Abstract
Chronic alcohol consumption increases the risk of osteoporosis and fracture by disrupting bone remodeling, in part by enhancing osteoclastogenesis. However, the cellular mechanisms underlying this process remain incompletely defined. We analyzed scRNA-seq data from osteoclasts differentiated in vitro from bone marrow mononuclear cells obtained from macaques following 12 months of chronic ethanol or isocaloric control solution consumption. Module scoring, trajectory inference with generalized additive modeling (tradeSeq), and CellChat-based analyses of intercellular communication were applied to uncover ethanol-induced changes in metabolic reprogramming, lineage progression, and signaling network dynamics. Module scoring indicated metabolic reprogramming toward oxidative phosphorylation, with reduced glycolytic, migratory, and phagocytic activities. Pseudotime analysis revealed accelerated osteoclast lineage commitment, broader intermediate differentiation states, and stabilization of mature osteoclasts. CellChat analysis showed globally amplified intercellular signaling, with mature osteoclasts functioning as dominant communication hubs sustained by autocrine feedback. Together, chronic alcohol consumption rewired osteoclastogenesis through early fate priming, metabolic adaptation, and hierarchical remodeling of intercellular communication, promoting enhanced osteoclastogenesis. These findings provide mechanistic insight into alcohol-induced bone pathology and highlight potential targets for therapeutic intervention.