Insulin-Like Growth Factor I Production Is Essential for Anabolic Effects of Thyroid Hormone in Osteoblasts

Huang, Bill K.; Golden, Laurence A.; Tarján, Gábor; Madison, Laird D.; Stern, Paula H.

doi:10.1359/jbmr.2000.15.2.188

Cited by 74 publications

(20 citation statements)

References 59 publications

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“…These positive effects on longitudinal growth, mediated by GH, correspond to the findings by Kindblom et al (27), who found that GH replacement increased longitudinal bone growth but did not normalize growth plate endochondral ossification in thyroid hormone receptor a1-, b1-, and b2-deficient mice. Furthermore, Huang et al (28) reported that increased local IGF1 production by T 3 is essential for the anabolic effects of thyroid hormone in mice osteoblasts. These reports and the findings in the present case suggest that GH could compensate for decreased T 3 anabolic effects on longitudinal bone growth to some extent; however, GH could not compensate for delayed ossification without a sufficient level of T 3 .…”

Section: Discussionmentioning

confidence: 99%

Novel compound heterozygous mutations in the SBP2 gene: characteristic clinical manifestations and the implications of GH and triiodothyronine in longitudinal bone growth and maturation

Hamajima¹,

Mushimoto²,

Kobayashi³

et al. 2012

European Journal of Endocrinology

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Objective: Mutations in the selenocysteine insertion sequence binding protein 2 gene (SECISBP2 also known as SBP2) lead to a multisystemic disorder. Our objectives are to examine the clinical manifestations of the present patient and evaluate the effects of GH and triiodothyronine (T 3 ) for longitudinal bone growth and maturation. Methods: A Japanese boy presented with unusual thyroid function tests (normal or slightly elevated TSH, low-normal or slightly decreased free T 3 (FT 3 ), and elevated free thyroxine (FT 4 )), short stature without GH deficiency, and delayed bone maturation. The entire coding region of the patient's SBP2 was analyzed. GH treatment was initiated when the patient was 4 years old, and combination therapy with GH plus T 3 was started when the patient was 10 years old. We monitored the patient's height and bone age until he was 11 years old. Results: The patient showed typical symptoms of SBP2 deficiency, and novel compound heterozygous mutations were identified in SBP2 (p.M515fsX563/p.Q79X). Six years of GH monotherapy improved the patient's height S.D. from K3.4 to K1.7 without accelerating bone maturation, whereas 6 months of T 3 treatment combined with GH almost normalized the thyroid function tests and improved both longitudinal bone growth and maturation. Conclusions: In the growth plate, GH may compensate for decreased local T 3 effects on longitudinal bone growth; however, GH does not appear to compensate for the effects of T 3 on bone maturation. We believe that the present case has important implications for understanding the mechanism of thyroid hormone and GH on longitudinal bone growth and maturation.

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Section: Discussionmentioning

confidence: 99%

Novel compound heterozygous mutations in the SBP2 gene: characteristic clinical manifestations and the implications of GH and triiodothyronine in longitudinal bone growth and maturation

Hamajima¹,

Mushimoto²,

Kobayashi³

et al. 2012

European Journal of Endocrinology

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“…In addition, T3 modulates key pathways involved in osteoblast proliferation and differentiation. T3 stimulates osteoblast responses to IGF1, PTH and FGFs both in cell cultures and in vivo (88)(89)(90)). These observations demonstrate that T3 stimulates osteoblast activity by complex direct and indirect mechanisms involving many growth factors and cytokines (Figure 3).…”

Section: Effects Of T3 In Bone Cells In Vitro Chondrocytesmentioning

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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“…Thus, T 3 increases synthesis of osteocalcin, type 1 collagen, alkaline phosphatase and matrix metalloproteinases 9 and 13 (Pereira et al 1999, Huang et al 2000, Gouveia et al 2001, Bassett & Williams 2003 and also regulates IGF1, parathyroid hormone (PTH) and FGF signalling (Huang et al 2000, Gu et al 2001, Pepene et al 2001, Bassett & Williams 2003, Stevens et al 2003, O'Shea et al 2007Fig. 6).…”

Section: T 3 Actions In the Bone Remodelling Cyclementioning

confidence: 99%

The skeletal phenotypes of TRα and TRβ mutant mice

Bassett

Williams

2008

Journal of Molecular Endocrinology

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Analysis of mice harbouring deletions or mutations of T 3 receptor a (TRa) and b (TRb) have clarified the complex relationship between central and peripheral thyroid status and emphasised the essential but contrasting roles of T 3 in skeletal development and adult bone. These studies indicate that TRa1 is the predominant TR expressed in bone and that T 3 exerts anabolic actions during growth but catabolic actions in the adult skeleton. Examination of key skeletal regulatory pathways in TR mutant mice has identified GH, IGF-1 and fibroblast growth factor signalling and the Indian hedgehog/parathyroid hormone-related peptide feedback loop as major targets of T 3 action in chondrocytes and osteoblasts. Nevertheless, although increased osteoclastic resorption is a major feature of thyrotoxic bone loss and altered osteoclast activity is central to the skeletal phenotype of TR mutant mice, it remains unclear whether T 3 has direct actions in osteoclasts. Detailed future analysis of the molecular mechanisms of T 3 action in bone will enhance our understanding of this emerging field and has the potential to identify novel strategies for the prevention and treatment of osteoporosis.

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Insulin-Like Growth Factor I Production Is Essential for Anabolic Effects of Thyroid Hormone in Osteoblasts

Cited by 74 publications

References 59 publications

Novel compound heterozygous mutations in the SBP2 gene: characteristic clinical manifestations and the implications of GH and triiodothyronine in longitudinal bone growth and maturation

Novel compound heterozygous mutations in the SBP2 gene: characteristic clinical manifestations and the implications of GH and triiodothyronine in longitudinal bone growth and maturation

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

The skeletal phenotypes of TRα and TRβ mutant mice

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