Bisphosphonate‐induced reactive oxygen species inhibit proliferation and migration of oral fibroblasts: A pathogenesis of bisphosphonate‐related osteonecrosis of the jaw

Abstract

BackgroundThe onset mechanism for bisphosphonate‐related osteonecrosis of the jaw (BRONJ) has been reported, with a focus on bone remodeling, biofilm formation, and epithelial cell proliferation and migration. However, the involvement of stromal cells, especially fibroblasts, in the oral cavity is unclear. Therefore, this study was focused on how bisphosphonates (BPs) affect orthotopic periodontal ligament fibroblasts from the viewpoint of oxidative stress compared with ectopically obtained fibroblasts.MethodsNormal human periodontal ligament fibroblasts (HPdLFs) and normal human dermal fibroblasts (NHDFs) were used to gain insight into the functional differences in sensitivity and reactions to BPs. Cell growth assay, measurement of reactive oxygen species (ROS) and nitric oxide (NO) production, and wound‐healing assay in vitro were performed. Maxillary first molars were extracted in C57BL/6 mice and either BP, N‐acetyl‐cysteine (NAC), and BP or saline were administered.ResultsBP‐induced IC50 values were significantly lower in HPdLFs (30.6 µM) than in NHDFs (109.7 µM). BP resulted in an increase in ROS, but not NO generation in HPdLFs. BPs also inhibited proliferation and migration of HPdLFs but not NHDFs, while the addition of a ROS inhibitor, NAC, reversed those inhibitions. A BRONJ mouse model in which BP was administered and then the tooth was extracted, impaired wound healing of the socket was observed. When NAC was administered before tooth extraction, wound healing was significantly improved.ConclusionThese results suggest that BP causes fibroblasts obtained from the oral cavity but not from skin to generate ROS and that the subsequent ROS‐mediated inhibition of fibroblast growth and migration definitely delays wound healing, thereby contributing to BRONJ pathogenesis.

Various Therapeutic Methods for the Treatment of Medication-Related Osteonecrosis of the Jaw (MRONJ) and Their Limitations: A Narrative Review on New Molecular and Cellular Therapeutic Approaches

“…Starting with a study by Bagan et al [ 45 ] in 2014, which reported that oxidative stress was detected in the MRONJ patients, animal experiments and clinical studies focusing on oxidative stress as a pathophysiological mechanism of MRONJ have been actively conducted in recent years. It is noteworthy that oxidative stress and bisphosphonate may induce osteonecrosis of the jaw after an invasive dentoalveolar surgery in mice [ 46 ] and that bisphosphonate-induced ROS could delay wound healing by preventing the growth and migration of oral fibroblasts [ 47 ]. Besides, it is interesting that hypotaurine, which acts as an antioxidant associated with cellular defense against oxidative stress, was significantly elevated in patients’ saliva with MRONJ and thus showed potential as a new biomarker for the early detection of MRONJ [ 48 ].…”

Pathogenesis and multidisciplinary management of medication-related osteonecrosis of the jaw

“…43 BPs increase apoptosis and decrease proliferation in a number of cell types in vitro. 12,13 In addition, the administration of zoledronic acid to oral gingival fibroblasts in vitro has been found to reduce the expression of extracellular matrix (ECM) proteins, including collagens I, II and III. 44 It has been shown that impairment of TGF-β1 signalling is related to oral mucosal soft tissue repair in BRONJ.…”

“…11 A recent report suggested that BPs can induce the production of reactive oxygen species, which inhibit the proliferation and migration of oral fibroblasts, thereby contributing to the pathogenesis of BRONJ. 12 Li et al 13 found that cell proliferation, adhesion, migration and osteogenic differentiation of periodontal ligament stem cells decreased significantly as a result of BRONJ lesions, a factor possibly important in the underlying mechanisms of BRONJ.…”

The Outcome of Bisphosphonate-Related Osteonecrosis of the Jaw Patients’ Gingiva-Derived Mesenchymal Stem Cells on Wound Healing in a Mice Excisional Skin Model.

“…Gingival mesenchymal stem cells (GMSCs) are a group of stem cells isolated from the gingival lamina propria, and perform remarkable tissue regenerative potential and noteworthy immunomodulatory properties (8). Previous studies have showed that BPs inhibited healthy GMSCs viability and brogenesis in vitro (5,(9)(10)(11), however, there is a lack of direct evidence demonstrating the regeneration capacity of oral mucosa in BRONJ patients.…”