Integrated single-cell and experimental analyses implicate GPRC5B in macrophage senescence-related alterations in postmenopausal osteoporosis.

Background: Post-menopausal osteoporosis (PMO) is characterized by senescence, estrogen deficiency, immune dysregulation and progressive bone loss, yet the molecular alterations involved in PMO remain incompletely understood. Methods: Single-cell and transcriptomic analyses were integrated with machine learning and experimental validation. Ovariectomized mouse models, primary bone marrow-derived macrophages and RAW264.7 cells were used to evaluate gene expression, senescence-associated changes, macrophage polarization and related signaling pathways. Results: Single-cell RNA sequencing revealed substantial remodeling of the bone marrow microenvironment in PMO and identified APOE-positive macrophages as a dominant subset with elevated KRAS-related signaling. Integrated co-expression and machine-learning analyses yielded GPRC5B as a PMO-associated candidate gene that was consistently upregulated across multiple datasets. Conclusions: GPRC5B is a macrophage-enriched, PMO-associated candidate identified through integrated transcriptomic analyses and supported by preliminary functional experiments. These findings suggest that GPRC5B may participate in macrophage-related alterations in PMO and warrant further mechanistic and translational investigation.