Abstract
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a clinical condition that specifically occurs in the oral cavity, characterized by retarded wound healing in oral mucosa accelerating the exposure of bone. Moreover, the pathological mechanism remains poorly understood. Gingival mesenchymal stem cells (GMSCs) play a critical role in gingival healing and soft tissue regeneration. Although previous studies have showed that bisphosphonates (BPs) are highly toxic to healthy GMSC, there is overall lack of direct evidence demonstrating the characterization of GMSCs derived from BRONJ patients. In present study, we isolated GMSCs for the first time from the central area of BRONJ patients’ gingiva (center-BRONJ GMSCs) and the peripheral area (peri-BRONJ GMSCs), and found that they exhibited decreased proliferation, adhesion, migration capacities and underwent early apoptosis in vitro compared control GMSCs. Notably, the central and peripheral BRONJ GMSCs transplantation in a mice excisional skin model also displayed lower cell survival rate and poor healing effects than that of controls. Mechanistically, TGF-β1 signaling pathway was suppressed not only in BRONJ patients’ gingival lesions but also in BRONJ GMSCs transplantation animal model. The results above suggested that under the microenvironment of BRONJ patients, the dysfunction of GMSCs and the suppressed TGF-β1 signaling pathway may be the vital factors in impaired gingival healing, thus contributing to persistent exposure of underlying bone and development of BRONJ. This study provides new insights into the prevention for BRONJ by improving the functions of GMSCs and upregulating TGF-β1 in accelerating gingival wound healing.Graphical Schematic illustration of the dysfunction of BRONJ GMSCs in vitro and BRONJ GMSCs transplantation in a mice skin model delaying cutaneous wound healing mainly via suppressing TGF-β1 signaling pathway.
Highlights
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a detrimental side effect that occurs in the oral cavity in cancer patients receiving high doses of intravenous bisphosphonates (BPs), severely affecting patients’ quality of life [1]
Apoptosis was evaluated as the number of TUNEL + cells in different groups (Fig. 1E), similar levels of TUNEL + cells existed between the center and peripheral area of BRONJ lesions, but the apoptotic cells in BRONJ lesions were significantly higher than in healthy gingival tissues (Fig. 1G)
The central and peripheral BRONJ Gingival mesenchymal stem cells (GMSCs) transplantation in a mice excisional skin model consistently exhibited poor wound healing effects than that of control group
Summary
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a detrimental side effect that occurs in the oral cavity in cancer patients receiving high doses of intravenous bisphosphonates (BPs), severely affecting patients’ quality of life [1]. Extended author information available on the last page of the article unclear why such the lesion should present with soft tissue defects as the primary clinical feature [2]. It is not known whether the BRONJ lesion initiates in the underlying bone or the superficial soft tissue. While numerous reports have been focusing on origin from the bone regarding the pathogenesis of BRONJ [4,5,6,7], our clinical observation that the progressive enlargement of gingiva defects in most BRONJ patients has inspired us to begin to investigate the microenvironment of oral mucosa as well as its role in the development of BRONJ. In comparison to other parts of the human body, the gingiva represent a unique oral tissue that
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
