Molecular Mechanisms of Thyroid Hormone Effects on Bone Growth and Function

Harvey, Clare B.; O’Shea, Patrick J.; Scott, A.; Robson, Helen; Siebler, Thomas; Shalet, Stephen M; Samarut, Jacques; Chassande, Olivier; Williams, Graham R.

doi:10.1006/mgme.2001.3268

Cited by 118 publications

(95 citation statements)

References 105 publications

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“…T 3 has been found to stimulate, inhibit or exert no effect on osteoblastic cell proliferation but a consensus suggests that T 3 stimulates osteoblast activity (Harvey et al 2002). There are no reports in the literature of T 4 effects on osteoblast proliferation.…”

Section: Discussionmentioning

confidence: 99%

Thyroid hormone stimulation of extracellular signal-regulated kinase and cell proliferation in human osteoblast-like cells is initiated at integrin αVβ3

Scarlett¹,

Parsons²,

Hanson³

et al. 2008

Journal of Endocrinology

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The aim of the present study was to examine whether triiodo-L-thyronine (T 3 ) or L-thyroxine (T 4 ) rapidly activated the mitogen-activated protein kinase (MAPK) intracellular signalling cascade in osteoblast-like cells and investigate whether this activation was initiated at the integrin a V b 3 cell surface receptor. Using PCR and western blotting, the expression of integrin a V b 3 mRNA and protein was demonstrated in the human osteoblast-like cell lines MG-63 and SaOS-2. The treatment of MG-63 cells with T 3 (10 nM) or T 4 (100 nM) for 10 min stimulated extracellular signal-regulated kinase activity (ERK, a component of the MAPK pathway) as determined by fluorescent immunocytochemistry and an immunocomplex activity assay (T 3 by 10 . 7-fold, P!0 . 01 and T 4 by 10 . 4-fold, P!0 . 01 compared with control). T 3 (10 nM) and T 4 (100 nM) also significantly stimulated thymidine incorporation into MG-63 cells by 2 . 3G0 . 7-fold (P!0 . 01) and 2 . 1G0 . 1-fold (P!0 . 05) respectively. To establish whether transient ERK activation via the integrin a V b 3 cell surface receptor mediated these effects, MG-63 cells were pretreated for 30 min with the specific MAPK kinase inhibitor, U0126 (1 mM), or an antiintegrin a V b 3 -blocking antibody. Both pretreatments significantly inhibited T 3 -and T 4 -stimulated ERK activation and abolished T 3 -stimulated thymidine incorporation (P!0 . 01).T 4 -stimulated incorporation was significantly inhibited from 2 . 1-to 1 . 3-fold above control (P!0 . 05). Thus, our results suggest that T 3 and T 4 rapidly stimulate ERK activation in MG-63 cells via integrin a V b 3 and that one functional effect of this ERK activation is increased DNA synthesis.

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Section: Discussionmentioning

confidence: 99%

Thyroid hormone stimulation of extracellular signal-regulated kinase and cell proliferation in human osteoblast-like cells is initiated at integrin αVβ3

Scarlett¹,

Parsons²,

Hanson³

et al. 2008

Journal of Endocrinology

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“…Osteoblasts T3 has been found to stimulate, inhibit, or exert no effect on osteoblastic cell proliferation, but a consensus suggests that T3 stimulates osteoblast activity (1). T3 has been shown to increase expression of the osteoblast differentiation markers collagen I, osteocalcin, osteopontin, alkaline phosphatase, MMP9 and MMP13 in osteoblasts (81,(84)(85)(86)(87).…”

Section: Effects Of T3 In Bone Cells In Vitro Chondrocytesmentioning

confidence: 99%

“…Thyroid hormone (TH) plays an important role in normal endochondral ossification and is essential for skeletal development, linear growth, maintenance of bone mass, and efficient fracture healing ( 1). Juvenile hypothyroidism causes growth arrest with delayed bone formation and mineralization, and T4 replacement induces rapid catch-up growth (2).…”

Section: Introductionmentioning

confidence: 99%

Role and Mechanisms of Actions of Thyroid Hormone on the Skeletal Development

Kim

Mohan

2013

Bone Res.

