Intravenous Transplantation of Apoptosis Repressor with Caspase Recruitment Domain-Overexpressing Mesenchymal Stem Cells Promotes Bone Formation in Bisphosphonate-Related Osteonecrosis of the Jaw Rats

Article Intravenous Transplantation of Apoptosis Repressor with Caspase Recruitment Domain-Overexpressing Mesenchymal Stem Cells Promotes Bone Formation in Bisphosphonate-Related Osteonecrosis of the Jaw Rats Ruixue Jiang 1,2,†, Yuwei Deng 1,2,†, Yuhui Zhu 1,2, Jin Wen 1,2, Xinquan Jiang 1,2,* and Longwei Hu 2,3,* 1 Department of Prosthodontics, Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China 2 Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China 3 Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China * Correspondence: [email protected] (X.J.); [email protected] (L.H.) † These authors contributed equally to this work. Received: 18 October 2024; Revised: 17 November 2024; Accepted: 20 November 2024; Published: 29 November 2024 Abstract: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious complication caused by the application of bisphosphonates (BPs) which are widely used in bone metastasis, osteoporosis and other metabolic bone diseases. Since bone marrow-derived mesenchymal stem cells (BMSCs) dysfunction potentially plays a critical role in the development of BRONJ, purposefully improving the function of BMSCs may help reduce the symptoms of BRONJ. Apoptosis repressor with caspase recruitment domain (ARC) can inhibit cell apoptosis and cell death, and was confirmed to possess an obvious reparative function in damaged tissues recently. Therefore, we aimed to investigate whether transplantation of ARC-overexpressing BMSCs had a therapeutic effect on BRONJ and explored possible mechanisms. First, we successfully established the BRONJ rat model and confirmed that BRONJ-derived BMSCs showed decreased proliferation and osteogenic differentiation ability. However, ARC-overexpressing BMSCs showed a significant therapeutic effect on BRONJ by promoting osteogenesis and inhibiting osteoclasts. The BRONJ tissue treated with ARC-overexpressing BMSCs also showed a decreased level of cell apoptosis. Further the RNA sequencing and bioinformatics results suggested that ARC can regulate BMSCs by inhibiting the TNF-α (tumor necrosis factor-α) pathway increased in the BRONJ samples and may alleviate the disease by reducing pro-inflammatory potential of BRONJ-derived BMSCs. In summary, ARC-overexpressing BMSCs can effectively repair BRONJ necrotic bone tissue which provides new ideas for the clinical treatment of BRONJ.