Inflammation as death or life signal in diabetic fracture healing

Abstract

Increased apoptosis of chondrocytes and osteoblasts and prolonged survival of osteoclasts lead to early destruction of callus tissue and impair bone remodeling in fracture healing of diabetic patients. Diabetes is accompanied by an increased inflammatory state, reactive oxgen species (ROS) generation and accumulation of advanced glycation end products (AGEs), a heterogenous group of toxic metabolites that can induce inflammation. Prolonged hyperglycemia and insulin resistance correlate with increased apoptosis rate and, accordingly, the proapoptotic role of several inflammatory mediators, ROS and AGEs has been also documented. In this review we summarize the most recent reports supporting the idea that inflammatory signaling increases chondrocyte and osteoblast death and prolongs osteoclast survival, resulting in impaired bone regeneration in diabetes. Antagonising inflammatory signal pathways and solution of inflammation may deserve greater attention in the management of diabetic fracture healing.

AGEs induce caspase-mediated apoptosis of rat BMSCs via TNFα production and oxidative stress

“…It is probably not the only MAPK pathway involved, since we were unable to completely abrogate the apoptosis of BMSCs with the p38 inhibitor. Since we found no indication that the activation of NF-kB is involved in this process, as it was not attenuated by SN50, other pathways, particularly JNK (Shen et al 2010, Roszer 2011, Shi et al 2013, must be further evaluated.…”

“…Previously, AGEs have been shown to induce the production of TNFa in many cell types, including osteoblastic cells (Franke et al 2011, Fernández et al 2013, chondrocytes (Nah et al 2007), and endothelial cells (Rashid et al 2004), so that the idea that AGEs induce the apoptosis of BMSCs via the induction of TNFa expression and secretion seems feasible (Roszer 2011) and is certainly supported by data obtained with pirfenidone treatment.…”

“…Navarro & Mora-Fernández (2006), Roszer (2011) and Xu et al (2013)). In addition to TNFa, AGE-BSA increased the mRNA levels of other apoptogenic ligands, such as lymphotoxin alpha (Etemadi et al 2013) and TRAIL (Falschlehner et al 2007).…”

Determining the Role of Sost and Sostdc1 During Fracture Healing

“…Elevated FOXO1 activity in chondrocytes was observed during impaired fracture healing in diabetic rodents, suggesting an enhanced inflammatory response and osteoclastogenesis [29]. FOXO1 may also regulate tumor necrosis factor (TNF alpha), which encourages cell death and inflammatory cytokines [30]. Therefore, elevated FOXO during fracture healing in diabetic patients may result in elevated inflammation, osteoclast activity, and chondrocyte apoptosis, possibly contributing to impaired healing.…”

Immune Modulation to Improve Tissue Engineering Outcomes for Cartilage Repair in the Osteoarthritic Joint

“…For example, disorders such as diabetes mellitus that are associated with an inflammatory state are also characterized by impaired tissue regeneration. 97 TERM strategies for cartilage regeneration may be compromised as a result of dysregulated inflammatory processes and pro-inflammatory mediators in the joint. IL-1b has been reported to reduce collagen type 2 expression and GAG content of human nasal and articular chondrocytes cultured on a type 1 collagen scaffold, 98 and both IL-1b and TNF-a have been shown to impact the integration of engineered cartilage with native tissue.…”