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The importance of the thyroid hormone axis in the regulation of skeletal growth and maintenance has been well established from clinical studies involving patients with mutations in proteins that regulate synthesis and/or actions of thyroid hormone. Data from genetic mouse models involving disruption and overexpression of components of the thyroid hormone axis also provide direct support for a key role for thyroid hormone in the regulation of bone metabolism. Thyroid hormone regulates proliferation and/or differentiated actions of multiple cell types in bone including chondrocytes, osteoblasts and osteoclasts. Thyroid hormone effects on the target cells are mediated via ligand-inducible nuclear receptors/transcription factors, thyroid hormone receptor (TR) α and β, of which TRα seems to be critically important in regulating bone cell functions. In terms of mechanisms for thyroid hormone action, studies suggest that thyroid hormone regulates a number of key growth factor signaling pathways including insulin-like growth factor-I, parathyroid hormone related protein, fibroblast growth factor, Indian hedgehog and Wnt to influence skeletal growth. In this review we describe findings from various genetic mouse models and clinical mutations of thyroid hormone signaling related mutations in humans that pertain to the role and mechanism of action of thyroid hormone in the regulation of skeletal growth and maintenance. Keywords: thyroid hormone; bone; cartilage; growth factors; bone cells Bone Research (2013) 2: 146-161. doi: 10.4248/BR201302004 IntroductionThyroid hormone (TH) plays an important role in normal endochondral ossification and is essential for skeletal development, linear growth, maintenance of bone mass, and efficient fracture healing ( 1). Juvenile hypothyroidism causes growth arrest with delayed bone formation and mineralization, and T4 replacement induces rapid catch-up growth (2). By contrast, childhood thyrotoxicosis accelerates bone formation with premature closure of the growth plates and skull sutures, leading to short stature and craniosynostosis (3). Although there is considerable evidence regarding the importance of TH in skeletal development, the molecular mechanisms of TH action in bone are poorly understood. In this chapter, we discuss regulation and mechanisms of action of TH during skeletal development with particular emphasis on areas in which recent advances have been made. Physiology of TH: Regulation, metabolism and TH receptorRegulation Systemic TH levels are maintained by the classical negative feedback loop involving the hypothalamus-pituitary--thyroid (HPT) axis ( Figure 1). Thyrotropin releasing hormone (TRH) is synthesized in the paraventricular nucleus (PVN) of the hypothalamus and stimulates synthesis and secretion of thyroid stimulating hormone (TSH) fromHa-Young Kim et al. www.boneresearch.org | Bone Research 147thyrotroph cells in the anterior pituitary gland. TSH subsequently acts via the TSH receptor (TSHR) on thyroid follicular cells to stimulate synthesis and release of 3,5...

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“…Grupo A Grupo B p (n = 60) (n = 28) IC (anos) (1) 9,9 ± 1,8 10,4 ± 2,1 (3) 0,22 IO (anos) (1) 9,6 ± 2,2 10,4 ± 2,6 (3) 0,18 Ingestão de cálcio (mg/dia) (1) 851,2 ± 466,9 955,4 ± 482,4 (3) 0,33 Escore-Z do peso (2) +0,21 (-1,87 -+2,34) +0,32 (-1,83 -+1,83) (4) 0,78 Escore-Z da estatura (2) -0,36 (-2,02 -+2,79) -0,32 (-1,55 -+1,55) (4) 0,98 Escore-Z do IMC (2) +0,35 (-1,78 -+2,22) +0,21 (-1,97 -+1,94) (4) 0,98 Área (cm 2 ) (1) 1180,95 ± 305,64 1268,67 ± 349,12 (3) 0,23 CMO (g) (1) 959,53 ± 343,57 1080,68 ± 402,58 (3) 0,14 DMO (g/cm 2 ) (1) 0,795 ± 0,075 0,832 ± 0,092 (3) 0,04…”

