Skeletal stem and progenitor cell niche organization, regulation and repair

Bone has traditionally been viewed through the lens of structural support and mineral homeostasis, but it is increasingly recognized as a dynamic endocrine organ. Similarly, the concept of skeletal maintenance and repair has historically been considered through tightly coordinated regulation of specialized mature cell types. Recently, a refined understanding of skeletal stem cells (SSCs) and skeletal stem/progenitor cells (SSPCs) as key cellular drivers of skeletal development, homeostasis and regeneration has underscored their importance and broadened that framework. In this review, we examine skeletal endocrine biology through the high-resolution mapping of SSCs and SSPCs and their crosstalk with immune and matrix-associated niche components. We discuss how bone-derived endocrine factors, systemic hormones and neuroendocrine cues may act as local and systemic niche modulators that shape SSC and SSPC behavior during skeletal maintenance, physiological adaptation and repair. We further highlight how timed immune activation as well as inflammatory resolution shape successful skeletal repair, whereas aging, osteoporosis and chronic inflammation disrupt SSC competence, progenitor lineage progression and niche coordination. Together, these insights define stem cell-based skeletal actions as a niche-regulated process in which endocrine and immune cell programs are temporally and spatially coordinated. Understanding the interactive endocrine-SSPC niche may open new therapeutic avenues for restoring regenerative capacity of the aging and diseased skeleton.