| First Author | Yu D | Year | 2023 |
| Journal | JCI Insight | Volume | 8 |
| Issue | 1 | PubMed ID | 36378535 |
| Mgi Jnum | J:344610 | Mgi Id | MGI:7433651 |
| Doi | 10.1172/jci.insight.159107 | Citation | Yu D, et al. (2023) CCL3 in the bone marrow microenvironment causes bone loss and bone marrow adiposity in aged mice. JCI Insight 8(1) |
| abstractText | The central physiological role of the bone marrow renders bone marrow stromal cells (BMSCs) particularly sensitive to aging. With bone aging, BMSCs acquire a differentiation potential bias in favor of adipogenesis over osteogenesis, and the underlying molecular mechanisms remain unclear. Herein, we investigated the factors underlying age-related changes in the bone marrow and their roles in BMSCs' differentiation. Antibody array revealed that CC chemokine ligand 3 (CCL3) accumulation occurred in the serum of naturally aged mice along with bone aging phenotypes, including bone loss, bone marrow adiposity, and imbalanced BMSC differentiation. In vivo Ccl3 deletion could rescue these phenotypes in aged mice. CCL3 improved the adipogenic differentiation potential of BMSCs, with a positive feedback loop between CCL3 and C/EBPalpha. CCL3 activated C/EBPalpha expression via STAT3, while C/EBPalpha activated CCL3 expression through direct promoter binding, facilitated by DNA hypomethylation. Moreover, CCL3 inhibited BMSCs' osteogenic differentiation potential by blocking beta-catenin activity mediated by ERK-activated Dickkopf-related protein 1 upregulation. Blocking CCL3 in vivo via neutralizing antibodies ameliorated trabecular bone loss and bone marrow adiposity in aged mice. This study provides insights regarding age-related bone loss and bone marrow adiposity pathogenesis and lays a foundation for the identification of new targets for senile osteoporosis treatment. |
