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

Area of Science:

• Oral and Maxillofacial Surgery
• Bone Biology
• Angiogenesis Research

Background:

• Pre-osteoclasts are implicated in alveolar bone healing after dental trauma.
• The SDF-1/CXCR4 pathway is a potential mediator of this process.
• Medication-related osteonecrosis of the jaw (MRONJ) involves impaired bone healing.

Purpose of the Study:

• To investigate the role of pre-osteoclast signaling in post-traumatic alveolar bone angiogenesis.
• To determine the effect of zoledronate (Zol) on the SDF-1/CXCR4 pathway and subsequent angiogenesis.
• To explore the potential link between Zol-induced disruption and MRONJ pathogenesis.

Main Methods:

• In vitro assessment of zoledronate's effect on SDF-1 expression in pre-osteoclasts.
• In vitro evaluation of conditioned media from zoledronate-treated pre-osteoclasts on HUVEC behavior (differentiation, migration, tube formation, CXCR4 expression).
• In vivo quantification of zoledronate's impact on post-traumatic alveolar bone vascularization in rats using microCT-angiography and immunohistochemistry.

Main Results:

• Zoledronate significantly reduced SDF-1 expression in pre-osteoclasts and CXCR4 expression/activity in HUVECs.
• Zoledronate inhibited HUVEC migration and tube formation, effects reversible by SDF-1.
• In vivo, zoledronate treatment led to reduced CD31+ HUVECs, blood vessel volume, and vessel number in rat alveolar bone.

Conclusions:

• Pre-osteoclasts are essential for initiating angiogenesis in alveolar bone post-trauma.
• Disruption of the SDF-1/CXCR4 pathway by zoledronate impairs this angiogenic response.
• This impairment may represent a key factor in the development of MRONJ.