MON-744 Serum proteomics unveils novel pathways of altered bone metabolism in metabolic syndrome and type 2 diabetes

Abstract Disclosure: M. Gerbaix: None. D. Courteix: None. F. Dutheil: None. S. Ferrari: None. Type 2 Diabetes Mellitus (T2D) is associated with low bone turnover and bone fragility despite normal-high bone mineral density (BMD). T2D frequently coexists with Metabolic Syndrome (MetS), characterized by central obesity, dyslipidemia, hypertension, and impaired fasting glucose. We previously reported that MetS and T2D progressively decrease bone turnover while increasing BMD, though underlying mechanisms remain unclear. This study aimed to explore regulatory pathways of altered bone metabolism in MetS and T2D using a proteomic approach. Serum proteomic profiles were assessed by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) in age-matched men and women with MetS (59±5 yrs; n=26), MetS-T2D (60±5 yrs; n=26), and healthy controls (Ctr; 60±5 yrs; n=26). Data were analyzed with Spectronaut (Biognosys) and R-based bioinformatics tools. Of 541 analyzed proteins, 56 were dysregulated between MetS and Ctr, 75 between MetS-T2D and Ctr, and 26 between MetS-T2D and MetS. Among them, PEDF (Pigment epithelium derived factor) was significantly upregulated in MetS and MetS-T2D vs Ctr (+6%; +23%; p<0.05) and correlated positively with HbA1c (r=0.3; p<0.01), lumbar spine BMD (r=0.2; p<0.05), hip BMD (r=0.4; p<0.01), and negatively with CTX, a marker of bone resorption (r=-0.4; p<0.01). IGFBP2 (Insulin like growth factor binding protein 2) was downregulated in MetS and MetS-T2D (-42%; -54%; p<0.0001) and correlated negatively with HbA1c (r=-0.4; p<0.001) and hip BMD (r=-0.3; p<0.01), but positively with OCN, P1NP (bone formation markers) and CTX (r=0.3; p<0.05). Gene ontology enrichment analysis highlighted pathways related to lipid transport, cholesterol metabolism, inflammation, and extra cellular matrix (ECM) degradation, with several proteins correlated to bone parameters. Among them, LBP (Lipopolysaccharide binding protein) was upregulated in MetS and MetS-T2D vs Ctr (+30%; +41%; p<0.05) and correlated positively with HbA1c (r=0.3; p<0.05) and negatively with P1NP (r=-0.3; p<0.05). CRP (C reactive protein) was upregulated in MetS and MetS-T2D vs Ctr (+137%; +194%; p<0.05) and negatively correlated with P1NP and CTX (r=-0.22; p<0.05). Moreover, MMP-9 (Matrix metalloproteinase 9), a key ECM-degrading enzyme, was upregulated in MetS and MetS-T2D vs Ctr (+78%; +56%; p<0.05) and negatively correlated with OCN, P1NP, and CTX (r=-0.3; p<0.05). Overall, this proteomic analysis delineates new potential mechanisms of low bone turnover and/or higher BMD in MetS and T2D. They include both systemic and bone-derived proteins related to osteoblastic functions (PEDF, IGFBP2), lipids transport (LBP), as well as inflammation (CRP) and ECM degradation (MMP-9), thereby potentially contributing to diabetic bone fragility. Presentation: Monday, July 14, 2025