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

Kim, Ha-Young; Mohan, Subburaman

doi:10.4248/br201302004

Cited by 80 publications

(76 citation statements)

References 130 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other hand, thyroxine (T4) replacement induced rapid catch-up growth in juvenile hypothyroidism patients [2,4]. Our laboratory has recently found that THs play a critical role in skeletal development and linear growth during prepuberty when the effects of growth hormone are surprisingly small [4,5]. By contrast, childhood thyrotoxicosis caused accelerated linear growth and bone maturation and resulted in premature fusion of the growth plates and short stature [6].…”

Section: Introductionmentioning

confidence: 95%

“…Thyroid dysfunctions such as juvenile hypothyroidism and a heterozygous mutation of thyroid hormone receptor alpha caused short stature and delayed bone formation and mineralization in humans [1][2][3]. On the other hand, thyroxine (T4) replacement induced rapid catch-up growth in juvenile hypothyroidism patients [2,4]. Our laboratory has recently found that THs play a critical role in skeletal development and linear growth during prepuberty when the effects of growth hormone are surprisingly small [4,5].…”

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

Effects of Thyroxine (T4), 3,5,3′-triiodo-l-thyronine (T3) and their Metabolites on Osteoblast Differentiation

et al. 2016

Self Cite

View full text Add to dashboard Cite

Studies involving human genetic mutations and mutant mouse models have provided irrevocable evidence for a key role for thyroid hormones (THs) in the regulation of skeletal growth. While T3 binds to TH receptors with higher affinity than T4, T4 occupied TH receptors have also been reported in the nucleus under euthyroid conditions raising the possibility that T4 bound nuclear receptors may be biologically relevant in thyroid syndromes with elevated free T4 and reduced T3 levels. We, therefore, evaluated the direct effects of T4, T3, and their metabolites (rT3 and T2) in stimulating osteoblast differentiation using MC3T3-E1 preosteoblasts which do not produce detectable levels of deiodinases. Under serum-free conditions, a 24-h treatment of MC3T3-E1 cells with THs and their metabolites caused a dose-dependent increase in the expression of osteoblast differentiation markers, osterix, and osteocalcin. Circulating concentrations of T3 (~1 ng/ml) and T4 (~30 ng/ml) showed similar potency in stimulating osteoblast differentiation marker expression, while rT3 and T2 were less potent than T3 and T4. Moreover, T3 and T4 treatments elevated the IGF-1 mRNA level suggesting the involvement of IGF-1 signaling in the TH regulation of osteoblast differentiation. We conclude that an elevated T4 level in the absence of T3 may exert stimulatory effects on osteoblast differentiation. The establishment of cell-specific effects of T4 on osteoblasts may provide a strategy to generate T4 mimics that exert skeletal specific effects without the confounding T3 effects on other tissues.

show abstract

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 97%

Effects of Thyroxine (T4), 3,5,3′-triiodo-l-thyronine (T3) and their Metabolites on Osteoblast Differentiation

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Dysregulation in the production and/or actions of any of the factors that regulate endochondral ossification can result in skeletal diseases including chondrodysplasias and osteoarthritis (21, 40). Although the processes leading to POC formation have been well established, signaling pathways that stimulate SOC formation are not well understood.Thyroid hormone (TH) is known to play an important role in normal endochondral ossification and is essential for skeletal development, linear growth, maintenance of bone density, and efficient fracture healing (20,45,47,48). Juvenile hypothyroidism causes dwarfism with delayed bone formation and mineralization, while TH replacement induces rapid catch-up growth (1,20,44,45).…”

mentioning

confidence: 99%

“…Thyroid hormone (TH) is known to play an important role in normal endochondral ossification and is essential for skeletal development, linear growth, maintenance of bone density, and efficient fracture healing (20,45,47,48). Juvenile hypothyroidism causes dwarfism with delayed bone formation and mineralization, while TH replacement induces rapid catch-up growth (1,20,44,45).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Thyroid hormone receptor-β1 signaling is critically involved in regulating secondary ossification via promoting transcription of the Ihh gene in the epiphysis

