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bioRxiv · 10.64898/2026.04.02.716153

Genetic and pharmacologic modulation of RAGE rescues the diabetes-mediated impairments to bone at multiple length scales

Broz, K. S.·Hung, T.·Walk, R. E.·LoTempio, S.·Flores, K. M.·Tang, S. Y.
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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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/716153v1_ufig1.gif" ALT="Figure 1000"> View larger version (26K): org.highwire.dtl.DTLVardef@8b4ce4org.highwire.dtl.DTLVardef@1652394org.highwire.dtl.DTLVardef@10301a8org.highwire.dtl.DTLVardef@61c23d_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Broz, K. S., Hung, T., Walk, R. E., LoTempio, S., Flores, K. M., Tang, S. Y.. 2026-04-06. Genetic and pharmacologic modulation of RAGE rescues the diabetes-mediated impairments to bone at multiple length scales. https://doi.org/10.64898/2026.04.02.716153

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