Zoledronate interrupts pre-osteoclast-induced angiogenesis via SDF-1/CXCR4 pathway.

Introduction: In this study, we tested the hypothesis that pre-osteoclast signaling is key in triggering post-traumatic angiogenesis in alveolar bone via the SDF-1/CXCR4 pathway. Interruption of osteoclast differentiation through zoledronate (Zol) disrupts the crosstalk between pre-osteoclasts and endothelial cells, hindering the initial angiogenic reaction following dental trauma. This disruption could therefore play a role in the pathogenesis of medication-related osteonecrosis of the jaw (MRONJ).
Methods: The effect of zoledronate on the expression of SDF1 was tested in pre-osteoclasts (POC) in vitro. Then, we tested the effect of pre-osteoclast conditioned medium on HUVEC cell differentiation, migration, tube-formation, and CXCR4 expression and activity in-vitro. Lastly, we quantified the effect of zoledronate treatment on post-traumatic vascular perfusion of alveolar bone, using microCT-angiography and immunohistochemistry.
Results: SDF-1 mRNA expression decreased in Zol-treated POCs ( p  = 0.02). Flow-Cytometry analysis showed a decrease in CXCL-12 ⁺ (SDF-1α) expressing POCs with Zol treatment ( p  = 0.0058). On the other hand, CXCR4 mRNA expression was significantly inhibited in Zol-treated HUVECs ( p  = 0.0063). CXCR4 protein expression and activity showed a corresponding dose-dependent downregulation HUVEC surface treated with conditioned media from POC treated with Zol ( p  = 0.008 and 0.03, respectively). Similar inhibition was observed of HUVEC migration ( p  = 0.0012), and tube formation ( p  < 0.0001), effects that were reversed with SDF-1. Finally, there was a significant reduction of CD31 ⁺ HUVECs in Alveolar bone of Zol-treated rats ( p  = 0.0071), confirmed by significantly lower percentage of blood vessel volume ( p  = 0.026), and marginally lower vessel number ( p  = 0.062) in the alveolar bone.
Conclusion: Pre-osteoclasts play a crucial role in the initial angiogenic response in alveolar bone following dental extraction. Disruption of this process may be a predisposing factor to osteonecrosis.
Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mohammed Elsalanty reports financial support was provided by 10.13039/100000002National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(© 2024 The Authors.)