Angiopoietin-like 8 governs osteoblast-adipocyte lineage commitment during skeletal aging

A distinguishing feature of older mesenchymal stem cells (MSCs) from bone marrow (BM) is the transition in their differentiation capabilities from osteoblasts to adipocytes. However, the mechanisms underlying these cellular events during the aging process remain unclear. We identified angiopoietin-like protein 8 (ANGPTL8), an adipokine implicated in lipid metabolism, that influenced the fate of MSCs in BM during skeletal aging. Our studies revealed that ANGPTL8 steered MSCs toward adipogenic differentiation, overshadowing osteoblastogenesis. Mice with overexpressed ANGPTL8 exhibited reduced bone mass and increased BM adiposity, while those with transgenic depletion of ANGPTL8 showed lowered bone loss and less accumulation of BM fat. ANGPTL8 influenced the BM niche of MSCs by inhibiting the Wnt/β-catenin signaling pathway. Partial inhibition of PPARγ rescued some aspects of the phenotype in MSCs with ANGPTL8 overexpression. Furthermore, treatment with an Angptl8 antisense oligonucleotide improved the phenotype of aging mice. Our research suggests that ANGPTL8 is a crucial regulator of senesence-related changes in the BM niche and the cell-fate switch of MSCs.