33 - Osteoclasts-induced Post-traumatic Angiogenesis in Alveolar Bone via SDF-1/CXCR4 Pathway

Poster Board Number: 33
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Co-authors:

Mohammed Awad - GRU Medical College of Georgia; Amany Tawfik - Oakland University, William Beaumont School of Medicine; james Borke - Western University of Health Sciences; William Hill - Medical University of South Carolina; Mohammed Elsalanty - Western University of Health Sciences

Abstract Body :Osteoclasts-induced post-traumatic angiogenesis in alveolar bone via SDF-1/CXCR4 pathway
Introduction and Objective: In this study, we hypothesize that pre-osteoclasts play a major role in the induction of post-traumatic angiogenesis through the SDF-1/CXCR4 pathway. Inhibition of osteoclast differentiation by the bisphosphonate zoledronate (Zol) reduces communication between pre-osteoclasts and endothelial cells, impairing the early angiogenic response after dental extraction and contributing to the induction of medication-related osteonecrosis of the jaw (MRONJ).

Materials and Methods: The effect of zoledronate on the expression of SDF1 was tested in murine pre-osteoclasts (POC) in vitro. We then tested the effect of pre-osteoclast conditioned medium on HUVEC cell differentiation, migration, tube-formation, and CXCR4 expression and activity in-vitro via Western Blots. Lastly, we quantified the effect of zoledronate treatment on post-traumatic vascular perfusion of alveolar bone using microCT-angiography.

Results: SDF-1 mRNA expression decreased in Zol-treated POCs (p=0.02). Flow-Cytometry analysis showed a decrease in CXCL-12⁺ (SDF-1a) 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). CXCR-4 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⁺ ECs 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 significant role in early post-extraction angiogenic response in alveolar bone. Zoledronic Acid interrupts angiogenesis-osteogenesis coupling by reducing SDF-1 expression and downregulates CXCR-4 expression and activity. The impairment of both of these molecules could be a predisposing factor to zoledronate induced osteonecrosis after tooth extraction.