Zoledronate interrupts pre-osteoclast-induced angiogenesis via SDF-1/CXCR4 pathway.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39583183.
- Also identified by DOI 10.1016/j.bonr.2024.101812 and PMC identifier 11585646.
- Licence recorded as CC BY-NC.
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Abstract
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). 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. SDF-1 mRNA expression decreased in Zol-treated POCs (<i>p</i> = 0.02). Flow-Cytometry analysis showed a decrease in CXCL-12<sup>+</sup> (SDF-1α) expressing POCs with Zol treatment (<i>p</i> = 0.0058). On the other hand, CXCR4 mRNA expression was significantly inhibited in Zol-treated HUVECs (<i>p</i> = 0.0063). CXCR4 protein expression and activity showed a corresponding dose-dependent downregulation HUVEC surface treated with conditioned media from POC treated with Zol (<i>p</i> = 0.008 and 0.03, respectively). Similar inhibition was observed of HUVEC migration (<i>p</i> = 0.0012), and tube formation (<i>p</i> < 0.0001), effects that were reversed with SDF-1. Finally, there was a significant reduction of CD31<sup>+</sup> HUVECs in Alveolar bone of Zol-treated rats (<i>p</i> = 0.0071), confirmed by significantly lower percentage of blood vessel volume (<i>p</i> = 0.026), and marginally lower vessel number (<i>p</i> = 0.062) in the alveolar bone. 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.