Fig. 2

Cellular senescence and other age-related mechanisms in the pathogenesis of OP. The senescence of different bone cells and OP is interwoven into a complex network of interactions. Senescent cells co-secreted the SASP to accelerate inflammatory microenvironment formation and bone loss. Fgfr3-creER, Lepr-cre, CXCL12⁺LepR⁺, P62⁺, and Prx1^Cre+Osx^Cre− labeled BMSCs were shown to be involved in the biological process of BMSCs senescence. Moreover, senescent BMSCs also showed increased expression of P62 and H3K4me1 and decreased expression of SOX5, TFEB, DMNT-1, and DNMT-3B. In addition, the senescence of BMSCs is induced by miRNA-34a-5p secreted by senescent skeletal muscle cells and by senescent ECs through the secretion of miRNA-31-5p. The OBs were differentiated osteoblastically from BMSCs. CD24⁺ and Osteolectin⁺ OBs exhibited a distinct senescent phenotype and osteogenic restriction. Increased mTORC1 and FOXO and decreased METTL3 and IGF-I in senescent OBs induced malfunction in OBs. Senescent OBs promoted OCs activation through massive secretion of M-CSF, RANKL, and WNT5A. SHN3 secreted by OBs promoted OP development through the inhibition of H-type angiogenesis. Treg cell-mediated inhibition of the CD39-CD93-AdoR signaling pathway directly suppresses osteogenesis in OBs. Overactivation of OCs is dependent on RANKL secreted by senescent BMSCs, OBs, OCYs, and ADs. In addition, the deficiency of OCs-derived SPP1 inhibited the osteogenic differentiation of BMSCs. OCs-secreted ANG is a key factor preventing the senescence of neighboring ECs. Increased C-telopeptide in the aged bone matrix is thought to induce OC activation. The expression of Atg7 and Map1lc3a in OCYs is reduced in aged animals. Senescent OCYs-derived TPM1 was significantly reduced, thereby inhibiting the osteogenic differentiation of BMSCs. Senescent ADs-derived DPP4 also significantly inhibited osteogenesis. In addition, PCLAF, derived from bone marrow MACs in aged mice, binds to ADGRL2 receptors on ADs and promotes the senescence of ADs. Senescent immune cells secrete increased GCA, TGFβ1⁺CCR5⁺, and decreased IL-17, OSM, leading to bone loss. Elevated levels of immune cell-derived TNF-α, IL-8, and RANKL markedly promoted the activation of OCs. Senescent ECs exhibited decreased HIF/Notch signaling pathway and exo secretion, as well as increased miRNA-31-5p, accelerating bone loss. Decreased Cystatin-A secretion by aged skin keratinocytes leads to restricted OB differentiation and enhanced OC differentiation. FOXO3 in skeletal muscle cells plays a key role in counteracting aging-related cellular senescence. EP4 in neuronal cells regulates bone homeostasis and promotes bone regeneration by sensing prostaglandin E2 secreted by OBs. These aging-related cellular senescence leads to changes in bone cell function and fate, which ultimately contribute to the onset and development of OP. The red frames represent upregulated genes, and the blue frames represent down-regulated genes