Estrogen deficiency is known to reduce bone mass and increase bone marrow fat. Since both osteoblasts and bone marrow adipocytes are originated from bone marrow mesenchymal stem cells, estrogen deficiency may influence the bone marrow environment and contribute to bone fragility. This study focused on Cxcl12-abundant reticular (CAR) cells, which are a major source of osteoblasts and adipocytes in adults. CAR cells express high levels of estrogen receptor α (ERα), while the regulatory mechanisms of ERα in their differentiation remain unclear.
To investigate the role of ERα in CAR cells, CAR cell-specific ERα knockout mice (Ebf3-CreERT2;ERαf/f, termed cKO) were generated. Tamoxifen was administered at 10 weeks of age, and analyses were performed at 22 weeks old.
Femoral bone mineral density (BMD) was significantly reduced in cKO females compared to control, especially in the distal region, while no significant difference between groups was seen in males. Bone structure analysis in females by µCT showed a decrease in cortical bone thickness in cKO mice. In trabecular bone, cKO mice exhibited significantly reduced bone mass, trabecular number, thickness, and BMD, while structure model index and trabecular spacing significantly increased. Osmium staining revealed a significant increase in bone marrow adipose tissue (BMAT) in cKO both sexes. In cKO females, both regulated (rBMAT) and constitutive BMAT (cBMAT) significantly increased, while in cKO males, only cBMAT was significantly elevated, with limited physiological impact due to lower fat volume than females. To assess age-related effects in males, older mice (9-14 months old) were examined. Tibial BMD was significantly reduced in cKO males, suggesting age-related declines in testosterone induce low estrogen synthesis and contribute to bone loss.
These findings highlight the role of ERα in CAR cell regulation and bone homeostasis, and we need further investigation into the mechanisms of CAR cell differentiation under estrogen-deficient conditions.