Genetic and pharmacologic modulation of RAGE rescues the diabetes-mediated impairments to bone at multiple length scales
Year: 2026
Type: preprint
Abstract: The bone matrix is precisely maintained and optimized to resist fractures. However, aging and disease deteriorate the bone matrix and increase fragility. Individuals with type 2 diabetes (T2D) have an elevated risk of bone fracture despite apparently normal bone mass. The chronic hyperglycemia in T2D promotes the formation of advanced glycation end-products (AGEs) in the bone tissue and modify the matrix mechanics. AGEs also bind to its receptor, RAGE, to activate inflammation and alter homeostasis. Using a leptin-receptor deficient mouse model of diabetes, we used a combination of high-resolution methods across multiple scales to evaluate the microarchitectural-, material- and cellular- level changes affected by the modulation of RAGE. To demonstrate the relevance of RAGE, we genetically ablated RAGE (RAGE-null) before the onset of diabetes; and to demonstrate the potency of RAGE as a disease modifying therapy, a RAGE antagonist (FPS-ZM1) was administered after prolonged diabetes. Diabetes impaired bone microstructure, the homeostatic actions of bone cells, the bone matrix nanomechanics, and whole-bone strength. The constitutive ablation of RAGE in diabetic animals prevented AGEs accumulation and the decline of trabecular connectivity; protected against the loss of osteocyte lacunae density and morphology; and maintained the matrix nanomechanics and bone strength. The inhibition of RAGE after the onset of diabetes reversed AGE accumulation and loss of bone volume; rescued osteocyte lacunae density and osteoclast activity; and restored matrix nanomechanics and bone strength. These results suggest that RAGE is a viable therapeutic target for diabetes-mediated impairments of bone quality.
Authors: Kaitlyn S. Broz, Timothy Hung, Remy E. Walk, Suzanne LoTempio, Katharine M. Flores, Simon Y. Tang
Institution: Washington University in St. Louis
Language: English
Subfield: Clinical Biochemistry
Domain: Life Sciences
Open Access status: green
Awards: Intervertebral Disc Degeneration and Cross-Talk with the Nervous System, Cabinet microCT System for Musculoskeletal Specimen Imaging, Imaging, Modeling and Engineering of Diabetic Tissues, The role of physiologic and pathologic AGEs on RAGE signaling in IVD degeneration, The Role of VEGF in the Development of Low Back Pain Following IVD Injury, RESOURCE BASED CENTER FOR MUSCULOSKELETAL BIOLOGY AND MEDICINE
OpenAlex ID: W7150890662