Cross-Tissue Transcriptomic Convergence Identifies a Leuko-Cyte-Shared, Myeloid-Enriched Inflammatory Program in Frailty and Osteoarthritis.

Frailty and osteoarthritis (OA) frequently coexist in older adults, yet the extent to which they share molecular programs across tissues remains unclear. We integrated bulk transcriptomics, peripheral immune and OA meniscal single-cell atlases, inferred cell-cell communication, and an in vitro myeloid-chondrocyte conditioned-medium model. Frailty-associated vastus lateralis and OA synovium shared a 16-gene program enriched for inflammatory and migratory processes, which was refined by protein-protein interaction analysis into a 15-gene hub module (Hub-15). Donor-aware pseudobulk analysis showed coordinated Hub-15 upregulation in CD8 T, natural killer, B, and monocyte/macrophage-like cells, with the highest scores in monocyte/macrophage populations. In the meniscal atlas, donor-level analysis of 7 normal and 6 OA donors identified a 20.5 percentage point lower proportion of inflammatory/stress cells and a 17.3 percentage point higher proportion of fibrochondrocyte-like cells in OA (both false discovery rate = 0.010), whereas state-specific Hub-15 differences were not significant after correction. Exploratory communication analysis nominated directionally consistent candidate myeloid-to-structural signaling axes, although none remained significant after multiple-testing correction. Conditioned medium from cytokine-primed THP-1 cells elicited inflammatory and matrix-catabolic responses in C28/I2 cells. These findings identify a cross-tissue, leukocyte-shared, and myeloid-enriched inflammatory program that converges across independent frailty and OA cohorts, providing a hypothesis-generating framework for future mechanistic testing.