Thra knockout protects male mice from hyperthyroidism-driven cortical bone loss by mitigating bone resorption.

Area of Science:

• Endocrinology
• Bone Biology
• Metabolic Diseases

Background:

• Secondary osteoporosis is a significant health issue linked to endocrine disorders like hyperthyroidism.
• Hyperthyroidism in mice causes high bone turnover, leading to trabecular and cortical bone loss and reduced bone strength.
• Osteocytes in hyperthyroid mice can develop osteoclast-like features, but the role of thyroid hormone receptor alpha (TRα) is unclear.

Purpose of the Study:

• To investigate the role of TRα in hyperthyroidism-induced bone resorption.
• To characterize the bone phenotype of TRα-deficient mice under hyperthyroid conditions.

Main Methods:

• Male TRα-deficient (Thra^0/0) and wild-type (WT) mice were rendered hyperthyroid using L-thyroxine (T4) treatment.
• Bone mineral density, bone strength, and serum bone resorption markers (TRAP) were analyzed.
• Osteoclast and osteocyte markers were assessed in bone tissue and cultured cells.

Main Results:

• T4-treated Thra^0/0 mice showed trabecular bone loss but maintained cortical bone mass and strength, unlike T4-treated WT mice.
• Elevated serum TRAP and osteoclast numbers were observed in hyperthyroid WT mice, but not in Thra^0/0 mice.
• Thyroid hormone-induced osteoclast marker expression in osteoblasts/osteocytes and the Rankl/Opg ratio were TRα-dependent.

Conclusions:

• TRα deficiency preserves cortical bone mass and strength in hyperthyroid male mice.
• TRα plays a critical role in mediating hyperthyroidism-induced bone resorption by promoting osteoclastogenesis and osteocyte dedifferentiation.
• Targeting TRα may offer a therapeutic strategy for hyperthyroidism-related osteoporosis.