Voriconazole Enhances the Osteogenic Activity of Human Osteoblasts In Vitro through a Fluoride-Independent Mechanism.
Periostitis, which is characterized by bony pain and diffuse periosteal ossification, has been increasingly reported with prolonged clinical use of voriconazole. While resolution of clinical symptoms following discontinuation of therapy suggests a causative role for voriconazole, the biological mechanisms contributing to voriconazole-induced periostitis are unknown. To elucidate potential mechanisms, we exposed human osteoblasts in vitro to voriconazole or fluconazole at 15 or 200 μg/ml (reflecting systemic or local administration, respectively), under nonosteogenic or osteogenic conditions, for 1, 3, or 7 days and evaluated the effects on cell proliferation (reflected by total cellular DNA) and osteogenic differentiation (reflected by alkaline phosphatase activity, calcium accumulation, and expression of genes involved in osteogenic differentiation). Release of free fluoride, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) was also measured in cell supernatants of osteoblasts exposed to triazoles, with an ion-selective electrode (for free fluoride) and enzyme-linked immunosorbent assays (ELISAs) (for VEGF and PDGF). Voriconazole but not fluconazole significantly enhanced the proliferation and differentiation of osteoblasts. In contrast to clinical observations, no increases in free fluoride levels were detected following exposure to either voriconazole or fluconazole; however, significant increases in the expression of VEGF and PDGF by osteoblasts were observed following exposure to voriconazole. Our results demonstrate that voriconazole can induce osteoblast proliferation and enhance osteogenic activity in vitro. Importantly, and in contrast to the previously proposed mechanism of fluoride-stimulated osteogenesis, our findings suggest that voriconazole-induced periostitis may also occur through fluoride-independent mechanisms that enhance the expression of cytokines that can augment osteoblastic activity.
Infectious Disease Service, Department of Medicine, San Antonio Military Medical Center, JBSA Fort Sam Houston, San Antonio, Texas, USA.
Kahtonna C
KC
Allen
Extremity Trauma and Regenerative Medicine Task Area, U.S. Army Institute of Surgical Research, JBSA Fort Sam Houston, San Antonio, Texas, USA.
Carlos J
CJ
Sanchez
Extremity Trauma and Regenerative Medicine Task Area, U.S. Army Institute of Surgical Research, JBSA Fort Sam Houston, San Antonio, Texas, USA.
Krista L
KL
Niece
Extremity Trauma and Regenerative Medicine Task Area, U.S. Army Institute of Surgical Research, JBSA Fort Sam Houston, San Antonio, Texas, USA.
Joseph C
JC
Wenke
Infectious Disease Service, Department of Medicine, San Antonio Military Medical Center, JBSA Fort Sam Houston, San Antonio, Texas, USA Extremity Trauma and Regenerative Medicine Task Area, U.S. Army Institute of Surgical Research, JBSA Fort Sam Houston, San Antonio, Texas, USA kevin.s.akers.mil@mail.mil.
Kevin S
KS
Akers
D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000935:Antifungal Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015725:Fluconazole / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D015398:Signal Transduction; D012969:Sodium Fluoride / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D065819:Voriconazole / Q000494:pharmacology*
D000935:Antifungal Agents; D010982:Platelet-Derived Growth Factor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D015725:Fluconazole; D012969:Sodium Fluoride; D000469:Alkaline Phosphatase; D065819:Voriconazole; D002118:Calcium