School of Podiatric Medicine Publications
Document Type
Article
Publication Date
10-27-2025
Abstract
Diabetes significantly impairs bone healing via several mechanisms, including sustained inflammation, oxidative stress, and poor osteogenic responses. Fully reduced isoform of High Mobility Group Box 1 with three serine substitutions (3S-HMGB1) has shown regenerative properties while being resistant to oxidative degradation.
Objective: This study evaluated the therapeutic potential of a single local injection of 3S-HMGB1 in early osseointegration under diabetic conditions in mice.
Methodology: A total of 48 male 129/Sv mice (24 non-diabetic [ND], 24 diabetic [D]) received titanium implants following maxillary first molar extraction. ND and D mice (n:12) were injected with either saline (control) or 3S-HMGB1 (0.75 mg/kg) into the fresh extraction socket. Osseointegration was evaluated at 7 and 21 days post-implantation using microCT, histology (bone-to-implant contact [BIC] and birefringence), and immunohistochemistry for Runx2 and CXCR4.
Results: ND controls exhibited early osteogenic activity, with a predominance of Runx2-positive cells at 7 days and successful osseointegration by 21 days. In contrast, D controls showed reduced numbers of Runx2-positive cells and markedly lower BV/TV, indicating compromised bone healing at 21 days. Treatment with 3S-HMGB1 resulted in significantly increased bone volume at the implant site in D animals (55.6±7.20% vs. 44.6±6.23%) and restored BIC from 44.9±9.32% (D controls) to 61.78±11.31% (D 3S-HMGB1), near ND levels (65.16±7.64%). Both ND and D groups treated with 3S-HMGB1 presented enhanced collagen organization. No significant differences were found in CXCR4 between groups; however, in D animals, a distinct peri-implant staining pattern suggested impaired recruitment despite preserved stem cell niches in the bone marrow.
Conclusions: Collectively, our findings indicate that a single injection of redox-stable 3S-HMGB1 may represent a promising regenerative strategy to mitigate early implant failure in diabetes. Future studies should explore sustained delivery approaches to enhance long-term outcomes.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Publication Title
Journal of Applied Oral Science
Academic Level
faculty
DOI
10.1590/1678-7757-2025-0358
Comments
This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.