A lack of thyroid hormones rather than excess thyrotropin causes abnormal skeletal development in hypothyroidism

Mol Endocrinol. 2008 Feb;22(2):501-12. doi: 10.1210/me.2007-0221. Epub 2007 Oct 11.


By proposing TSH as a key negative regulator of bone turnover, recent studies in TSH receptor (TSHR) null mice challenged the established view that skeletal responses to disruption of the hypothalamic-pituitary-thyroid axis result from altered thyroid hormone (T(3)) action in bone. Importantly, this hypothesis does not explain the increased risk of osteoporosis in Graves' disease patients, in which circulating TSHR-stimulating antibodies are pathognomonic. To determine the relative importance of T(3) and TSH in bone, we compared the skeletal phenotypes of two mouse models of congenital hypothyroidism in which the normal reciprocal relationship between thyroid hormones and TSH was intact or disrupted. Pax8 null (Pax8(-/-)) mice have a 1900-fold increase in TSH and a normal TSHR, whereas hyt/hyt mice have a 2300-fold elevation of TSH but a nonfunctional TSHR. We reasoned these mice must display opposing skeletal phenotypes if TSH has a major role in bone, whereas they would be similar if thyroid hormone actions predominate. Pax8(-/-) and hyt/hyt mice both displayed delayed ossification, reduced cortical bone, a trabecular bone remodeling defect, and reduced bone mineralization, thus indicating that the skeletal abnormalities of congenital hypothyroidism are independent of TSH. Treatment of primary osteoblasts and osteoclasts with TSH or a TSHR-stimulating antibody failed to induce a cAMP response. Furthermore, TSH did not affect the differentiation or function of osteoblasts or osteoclasts in vitro. These data indicate the hypothalamic-pituitary-thyroid axis regulates skeletal development via the actions of T(3).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Bone Development / drug effects
  • Bone Development / genetics
  • Bone Development / physiology*
  • Bone Remodeling / drug effects
  • Bone Remodeling / genetics
  • Bone Remodeling / physiology
  • Bone and Bones / abnormalities
  • Bone and Bones / metabolism
  • Calcification, Physiologic / drug effects
  • Calcification, Physiologic / genetics
  • Calcification, Physiologic / physiology
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Hypothyroidism / blood
  • Hypothyroidism / genetics
  • Hypothyroidism / pathology*
  • In Situ Hybridization
  • Mice
  • Mice, Knockout
  • Osteoblasts / cytology
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism
  • Osteoclasts / cytology
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism
  • Osteogenesis / drug effects
  • Osteogenesis / physiology
  • PAX8 Transcription Factor
  • Paired Box Transcription Factors / genetics
  • Paired Box Transcription Factors / metabolism
  • Paired Box Transcription Factors / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thyroid Gland / metabolism
  • Thyroid Hormones / blood*
  • Thyroid Hormones / pharmacology
  • Thyrotropin / blood*


  • PAX8 Transcription Factor
  • Paired Box Transcription Factors
  • Pax8 protein, mouse
  • Thyroid Hormones
  • Thyrotropin
  • Cyclic AMP