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Intermittent Parathyroid Hormone Mitigates Cyclophosphamide-Impaired Angiogenic-Osteogenic Patterns during Socket
Zhiwei Wang1, Naoki Tsuji2, Kazuto Hoshi3
1Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8655, Tokyo, Japan.
Background:
Medication-related osteonecrosis of the jaw (MRONJ) is characterized by impaired post-extraction bone healing, and altered angiogenesis has been implicated in its multifactorial pathogenesis. However, how vascular patterning evolves during impaired extraction socket healing remains insufficiently described. In this study, cyclophosphamide (Cy) and intermittent PTH (iPTH) were applied as opposing modulators of angiogenesis and osteogenesis to investigate how altered angiogenic patterning relates to bone regeneration during Cy-induced delayed extraction socket healing.
Materials And Methods:
Following Cy administration, six- to eight-week-old female C57BL/6J mice underwent maxillary first molar extraction, and iPTH was administered daily to designated groups. Samples were collected on day 3 and day 7. Newly formed vessels and bone in the extraction socket were assessed using micro-CT, histology, immunofluorescence staining, and qualitative lightsheet imaging. In vitro experiments using HUEhT-2 and MC3T3-E1 cells assessed how 4-hydroperoxy cyclophosphamide (4-HC) and iPTH influenced cell viability, migration, and functional behavior.
Results:
Cy treatment was associated with impaired early vascular growth and altered vascular morphology, together with reduced bone formation. Compared with Cy alone, iPTH was associated with greater vessel area and length on day 3 and more vascular branch points on days 3 and 7, but did not significantly improve all vascular or bone outcomes. In vitro, iPTH improved the viability and migration of 4-HC-treated HUEhT-2 endothelial cells, whereas clear recovery was not observed in MC3T3-E1 preosteoblast-like cells.
Conclusions:
Cy-induced delayed extraction socket healing was accompanied by vascular impairment, suggesting that altered angiogenesis may be one of several contributors to delayed healing. iPTH improved some vascular features but did not uniformly restore vascular or bone outcomes, indicating that angiogenic-osteogenic coupling in impaired extraction socket healing needs further study.
