Research Article Synergistic Enhancement of Bone Fracture Healing Using frHMGB1 and Metformin in Diabetic Rats
by Jianying Zhang1, Kengo Shimozaki1, Roshawn Brown1, MaCalus V Hogan1,2, Jarrett Cain1,3, James H-C Wang1-3*
1MechanoBiology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, USA
2Department of Bioengineering, University of Pittsburgh, USA
3Department of Physical Medicine and Rehabilitation, University of Pittsburgh, USA
*Corresponding author: James HC Wang, Department of Orthopaedic Surgery, University of Pittsburgh, E1640 BST, 200 Lothrop Street, Pittsburgh, PA, USA.
Received Date: 20 September, 2024
Accepted Date: 27 September, 2024
Published Date: 03 October, 2024
Citation: Zhang J, Shimozaki K, Brown R, Hogan MV, Wang JHC, et al. (2024) Synergistic Enhancement of Bone Fracture Healing Using frHMGB1 and Metformin in Diabetic Rats. J Orthop Res Ther 9: 1362. https://doi.org/10.29011/2575-8241.001362
Abstract
Background: In diabetic patients, the healing process of bone fractures is impaired. This study aimed to assess the effects of combining fully-reduced high mobility group box 1 (frHMGB1) and metformin (Met) on bone fracture healing in diabetic rats. Methods: Diabetes was induced in Sprague Dawley rats via streptozotocin (STZ) injection followed by tibia bone fracture. Rats were treated with local frHMGB1 injection weekly, or Met intraperitoneal (IP) injection daily, and/or combined frHMGB1 with Met IP injection for 28 or 90 days. Untreated rats served as controls. HMGB1 and IL-1β levels in blood were analyzed using ELISA. Bone tissues from the tibia fracture site were assessed for healing through visual inspection, micro-CT imaging, and histological examinations. Results: frHMGB1 treatment alone improved non-union fracture healing by promoting cell growth, fibroblast migration, and collagen synthesis, albeit leading to fibro-cartilaginous tissue formation at fracture sites. Conversely, met treatment alone resulted in higher quality bone tissue formation by reducing inflammation, restraining fibroblast migration, enhancing AMPK activity, and decreasing collagen III synthesis. Combined frHMGB1 and Met treatment was more effective, decreasing collagen III levels, increasing collagen I levels at fracture sites, and significantly enhancing healing by fostering bone tissue formation. frHMGB1 treatment enhanced non-union bone fracture healing but may induce fibrocartilage tissue due to extensive cell recruitment to the wound area. Conclusion: Combining Met with frHMGB1 improves fractured bone healing by inhibiting frHMGB1 activity, reducing cell migration, and controlling collagen production, thereby forming high-quality bone tissue that can enhance diabetic bone fracture healing in high-risk patients.
Keywords: Diabetes; Bone fracture; frHMGB1; Metformin; AMPK
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