Journal Article

Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes

Singh, Ravinder J., Hines, Jolaine M., Eckhardt, Brittany A., Thoreson, Andrew R., Farr, Joshua N., Khosla, Sundeep, O’Grady, Katherine L., Vella, Adrian, Rowsey, Jennifer L., Passos, João F., Lagnado, Anthony B., Monroe, David G., Fraser, Daniel G., Matveyenko, Aleksey V., Rakshit, Kuntol, Thicke, Brianne S., Bondar, Olga P.

2020

Overview

The worldwide prevalence of type 2 diabetes (T2D) is increasing. Despite normal to higher bone density, patients with T2D paradoxically have elevated fracture risk resulting, in part, from poor bone quality. Advanced glycation endproducts (AGEs) and inflammation as a consequence of enhanced receptor for AGE (RAGE) signaling are hypothesized culprits, although the exact mechanisms underlying skeletal dysfunction in T2D are unclear. Lack of inducible models that permit environmental (in obesity) and temporal (after skeletal maturity) control of T2D onset has hampered progress. Here, we show in C57BL/6 mice that a onetime pharmacological intervention (streptozotocin, STZ) initiated in adulthood combined with high-fat diet-induced (HFD-induced) obesity caused hallmark features of human adult-onset T2D, including prolonged hyperglycemia, insulin resistance, and pancreatic β cell dysfunction, but not complete destruction. In addition, HFD/STZ (i.e., T2D) resulted in several changes in bone quality that closely mirror those observed in humans, including compromised bone microarchitecture, reduced biomechanical strength, impaired bone material properties, altered bone turnover, and elevated levels of the AGE CML in bone and blood. Furthermore, T2D led to the premature accumulation of senescent osteocytes with a unique proinflammatory signature. These findings highlight the RAGE pathway and senescent cells as potential targets to treat diabetic skeletal fragility.

• Publisher: American Society for Clinical Investigation
• Subject: Adults / Advanced glycosylation end products / Age / Animals / Beta cells / Body composition / Bone and Bones - metabolism / Bone and Bones - pathology / Bone Density / Bone strength / Bone turnover / Cellular Senescence / Diabetes / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - metabolism / Diet / Disease Models, Animal / Fractures / Glucose / Glycation End Products, Advanced - metabolism / High fat diet / Homeostasis / Hyperglycemia / Insulin Resistance / Male / Metabolism / Mice / Mice, Inbred C57BL / Obesity / Osteocytes / Osteocytes - metabolism / Osteocytes - pathology / Receptor for Advanced Glycation End Products - metabolism / Senescence / Streptozocin