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

J. H.Duncan Bassett, Allan J. Williams, Elaine Murphy, Alan Boyde, Peter G.T. Howell, Rowan Swinhoe, Marta Archanco, Frédéric Flamant, Jacques Samarut, Sabine Costagliola, Gilbert Vassart, Roy E. Weiss, Samuel Refetoff, Graham R. Williams

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


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-pituitarythyroid axis result from altered thyroid hormone (T3) 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 T3 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 T3.

Original languageEnglish (US)
Pages (from-to)501-512
Number of pages12
JournalMolecular Endocrinology
Issue number2
StatePublished - Feb 2008
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology


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