Estrogen is essential for keeping bones strong and healthy. A new study explores how membrane-initiated estrogen receptor alpha (mERα) signaling in specific cell types affects bone integrity in female mice. Researchers found that mERα signaling in bone-forming cells (osteoblasts) is vital for maintaining strong cortical bone, whereas its role in blood-forming (hematopoietic) cells appears minimal. These insights help clarify how estrogen protects bone and may inform the development of safer bone-strengthening therapies with fewer side effects.
Estrogen supports bone growth, development, and the remodeling process that balances bone formation and resorption. After menopause, declining estrogen levels often lead to osteoporosis, a condition where bones become fragile and prone to fractures. Although hormone replacement therapy can counter bone loss by restoring estrogen, its broader effects on multiple organs raise safety concerns, including increased risks of certain cancers and blood clots.
Understanding the precise mechanisms behind estrogen’s protective effects is crucial for developing safer, targeted treatments. Estrogen primarily acts through estrogen receptor alpha (ERα), a protein that triggers cellular signals to preserve bone mass and strength. Without this pathway, bones can lose density and become weak.
In a recent study published in Bone Research on June 17, 2025, Dr. Karin Horkeby and colleagues from the University of Gothenburg, the University of Oulu, and Sahlgrenska University Hospital investigated the role of mERα signaling specifically in osteoblast lineage cells. Unlike the classic nuclear ERα pathway, this membrane pathway operates at the cell’s surface. Previous studies suggested that this signaling route may be important for maintaining bone mass, but its role in specific bone cells was unclear.
To explore this, the team developed a unique female mouse model (Runx2-C451Af/f mice) in which mERα signaling was selectively disrupted in osteoblast lineage cells. Using high-resolution microcomputed tomography, they found that these mice had consistently reduced cortical bone mass in the tibia, femur, and vertebrae compared to normal mice. Mechanical tests showed these bones were weaker and more prone to fractures. Lab studies further confirmed that osteoblasts lacking mERα signaling did not mature properly, indicating that this pathway is essential for healthy bone formation and strength.
In contrast, turning off mERα signaling in hematopoietic cells—including immune cells and bone-resorbing osteoclasts—had no significant effect on bone mass or structure. This suggests that the membrane pathway is not essential for bone maintenance in these cell types. Notably, while cortical bone was significantly affected, the impact on trabecular bone was minor, highlighting the pathway’s specialized role in maintaining the dense outer layer of bones.
Importantly, blocking mERα signaling in osteoblasts did not interfere with estrogen’s other roles in the body. The mice showed normal body weight, hormone levels, and reproductive organ development, suggesting that targeting this pathway could reduce bone loss without causing unwanted systemic effects.
These findings reveal that membrane-initiated ERα signaling in osteoblasts is key to preserving cortical bone strength and mass in females, while its role in hematopoietic cells is negligible. According to Dr. Horkeby, “Our results show that mERα signaling in osteoblasts is crucial for cortical bone regulation, whereas it’s not required in hematopoietic cells.”
This deeper understanding could guide the development of next-generation bone therapies that safely harness estrogen’s benefits, providing stronger bones while minimizing risks to other tissues.
