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Genetic confirmation for a central role for TNFα in the direct action of thyroid stimulating hormone on the skeleton

Li Sun1, Ling-Ling Zhu, Ping Lu

  • 1The Mount Sinai Bone Program and Department of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY 10029, USA.

Proceedings of the National Academy of Sciences of the United States of America
|May 30, 2013
PubMed

Insights

Thyroid-stimulating hormone (TSH) deficiency causes osteoporosis partly via TNFα. Blocking TNFα in mice fully rescued bone loss, revealing a new pathway in bone metabolism.

Area of Science:

  • Endocrinology
  • Bone Biology
  • Immunology

Background:

  • Low thyroid-stimulating hormone (TSH) levels correlate with low bone mineral density and increased fracture risk.
  • Previous studies suggest TSH directly impacts skeletal health.
  • The precise mechanisms linking TSH deficiency to bone loss remain incompletely understood.

Purpose of the Study:

  • To investigate the role of Tumor Necrosis Factor alpha (TNFα) in mediating the skeletal effects of TSH deficiency.
  • To explore the interplay between TSH, TNFα, and bone cell activity.

Main Methods:

  • Generation of compound mouse mutants by deleting the Tnfα gene in Tshr(-/-) and Tshr(+/-) backgrounds.
  • Assessment of bone mineral density, bone formation, and bone resorption markers in mutant mice.
  • Ex vivo studies using bone marrow cell cultures to analyze TSH and TNFα interactions.

Main Results:

  • Genetic deletion of Tnfα fully rescued osteoporosis, low bone formation, and hyperresorption in TSH-deficient mice.
  • TSH differentially regulates TNFα production in macrophages and osteoblasts.
  • TNFα stimulates osteoclastogenesis and enhances local TSHβ production, creating a negative feedback loop.

Conclusions:

  • TNFα is a key mediator of skeletal pathology in TSH deficiency.
  • The TSH-TNFα axis represents a novel pathway influencing bone metabolism.
  • Elevated TNFα in human hyperthyroidism may contribute to bone loss.
Keywords:
bone densitybone metabolismthyroid disease

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