Estrogen receptor-α expression in neuronal cells affects bone mass

Area of Science:

• Neuroendocrinology
• Skeletal Biology
• Hormone Action

Background:

• Bone mass is traditionally linked to endocrine and local factors.
• Emerging evidence highlights the role of central nervous system (CNS) pathways in bone regulation.
• Estrogen influences bone homeostasis and exerts actions within the CNS.

Purpose of the Study:

• To elucidate the in vivo role of central estrogen receptor-alpha (ERα) expression in regulating bone mass.
• To investigate how the specific absence of ERα in nervous tissue affects skeletal parameters.

Main Methods:

• Generation of nestin-ERα(-/-) mice with targeted ERα deletion in neural tissue using Nestin-Cre and ERα(flox) mouse lines.
• Assessment of bone mineral density (trabecular and cortical bone) and femoral bone strength (stiffness, maximal load).
• Analysis of bone formation rates, serum leptin levels, white adipose tissue (WAT) leptin expression, WAT mass, and hypothalamic leptin receptor mRNA levels.

Main Results:

• Nestin-ERα(-/-) mice exhibited significantly increased bone mineral density in both trabecular and cortical compartments.
• Enhanced femoral bone strength, indicated by increased stiffness and maximal load, was observed in nestin-ERα(-/-) mice.
• The high bone mass phenotype was primarily attributed to elevated bone formation, linked to increased serum leptin and reduced hypothalamic leptin receptor sensitivity.

Conclusions:

• Central ERα signaling plays a critical inhibitory role in bone mass regulation.
• The balance between peripheral stimulatory and central inhibitory ERα actions is crucial for maintaining bone homeostasis.
• Inactivation of central ERα signaling leads to increased bone mass, potentially mediated by altered central leptin sensitivity and subsequent increases in WAT-derived leptin influencing peripheral bone formation.