Endocrine Abstracts (2004) 7 P142

Regulation of the growth hormone (GH) and insulin-like growth factor-1 (IGF-1) paracrine pathway by thyroid hormone (T3) during bone development

S Sriskantharajah1, PJ O'Shea1, H Yao2, H Suzuki2, SY Cheng2 & GR Williams1

1Molecular Endocrinology Group, Division of Medicine & MRC Clinical Sciences Centre, Imperial College London, UK; 2Gene Regulation Section, National Cancer Institute, NIH, Bethesda, USA.

T3, GH and IGF-1 are essential for skeletal development, growth and bone mineralisation. The major growth-promoting actions of GH occur in epiphyseal chondrocytes via direct effects on GH-receptor expressing cells and via a local paracrine pathway involving IGF-1. There is controversy regarding whether T3-actions in bone are direct or occur via regulation of GH secretion and action. We examined this in mice with a mutation (PV) targeted to either T3-receptor (TR) beta or alpha. TRbetaPVPV homozygous mice have reduced pituitary GH expression, but display advanced bone formation due to skeletal thyrotoxicosis. TRalphaPV mutants have normal GH expression, but are dwarfs with severely retarded bone development due to skeletal hypothyroidism. GH-receptor, IGF-1 and IGF-1 receptor (IGF-1R) mRNAs were determined by in situ hybridisation in growth plates from 2-7 week-old PV-mutants and wild-type littermates. GH-receptor was expressed throughout the growth plate in 2-week wild-type mice but decreased with age, becoming virtually undetectable at 4-weeks. GH-receptor was increased in 2-week TRbetaPV/+ heterozygotes, a greater increase was evident in homozygotes and increased expression was maintained in 3 and 4-week mutant mice. GH-receptor was undetectable in TRalphaPV mice at all ages. In contrast, IGF-1 was expressed equally in proliferating chondrocytes in wild-type and mutants at all ages. IGF-1R, however, was expressed in proliferating and prehypertrophic chondrocytes in 2 week wild-type mice but was restricted to pre-hypertrophic cells in 3 and 4-week mice. Increased and widespread IGF-1R expression was present in TRbetaPV/+ heterozygotes at all ages, with a further increase evident in homozygotes. IGF-1R was undetectable in TRalphaPV mice. These data suggest that T3 specifies the sensitivity of growth plate chondrocytes to local paracrine actions of GH and IGF-1 by regulating expression of GH- and IGF-1 receptors. These studies identify a novel pathway that controls the rate of bone formation and linear growth.

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