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

Abstract

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

Angiogenesis in the Development of Medication-Related Osteonecrosis of the Jaws: An Overview

“…For a long time it has been assumed that (III) intussusception has a special importance during embryonic development and is only a minor player in adults. This thesis had to be reconsidered since recent studies have demonstrated that intussusception does also have a key role in adults [ 21 , 33 , 34 ]. The current in vitro and in vivo studies strictly focused on sprouting angiogenesis from HUVEC cell spheroids in vitro or from preexisting blood vessels in murine matrigel assays in vivo [ 21 , 22 , 23 ].…”

“…This thesis had to be reconsidered since recent studies have demonstrated that intussusception does also have a key role in adults [ 21 , 33 , 34 ]. The current in vitro and in vivo studies strictly focused on sprouting angiogenesis from HUVEC cell spheroids in vitro or from preexisting blood vessels in murine matrigel assays in vivo [ 21 , 22 , 23 ]. The influence of bisphosphonates on special types of angiogenesis, such as intussusceptive angiogenesis, has not yet been sufficiently explored and might be an interesting topic for further studies.…”

“…In vivo studies on this topic are still missing. In this context, the mode of GGOH application (topically vs. systemically) is often discussed in the literature [ 16 , 21 , 22 , 24 ]. The systemic application of GGOH has been reported to be dangerous because it can reduce the systemic power of the bisphosphonates in the entire organism, which can be especially critical for malignancies.…”

“…For controls and clodronate, no significant differences could be detected within the experimental set-ups with or without GGOH substitution. In contrast, the strong negative influence of nitrogen-containing bisphosphonates (pamidronate and zoledronate) on microvessel sprouting could be significantly reversed by GGOH substitution [ 21 ]. To summarize, the recent studies concerning the influence of GGOH on angiogenesis, revascularization, and microvessel sprouting after bisphosphonate substitution clarified that GGOH is able to reverse bisphosphonates’ strong negative influence on angiogenesis in vitro and might be a promising candidate for MR-ONJ prevention and therapy since supportive therapeutic options for MR-ONJ are lacking.…”

“…The role of angiogenesis might be very relevant since angiogenesis plays a fundamental key role in wound healing as well as in soft and hard tissue regeneration (oral mucosa and jaw); further, reduced angiogenesis could explain both clinical manifestations of MR-ONJ: reduced wound healing of oral soft tissues as well as avascular and necrotic bone in the context of MR-ONJ. Bisphosphonates might contact and influence blood vessel development, and thereby MR-ONJ development, in two different ways: (I) through high circulating bisphosphonate concentrations in the entire circulatory system immediately after intravenous bisphosphonate application and (II) in the region of wound healing (e.g., the oral cavity) where new blood vessels should sprout into a wound in the presence of high local bisphosphonate concentrations in the bone and the surrounding soft tissues [ 21 ].…”