Xing

Aghajanian

Goodluck

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

View full text Add to dashboard Cite

roid hormone (TH) action is mediated through two nuclear TH receptors, THR␣ and THR␤. Although the role of THR␣ is well established in bone, less is known about the relevance of THR␤-mediated signaling in bone development. On ther basis of our recent finding that TH signaling is essential for initiation and formation of secondary ossification center, we evaluated the role of THRs in mediating TH effects on epiphysial bone formation. Two-day treatment of TH-deficient Tshr Ϫ/Ϫ mice with TH increased THR␤1 mRNA level 3.4-fold at day 7 but had no effect on THR␣1 mRNA level at the proximal tibia epiphysis. Treatment of serum-free cultures of tibias from 3-day-old mice with T3 increased THR␤1 expression 2.1-and 13-fold, respectively, at 24 and 72 h. Ten-day treatment of Tshr Ϫ/Ϫ newborns (days 5-14) with THR␤1 agonist GC1 at 0.2 or 2.0 g/day increased BV/TV at day 21 by 225 and 263%, respectively, compared with vehicle treatment. Two-day treatment with GC1 (0.2 g/day) increased expression levels of Indian hedgehog (Ihh) 100-fold, osterix 15-fold, and osteocalcin 59-fold compared with vehicle at day 7 in the proximal tibia epiphysis. Gel mobility shift assay demonstrated that a putative TH response element in the distal promoter of mouse Ihh gene interacted with THR␤1. GC1 treatment (1 nM) increased Ihh distal promoter activity 20-fold after 48 h in chondroctyes. Our data suggest a novel role for THR␤1 in secondary ossification at the epiphysis that involves transcriptional upregulation of Ihh gene. thyroid hormones; ossification; bone formation; osteoblasts; chondrocytes; hypothyroidism; Indian hedge hog ENDOCHONDRAL OSSIFICATION is one of two essential processes required for fetal development of the mammalian skeletal system and for fracture healing. Unlike intramembranous ossification, which is the other process by which mesenchymal cells from the cranial neural crest, sclerotomes, and lateral plate mesoderm migrate and proliferate, forming mesenchymal condensations, cartilage is present and replaced by trabecular bone during endochondral ossification (16,35). There are two centers of ossification for endochondral ossification, a primary and a secondary center. The primary ossification center (POC) usually appears in the diaphysis of the long bones or in the body of the irregular bones during prenatal development while the secondary ossification center (SOC) occurs in the epiphysis of long bones at the time of birth in mammals (11). Endochondral ossification at the POC is tightly regulated by a number of growth factors (PTHrp, IHH, IGF-I, BMP/TGF␤, Wnt, VEGF) and transcription factors (Sox9, Runx2, osterix, ␤-catenin) (3, 10, 21-23, 29, 42, 53). Dysregulation in the production and/or actions of any of the factors that regulate endochondral ossification can result in skeletal diseases including chondrodysplasias and osteoarthritis (21, 40). Although the processes leading to POC formation have been well established, signaling pathways that stimulate SOC formation are not well understood.Thyroid hormone (TH) is known ...

show abstract

Effects and phenotypic consequences of transient thyrotoxicosis and hypothyroidism at different stages of zebrafish Danio rerio (Teleostei; Cyprinidae) skeleton development

Borisov,

Shkil

2024

The Anatomical Record

View full text Add to dashboard Cite

The effects and consequences of changes in thyroid hormones (THs) level are among the actively studied topics in teleost developmental and evolutionary biology. In most of the experimental models used, the altered hormonal status (either hypo‐ or hyperthyroidism) is a stable characteristic of the developing organism, and the observed phenotypic outcomes are the cumulative consequences of multiple TH‐induced developmental changes. Meanwhile, the influence of the transient fluctuations of TH content on skeleton development has been much less studied. Here, we present experimental data on the developmental effects and phenotypic consequences of transient, pharmacologically induced thyrotoxicosis and hypothyroidism at different stages of ossified skeleton patterning in zebrafish. According to the results, the skeleton structures differed in TH sensitivity. Some showed a notable shift in the developmental timing and rate, while other demonstrated little or no response to changes in TH content. The developmental stages also differed in TH sensitivity. We identified a relatively short developmental period, during which changes in TH level significantly increased the developmental instability and plasticity, leading to phenotypic consequences comparable to those in fish with a persistent hypo‐ or hyperthyroidism. These findings allow this period to be considered as a critical developmental window.

show abstract

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

Cited by 80 publications

References 130 publications

Effects of Thyroxine (T4), 3,5,3′-triiodo-l-thyronine (T3) and their Metabolites on Osteoblast Differentiation

Effects of Thyroxine (T4), 3,5,3′-triiodo-l-thyronine (T3) and their Metabolites on Osteoblast Differentiation

Thyroid hormone receptor-β1 signaling is critically involved in regulating secondary ossification via promoting transcription of the Ihh gene in the epiphysis

Effects and phenotypic consequences of transient thyrotoxicosis and hypothyroidism at different stages of zebrafish Danio rerio (Teleostei; Cyprinidae) skeleton development

Contact Info

Product

Resources

About