Spatial transcriptomics reveals microenvironmental heterogeneity in osteoarthritic subchondral bone

Although increasing evidence implicates subchondral bone alterations in osteoarthritis, the spatial organization of subchondral bone remodeling remains unclear. Applying spatial transcriptomics on human subchondral bone, we identify a spatially conserved osteogenic core-halo architecture that displays transcriptional reprogramming in sclerotic microenvironments. Spatial dependency and a customized cell-cell communication framework reveal disrupted osteoblast-osteoclast spatial coupling, enhanced osteoblast-mesenchymal interactions, and identify FN1-SDC2 and COL1A1-DDR2 as candidate stromal-osteogenic signaling axes that may contribute to aberrant bone remodeling. Additionally, we present the first in situ transcriptional landscape of osteocytes and reveal its potential regulatory role in aberrant bone remodeling. We further delineate a continuum of spatial ecotypes exhibiting distinct enrichment, spatial topology reorganization, and inter-ecotype communication rewiring across pathological states. Metabolic flux inference additionally reveals substrate-limited, stressed states across multiple ecotypes in sclerotic microenvironments. Collectively, our findings provide critical insights into aberrant subchondral bone remodeling in osteoarthritis and offer a valuable framework for future mechanistic studies and therapeutic exploration.