Estrogen receptor α in mature osteoblasts regulates the late stage of bone regeneration

Estrogen deficiency impairs fracture healing and homeostasis of bone tissue. OVX-induced estrogen deficiency in mice attenuates fracture healing and changes the expression ratio of estrogen receptor (ER) alpha and ER beta in callus during the process of fracture healing. Therefore, ERs may be involved in the regulation of fracture healing. However, the roles of ERs in fracture healing are largely unknown. The purpose of this study was to clarify the significance of ERs during fracture healing using osteoblast-specific ER knockout mice in a mono- cortical drill hole bone regeneration model. The mature osteoblast-specific ER knockout mice were generated using osteocalcin (OCN)-Cre mice, and ER alpha and ER beta flox mice (OCN-Cre; ER alpha(f/f), ER alpha(Delta Ob/Delta Ob) and OCN-Cre; ER beta(f/f), ER beta(Delta Ob/Delta Ob)). Drill hole surgery was conducted on the tibiae of 8-week-old female mice. The mice were sacrificed 10 or 14 days after surgery and the bones were analyzed by DXA, mu CT and bone histomorphometry. DXA analysis revealed that intact femoral BMD was significantly decreased in ER alpha(Delta Ob/Delta Ob) mice compared with ER alpha(f/f) mice, but there was no difference in bone mass between ER beta(Delta Ob/Delta Ob) and ER beta(f/f) mice. Micro CT analyses showed that the callus volume at the restricted drill hole site in tibiae was significantly less in ER alpha(Delta Ob/Delta Ob) compared to ER alpha(f/f) mice only at day 14 but not at day 10. In addition to femoral BMD, there was no significant difference in callus volume between ER beta(Delta Ob/Delta Ob) and ER beta(f/f) mice. Bone histomorphometric analyses showed that Ob.S/BS and N.Ob/B.Pm were significantly less in ER alpha(Delta Ob/Delta Ob) mice compared with ER alpha(f/f) mice only at day 10. In addition, Oc.S/BS and N.Oc/B.Pm were significantly less in ER alpha(Delta Ob/Delta Ob) mice compared with ER alpha(f/f) mice only at day 14. These results suggest that ER alpha but not ER beta in osteocalcin-positive osteoblasts may contribute to the late stage of bone regeneration. (C) 2021 Elsevier Inc. All rights reserved.

Automated summary

Estrogen deficiency impairs fracture healing by affecting the expression ratio of estrogen receptors, especially ERα, in callus during the process. The study clarified the significance of ERs during fracture healing using osteoblast-specific ER knockout mice, showing that ERα in osteocalcin-positive osteoblasts may contribute to the late stage of bone regeneration.