A Meta-analysis of immune signaling pathways between human type 2 diabetic tissue and mouse bone repair

Abstract

Type II diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin insensitivity, hyperglycemia, and immune dysregulation. Recent findings have shown that T2DM has a significant impact on the skeletal system, including the impairment of the fracture healing process which commonly leads to nonunion. Throughout the process, heterotypic interactions between different immune cells are required for the recruitment and differentiation of osteogenic cells vital for fracture repair. The purpose of this study was to compare inflammatory gene expression induced in T2DM with those occurring during fracture repair with a specific focus on immune cell expression. Using publicly available RNA-seq datasets and Ingenuity Pathway Analysis (IPA), we compared gene expression profiles of human diabetic and non-diabetic data to gene expression profiles of mice post-fracture. IPA core analysis of diabetic vs. non-diabetic immune gene expression revealed top canonical pathways (p-value < 1.0 x 10-6) involved in the Th1 Activation Pathway, Granulocyte Adhesion and diapedesis, and IL-7 Signaling, had an average activation z-score of -2.373, thus exhibiting a predicted inhibition when compared to non-diabetic controls. Additionally, top upstream inflammatory regulators such as TNF-α, IL-1B, and IL-6 also exhibited an average 3.5 log-fold reduction in expression. When examining gene expression in normal fracture repair, previous upstream inflammatory regulators exhibit an average 2.1 log-fold increase. Our results suggest that during fracture repair, the early immune response required for recruitment of osteogenic cells and repair is impaired in T2DM signaling. *Correspondence to: Sulie L. Chang, Seton Hall University, 400 South Orange Avenue, South Orange, NJ, USA, Tel: 973-761-9456; E-mail: sulie.chang@shu.edu