bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.01.01.631018

The sex-specific effects of RAGE signaling and Type 2 Diabetes on mouse cortical bone mechanics, structure, and material properties

Hung, T.·Broz, K. S.·Walk, R.·Tang, S. Y.
View original source ↗Export metadata ↓

Abstract

Individuals with type 2 diabetes (T2D) are prone to fracture at numerous skeletal sites despite presenting with a higher bone mineral density (BMD). The accumulation of Advanced Glycation End-products (AGEs) in the bone tissues of patients with T2D could be contributing to this paradox, of increased skeletal fragility with higher BMD. AGEs can impair bone cell homeostasis via the receptor for AGEs (RAGE). To investigate the effects of diabetes, AGE accumulation, and RAGE signaling on mouse cortical bone, we utilized male and female leptin receptor-deficient (db/db) mice from three age groups ranging from 3-14 months of age, which were crossed with animals carrying constitutively RAGE-deficient alleles (RAGE-/-). The morphological, mechanical and material outcomes were measured using microCT, 3-pt bending, and an AGE assay. We observed significant impairments dependent on age and sex to the bone matrix and whole-bone mechanical behavior due to diabetes with some impairments alleviated with the ablation of RAGE. In older female diabetic mice, the removal of RAGE signaling prevented the deficits in bone mechanics, morphology and tissue mineral density (TMD). Male diabetic mice without RAGE signaling exhibited improved material properties. The study demonstrated that some bone impairments associated with T2D are prevented with RAGE ablation and may be partially reversible with the inhibition of RAGE signaling. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=145 HEIGHT=200 SRC="FIGDIR/small/631018v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@75acedorg.highwire.dtl.DTLVardef@1ac01fforg.highwire.dtl.DTLVardef@1b70d34org.highwire.dtl.DTLVardef@c3f3a7_HPS_FORMAT_FIGEXP M_FIG C_FIG

Source connections

Explore related subjects

pathologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Hung, T., Broz, K. S., Walk, R., Tang, S. Y.. 2025-01-02. The sex-specific effects of RAGE signaling and Type 2 Diabetes on mouse cortical bone mechanics, structure, and material properties. https://doi.org/10.1101/2025.01.01.631018

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Autophagic flux is increased in peripheral blood mononuclear cells in atherosclerotic vascular disease and associates inversely with adverse cardiovascular events

Background: Autophagy is a homeostatic pathway supporting stress adaptation and is dysregulated in atherosclerosis. Its potential as a biomarker or therapeutic target in atherosclerotic vascular disease (ASVD) remains incompletely defined. We measured autophagic flux in peripheral blood mononuclear cells (PBMCs) from patients with peripheral arterial disease (PAD) or carotid stenosis (CS), compared with healthy controls, and explored clinical outcome associations. Methods: Ninety-four patients with PAD or CS and 19 healthy controls were studied. Autophagic flux was quantified from fresh blood using a validated ex vivo chloroquine inhibition ELISA measuring LC3BII accumulation. Major adverse cardiovascular events (MACE) and major adverse limb events (MALE) were ascertained over a median follow up of 828 days. Results: The ASVD cohort comprised claudication (n = 16), chronic limb threatening ischemia (CLTI; n = 49), and CS (n = 29). Autophagic flux was higher in ASVD than controls (mean 281.4 vs. 182.3 ng LC3BII/mg protein/h; p < 0.0001) and remained independently associated after multivariable adjustment. Within CLTI, concurrent infection was associated with lower flux (p = 0.001), approaching control levels (p = 0.327). In CLTI, higher flux quartiles were associated with lower MACE risk, most strongly for quartile 3 (hazard ratio 0.07 vs. quartile 1, 95% CI 0.01 to 0.50; p = 0.009). Conclusion: Autophagic flux is elevated in PBMCs from ASVD patients, independent of age and sex. Attenuated flux in CLTI with concurrent infection may indicate autophagic exhaustion in advanced disease. The association between higher flux and lower MACE in CLTI suggests prognostic utility, warranting evaluation in larger prospective studies.

pathology↗
bioRxiv2026

Quantitative Model of the Ocular Immune Response during Seasonal Allergic Conjunctivitis

Allergic conjunctivitis is an inflammation of the conjunctiva caused by allergen; it is common disorder affecting up to 40% of the population. In this work, we study seasonal allergic conjunctivitis (SAC), also called "hay fever eyes", which is caused by exposure to airborne pollens. We develop a mathematical model quantifying the ocular immune system response to the allergens. First, we present a simplified qualitative description of the immunopathogenesis of SAC. Then, we express each chosen immunopathological mechanism mathematically to construct a system of thirty-one ordinary differential equations. We compare summary statistics of the predicted observable immune signals to experimental measurements and find our model captures key qualitative features of SAC progression. We then compare our predicted time series of histamine concentration to symptom scores and find a strong correlation suggesting the model predicts relevant clinically trends. Next, we calibrate the model through multi-step process. We find the most influential parameters are the production and depletion rates of IL-4, and the production rates of IL-5 and IL-8. These cytokines are targeted in treatments for asthma, atopic dermatitis, and severe eosinophilic associated disorder and suggest potential therapeutic targets for SAC. Our calibrated model mimics most of the summary statistics of the experimentally observable immune signals with discrepancies for IL-5 and IL-13 indicating that additional immunopathological mechanisms could be important.

pathology↗
bioRxiv2026

Dysregulated Platelet GPIb alpha - VWF Signalling in Abdominal Aortic Aneurysm formation and Progression

Background: Platelets are critical drivers of thrombo-inflammatory responses in different cardiovascular diseases. Abdominal aortic aneurysm (AAA) is a progressive, life-threatening vascular disorder mainly characterised by chronic inflammation, extracellular matrix degradation, and the formation of a platelet-rich intraluminal thrombus (ILT). Experimental and clinical evidence identified platelets as main players in AAA pathology as evidenced by elevated platelet activation and procoagulant activity that critically contribute to AAA progression. Methods: The present study investigated the contribution of glycoprotein (GP)Ib alpha, the von Willebrand factor (VWF)-binding subunit of the platelet GPIb-IX-V complex, to AAA initiation and progression in experimental AAA using the ePPE mouse model and in patients. Results: Genetic ablation of platelet GPIb alpha significantly attenuated early aneurysm expansion in experimental AAA, indicating a critical role for GPIb alpha during the initial stages of aneurysm development. This initial effect was compensated at later time points showing no differences in aneurysm progression between groups. Notably, genetic deletion of GPIb alpha induced a constitutively hyperactive platelet phenotype already in naive mice that was further amplified during experimental AAA. This elevated platelet hyperactivity was mainly due to increased GPVI activation of platelets 28 days post-surgery. To assess the clinical relevance, spatial profiles of human ILT specimens from patients with AAA were analysed. In the ILT, we detected a highly compartmentalised distribution of GPIb alpha and VWF with pronounced enrichment within the luminal layer. In parallel, circulating VWF activity as well as platelet surface expression of GPIb alpha were significantly increased in patients with AAA. Conclusion: Collectively, these findings identify a dysregulated GPIb alpha-VWF axis in human AAA pathology, mainly characterised by enhanced platelet GPIb alpha surface expression and increased activity of circulating VWF.

pathology↗