Short-Term Administration of HIV Protease Inhibitor Saquinavir Improves Skull Bone Healing with Enhanced Osteoclastogenesis.

Abstract

BACKGROUND:

Using immunomodulatory methods to address the challenging issue of craniofacial bone repair may be a potentially effective approach. The protease inhibitor saquinavir has been shown to inhibit the inflammatory response by targeting the toll-like receptor 4/myeloid differentiation primary response complex. Independently, inhibition of toll-like receptor 4 or myeloid differentiation primary response led to enhanced skull bone repair. Therefore, the authors aimed to investigate the effects of saquinavir on skull bone healing.

METHODS:

The effects of saquinavir on skull bone healing were assessed by means of gene expression, histology, immunohistochemistry, and tomography in a mouse calvarial defect model. Subsequently, the role of saquinavir in cell viability, migration, and osteogenic and osteoclastogenic differentiation was also evaluated in vitro.

RESULTS:

One-week saquinavir administration improved skull bone healing based on micro-computed tomographic and histomorphometric analyses. Compared to the vehicle control, 1-week saquinavir treatment (1) enhanced osteoclast infiltration (tartrate-resistant acid phosphatase staining) at day 7, but not at days 14 and 28; (2) induced more CD206 + M2 macrophage infiltration, but not F4/80 + M0 macrophages at days 7, 14, and 28; and (3) elevated osteoclastogenic gene RANKL (quantitative polymerase chain reaction) expression and other osteogenic and cytokine expression. Furthermore, in vitro data showed that saquinavir administration did not influence MC3T3-E1 cell migration or mineralization, whereas higher concentrations of saquinavir inhibited cell viability. Saquinavir treatment also enhanced the osteoclastic differentiation of bone marrow-derived precursors, and partially reversed high-mobility group box 1-driven osteoclastogenesis inhibition and elevated proinflammatory cytokine expression.

CONCLUSION:

The improved skull bone repair following short-term saquinavir treatment may involve enhanced osteoclastogenesis and modulated inflammatory response following skull injury.

CLINICAL RELEVANCE STATEMENT:

The authors' work demonstrates improved skull bone healing by short-term application of saquinavir, a drug traditionally used in the treatment of acquired immunodeficiency syndrome. As such, saquinavir may be repurposed for skeletal repair.

• Authors: Haixia Liu, Yun Shen, Bingkun Zhao, Enoch H Poon, Shengcai Qi, Dai Fei Elmer Ker, Timothy R Billiar, Gregory M Cooper, Yuanzhi Xu, Dan Wang
• Journal: Plastic and reconstructive surgery (Plast Reconstr Surg) Vol. 150 Issue 6 Pg. 1264e-1274e (12 01 2022) ISSN: 1529-4242 [Electronic] United States
• PMID: 36112847 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.

Chemical References

• Saquinavir
• HIV Protease Inhibitors
• Toll-Like Receptor 4

Topics

• Mice
• Animals
• Saquinavir (pharmacology, metabolism, therapeutic use)
• HIV Protease Inhibitors (pharmacology, metabolism, therapeutic use)
• Toll-Like Receptor 4 (physiology)
• Osteogenesis
• Skull (injuries)