1. Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
2. Department of Medicine, University of California Los Angeles, CA, USA
3. Smidt Heart Institute, Department of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
4. Division of Orthodontics, College of Dentistry, The Ohio State University, Columbus, OH, USA
5. Division of Oral Surgery, College of Dentistry, The Ohio State University, Columbus, OH, USA
6. Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, USA
Objectives: Bisphosphonates (BPs) are powerful inhibitors of osteoclastogenesis and are used to prevent osteoporotic bone loss and reduce the risk of osteoporotic fracture in patients suffering from postmenopausal osteoporosis. Patients with breast cancer or gynecological malignancies being treated with BPs or those receiving bone-targeted therapy for metastatic prostate cancer are at increased risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Although BPs markedly ameliorate osteoporosis, their adverse effects largely limit the clinical application of these drugs. This study focused on providing a deeper understanding of one of the most popular BPs, the alendronate (ALN)-induced perturbation of the bone proteome and microenvironmental pathophysiology.
Methods: To understand the molecular mechanisms underlying ALN-induced side-effects, an unbiased and global proteomics approach combined with big data bioinformatics was applied. This was followed by biochemical and functional analyses to determine the clinicopathological mechanisms affected by ALN.
Results: The findings from this proteomics study suggest that the RIPK3/Wnt/GSK3/β-catenin signaling pathway is significantly perturbed upon ALN treatment, resulting in abnormal angiogenesis, inflammation, anabolism, remodeling, and mineralization in bone cells in an in vitro cell culture system.
Conclusion: Our investigation into potential key signaling mechanisms in response to ALN provides a rational basis for suppressing BP-induced adverse effect and presents various therapeutic strategies.
Keywords: Osteonecrosis of the jaw, bisphosphonate, GSK signaling, clinical cone beam computed tomography, bone mineral density, proteomics, biomarker