Section: Parâmetrounclassified

“…(1) Média ± DP (2) Mediana (mín-máx) (3) Teste t de Student (4) Teste de Mann-Whitney bolismo do cálcio, como a dosagem dos hormônios calciotrópicos (PTH e vitamina D) e dos marcadores bioquímicos da remodelação óssea. Hipertireoidismo é descrito como fator de risco para osteoporose, tradicionalmente atribuída aos altos ní-veis de hormônios tireoideanos (23)(24)(25).…”

Section: Parâmetrounclassified

Densidade mineral óssea de crianças e adolescentes com hipotireoidismo congênito

Demartini

Kulak

Borba

et al. 2007

Arq Bras Endocrinol Metab

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RESUMORealizou-se estudo transversal com 60 pacientes (9,9 ± 1,8 anos) com hipotireoidismo congênito (HC) (grupo A): 40 meninas (23 pré-púberes) e 20 meninos (18 pré-púberes), com grupo controle (grupo B) constituído por 28 indivíduos (10,4 ± 2,1 anos): 18 meninas (8 pré-púberes) e 10 meninos (9 pré-púberes). Objetivos: Avaliar a densidade (DMO) e o conteúdo mineral ósseo (CMO) e correlacioná-los com idade cronológica e óssea (IO), sexo, maturação sexual, dose de l-T 4 , TSH, TT 4 , FT 4 , e etiologia do HC. IO, DMO e CMO de corpo total (DXA) foram obtidos dos 2 grupos; TSH, TT 4 e FT 4 , apenas dos pacientes. DMO foi menor no grupo A (0,795 ± 0,075 g/cm 2 vs. 0,832 ± 0,092; p = 0,04) e maior nas meninas púberes do que nas pré-púberes (p = 0,004). Não houve diferença significativa de DMO e CMO quanto ao sexo e etiologia do HC. Nosso estudo mostra que a DMO foi significativamente menor no grupo com HC, diferente dos dados da literatura. ABSTRACT Bone Mineral Density of Children and Adolescents with Congenital Hypothyroidism.A cross sectional study was made on 60 patients (9.9 ± 1.8 yr-old) with congenital hypothyroidism (CH) (group A): 40 girls (23 prepubertal) and 20 boys (18 prepubertal). Control group (group B) was constituted of 28 healthy children (10.4 ± 2.1 yr-old): 18 girls (8 prepubertal) and 10 boys (9 prepubertal). Aims: To evaluate bone mineral density (BMD) and content (BMC) and to correlate them with chronological and bone age (BA), sex, sexual maturation, l-T 4 dose, TSH, TT 4 , FT 4 , and CH etiology. BA, total body BMD, and BMC (DXA) were obtained of both groups. TSH, TT 4 , and FT 4 were measured in patients only. BMD was lower in group A (0.795 ± 0.075 g/cm 2 vs. 0.832 ± 0.092; p = 0.04) and higher in pubertal than in prepubertal girls (p = 0.004). There was no significant difference between BMD and BMC related to sex and CH etiology. Our data demonstrated that BMD was significantly lower in children with CH, different from what has been published in the literature.

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Molecular Mechanisms of Thyroid Hormone Effects on Bone Growth and Function

Cited by 118 publications

References 105 publications

Thyroid hormone stimulation of extracellular signal-regulated kinase and cell proliferation in human osteoblast-like cells is initiated at integrin αVβ3

Thyroid hormone stimulation of extracellular signal-regulated kinase and cell proliferation in human osteoblast-like cells is initiated at integrin αVβ3

Role and Mechanisms of Actions of Thyroid Hormone on the Skeletal Development

Densidade mineral óssea de crianças e adolescentes com hipotireoidismo congênito

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