Abstract 1257: Microarray analysis of BRONJ-like oral mucosal lesions in mice

Abstract

Abstract Bisphosphonates (BPs) are potent anti-resorptive agents that are widely used to treat bone-associated diseases including metastatic bone cancer. Many reports have indicated that long-term use of BPs can develop BP-related osteonecrosis of the jaw (BRONJ) that occurs largely at the site of tooth extraction; however, the pathophysiology of BRONJ is still poorly understood. Clinically, BRONJ is defined as exposed necrotic bone with unhealed and open oral mucosa, implying that the lack of wound closure may be caused either directly by BPs or indirectly via biological signals (i.e., cytokines) from the BP-affected surrounding structures. We hypothesize that oral mucosal tissues lose their capacity to close the wound properly at the affected sites and that the genes involved in wound healing processes are differentially expressed between BRONJ lesions and the normal counterparts. To test our hypothesis, we utilized the established BRONJ mice model. Zometa was administered via tail vein 1 week prior to tooth extraction. After extracting the upper first molar, the extracted socket was allowed to heal, and the overlaying oral mucosal tissues were harvested after 2 weeks from control and BRONJ groups (n=3). The fresh tissue samples were subjected to RNA isolation, cDNA sysnthesis, and cDNA hybridization onto microarray chip (Affymetrix MG 430 2.0). The data analysis by functions using IPA software revealed that the genes involved in skeletal and muscular disorders, dermatological diseases, cellular movement, cellular assembly and organization, and inflammatory disease were significantly associated with BRONJ. In particular, we found that growth factors (i.e., Igf2, Fgf7, Pdf2bp2), collagens (i.e., Col1a1, Col1a2, Col2a1, Col2a2, Col5a1, Col5a2, Col11a1, and Col11a2), and non-collagenous proteins (i.e., DMP-1, ITBP, and SPP1) were significantly down-regulated in BRONJ groups. Taken together, our study suggests that the diminution of growth factors as well as collagenous and non-collagenous structural proteins may be associated with the development of BRONJ. This study was supported by NIDCR/NIH (R03DE021114 and K08DE017121). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1257. doi:1538-7445.AM2012-1257