Bone formation niche dysfunction in osteoporosis: insights from single-cell and spatial transcriptomic studies
Abstract
Bone formation is spatially organized, yet the molecular architecture of the bone formation niche has only recently become accessible. Osteoporosis is a major skeletal disorder characterized by bone loss, microarchitectural deterioration, and increased fracture risk. Although antiresorptive and anabolic therapies are effective, a key conceptual gap remains: the cellular components of bone formation are increasingly well defined, but how these cells are spatially arranged and coordinated in health and disease is less understood. Recent advances in single-cell RNA sequencing and spatial transcriptomics now allow transcriptome-wide mapping of bone-forming microenvironments in intact human and mouse tissues. This review synthesizes emerging findings into a spatial framework for understanding bone formation and osteoporosis. We trace the conceptual lineage from the bone-remodeling compartment canopy hypothesis to its molecular refinement through recent single-cell and spatial atlases. We integrate evidence for mesenchymal stromal cell heterogeneity and spatial niche organization to propose a three-zone model of the bone formation niche, comprising a canopy or marrow-side stromal zone, a reversal or transition zone, and a bone-surface formation zone. We further propose "spatial de-zonation" as a hypothesis-generating framework for osteoporosis, referring to the potential erosion of spatial gradients that normally separate osteogenic, stromal, vascular, and adipogenic domains.…
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