Molecular signatures of bone remodeling imbalance in type 2 diabetes and osteoporosis comorbidity: a multi-omics study with in vivo support

Abstract Type 2 diabetes (T2D) and osteoporosis (OP) frequently coexist, but the molecular features linking metabolic dysfunction to impaired bone remodeling remain incompletely defined. Here, we integrated public bulk transcriptomic datasets, a clinical serum proteomics cohort, and descriptive single-cell resources to prioritize candidates for investigation in a T2D-OP mouse model. The existing differential-expression screens, weighted gene co-expression network analysis (WGCNA) and set intersections nominated TTC1. A documented TTC1 expression-stratified GSEA in the low-versus-high BMD dataset was used for exploratory pathway context; it was not a disease-case-control enrichment analysis and did not apply a p-value adjustment method. These analyses are hypothesis-generating: TTC1 met the nominal screening criteria but did not meet BH-FDR < 0.05 in the low-versus-high BMD transcriptomic or serum proteomic results, and the T2D bulk analysis did not account for longitudinal sampling. Pre-imputation serum TTC1 measurements were available in only 1/14 controls and 6/14 patients, and TTC1 was excluded by detection-coverage filters. Single-cell analyses provided cellular context without cross-study disease-effect inference. In the T2D-OP mouse model, bone microstructural deterioration and histopathological damage were accompanied by increased TTC1, TNF-α, iNOS, NFATc1 and TRAP expression and reduced RUNX2 and OCN expression in bone tissue. The combined observations motivate further study of TTC1 in abnormal bone remodeling; independent clinical validation and functional perturbation are needed to establish its biological role.