Zoledronate Inhibits αvβ3 and αvβ5 Integrin Cell Surface Expression in Endothelial Cells

Abstract

Zoledronate exhibits antiangiogenic properties in vitro and in vivo. Integrins alphavbeta3 and alphavbeta5 are involved in angiogenesis. Because zoledronate inhibits endothelial cell adhesion, the authors explored the hypothesis that it could alter these integrins recruitment to focal adhesion sites. Human umbilical vein endothelial cells (HUVECs) were treated with zoledronate or with mevalonate pathway intermediates geranylgeraniol (GGOH) and farnesol (FOH). Zoledronate generated a significant decrease in alphavbeta3 and alphavbeta5 expression at HUVEC cell surface using flow cytometry and immunofluorescence. This inhibition was reversed by GGOH but not by FOH. Cells cotreated with zoledronate and GGOH were able to attach to vitronectin through alphavbeta3 and alphavbeta5, as confirmed by the use of specific function-blocking antibodies. The authors showed that zoledronate alters endothelial cell integrin-mediated adhesion. This effect is likely to contribute to the previously demonstrated antiangiogenic effect of zoledronate. Whether this mechanism of action also applies to metastatic tumor cells is under investigation.

Anti-Angiogenic Property of Zoledronic Acid by Inhibition of Endothelial Progenitor Cell Differentiation

“…As expected, it could also completely override the inhibitory effects of ZOL on EPCs. It has been shown in other reports to reverse the effect of ZOL, such as the decreased expression of integrins ␣V␤3 and ␣V␤5 [27].…”

Site Specific Effects of Zoledronic Acid during Tibial and Mandibular Fracture Repair

“…Impaired angiogenesis could result from delayed hypertrophy and delayed VEGF expression in cartilage. Several studies reported that bisphosphonates interfere with the angiogenic process through various molecular pathways [37]–[41]. This delay in re-vascularisation of the fracture site might also affect cartilage formation.…”

Zoledronic acid effectiveness against breast cancer metastases - a role for estrogen in the microenvironment?

“…In mouse tumors comprised of species-specific breast cancer and stromal cells, Saarinen and colleagues demonstrated estrogen induction of the angiogenic cytokines in the stroma, implicating these as mediators of host angio-genesis [33]. In addition, estrogen has been reported to upregulate α 5 -integrin [34] whereas ZA downregulates these integrins and adhesion in endothelial cells [35]. …”