Unveiling two distinct osteolineage cell populations linked to age-related osteoporosis in adult mice through integrative single-cell analyses

The bone marrow microenvironment contains heterogeneous stromal cells, which are critical for bone remodeling and provide essential supportive roles for hematopoietic functions. Although the diversity of PDGFRα⁺β⁺ mesenchymal stromal/stem cells (MSCs) get consensus, the osteo-lineage cells (OLCs) that constitute the developmental trajectory of osteoblasts are largely remain unclear. Here, we construct a comprehensive atlas of stromal cell via performing integrative single cell analyses for 77 samples from 14 datasets. Besides previously defined Lepr⁺ BM-MSCs derived OLC1, we present a novel OLC2 with unique molecular signatures and differentiation pathway. Both OLC1 and OLC2 show significant polygenic association with bone mineral density (BMD), while extracellular matrix (ECM) proteins specifically expressed by OLC2 are particularly decreased in bone tissue of aged mice. Notably, OLC1 and OLC2 are consistently reduced in aged mice, which might be induced by the decreased expression of several lineage drivers. Collectively, our study presents a thorough prospect of OLCs in the bone marrow microenvironment and highlights their important roles in age-related osteoporosis.