates-associated osteonecrosis of the jaw have reduced circulating endothelial cells. Hematol Oncol 25(4):164–169CrossRefPubMed

18.

Santini D, Vincenzi B, Avvisati G et al (2002) Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res 8(5):1080–1084PubMed

19.

Hasmim M, Bieler G, Ruegg C (2007) Zoledronate inhibits endothelial cell adhesion, migration and survival through the suppression of multiple, prenylation-dependent signaling pathways. J Thromb Haemost 5(1):166–173CrossRefPubMed

20.

Mashiba T, Hirano T, Turner CH et al (2000) Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 15(4):613–620CrossRefPubMed

21.

Allen MR, Burr DB (2009) The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: so many hypotheses, so few data. J Oral Maxillofac Surg 67(5 Suppl):61–70CrossRefPubMed

22.

Conway EM, Collen D, Carmeliet P (2001) Molecular mechanisms of blood vessel growth. Cardiovasc Res 49(3):507–521CrossRefPubMed

23.

Aicher A, Kollet O, Heeschen C et al (2008) The Wnt antagonist Dickkopf-1 mobilizes vasculogenic progenitor cells via activation of the bone marrow endosteal stem cell niche. Circ Res 103(8):796–803CrossRefPubMed

24.

Soltau J, Zirrgiebel U, Esser N et al (2008) Antitumoral and antiangiogenic efficacy of bisphosphonates in vitro and in a murine RENCA model. Anticancer Res 28(2A):933–941PubMed

25.

Santini D, Vespasiani Gentilucci U, Vincenzi B et al (2003) The antineoplastic role of bisphosphonates: from basic research to clinical evidence. Ann Oncol 14(10):1468–1476CrossRefPubMed

26.

Wood J, Bonjean K, Ruetz S et al (2002) Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 302(3):1055–1061CrossRefPubMed

27.

Bezzi M, Hasmim M, Bieler G et al (2003) Zoledronate sensitizes endothelial cells to tumor necrosis factor-induced programmed cell death: evidence for the suppression of sustained activation of focal adhesion kinase and protein kinase B/Akt. J Biol Chem 278(44):43603–43614CrossRefPubMed

28.

Fournier P, Boissier S, Filleur S et al (2002) Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 62(22):6538–6544PubMed

29.

Okamoto T, Yamagishi S, Inagaki Y et al (2002) Incadronate disodium inhibits advanced glycation end products-induced angiogenesis in vitro. Biochem Biophys Res Commun 297(2):419–424CrossRefPubMed

30.

Yamada J, Tsuno NH, Kitayama J et al (2009) Anti-angiogenic property of zoledronic acid by inhibition of endothelial progenitor cell differentiation. J Surg Res 151(1):115–120CrossRefPubMed

31.

Frith JC, Monkkonen J, Blackburn GM et al (1997) Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5′-(beta, gamma-dichloromethylene) triphosphate, by mammalian cells in vitro. J Bone Miner Res 12(9):1358–1367CrossRefPubMed

32.

Nogawa M, Yuasa T, Kimura S et al (2005) Zoledronic acid mediates Ras-independent growth inhibition of prostate cancer cells. Oncol Res 15(1):1–9PubMed

33.

Bifulco M (2005) Role of the isoprenoid pathway in ras transforming activity, cytoskeleton organization, cell proliferation and apoptosis. Life Sci 77(14):1740–1749CrossRefPubMed

34.

Crick DC, Andres DA, Waechter CJ (1997) Novel salvage pathway utilizing farnesol and geranylgeraniol for protein isoprenylation. Biochem Biophys Res Commun 237(3):483–487CrossRefPubMed

Title: Bisphosphonates: restrictions for vasculogenesis and angiogenesis: inhibition of cell function of endothelial progenitor cells and mature endothelial cells in vitro
Authors: Thomas Ziebart
Andreas Pabst
Marcus Oliver Klein
Peer Kämmerer
Leonie Gauss
Dan Brüllmann
Bilal Al-Nawas
Christian Walter
Publication date: 01-02-2011
Publisher: Springer-Verlag
Published in: Clinical Oral Investigations / Issue 1/2011
Print ISSN: 1432-6981
Electronic ISSN: 1436-3771
DOI: https://doi.org/10.1007/s00784-009-0365-2

At a glance: The STEP trials

Springer Medicine

Bisphosphonates: restrictions for vasculogenesis and angiogenesis: inhibition of cell function of endothelial progenitor cells and mature endothelial cells in vitro

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2011

Assessment of factors associated with dental caries in rural communities in Rakai District, Uganda

Bone crestal height and bone density after third-molar extraction and grafting: a long-term follow-up study

Effects of metallic or translucent matrices for class II composite restorations: 4-year clinical follow-up findings

Fracture behaviour of implant–implant- and implant–tooth-supported all-ceramic fixed dental prostheses utilising zirconium dioxide implant abutments

Oral health in predialysis patients with emphasis on diabetic nephropathy

Periodontal surgery in furcation-involved maxillary molars revisited—an introduction of guidelines for comprehensive treatment