Thyroid hormone 5′-deiodinase activity, nuclear binding, and effects on mitogenesis in umr-106 osteoblastic osteosarcoma cells

Ba, LeBron; Ae, Pekary; Mirell, Carol J.; Tj, Hahn; Jm, Hershman

doi:10.1002/jbmr.5650040207

Cited by 48 publications

(17 citation statements)

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“…This phenotype is consistent with restricted expression Dio2 in osteoblasts and its absence from osteoclasts (19). D1/D2KO mice exhibited a phenotype comparable with D2KO mice, reflecting the absence of D1 activity in bone (16)(17)(18)(19). Thus, reduced toughness and resistance to fracture in D2KO and D1/D2KO mice reveals an important role for D2 in osteoblasts in the optimization of bone strength.…”

Section: Discussionsupporting

confidence: 71%

“…A minor and transient impairment of weight gain was reported in male D2KO mice, whereas weight gain and growth were normal in D1KO and D1-deficient C3H/HeJ mice and in C3H/HeJ D2KO mutants with D1 and D2 deficiency (11-15). We and others have shown that D1 is not expressed in skeletal cells (16)(17)(18)(19), indicating D1 does not influence T3 action in bone directly. D2 activity has been demonstrated in the embryonic growth plate where it is regulated by the skeletal morphogen Hedgehog (20).…”

mentioning

confidence: 72%

“…Nevertheless, D2 activity was not identified in primary chondrocytes, growth plate tissue extracts, or primary organ cultures from postnatal animals (19,(21)(22)(23), suggesting a discrete role during embryonic development. In osteoblasts data are conflicting (16,18,24), although specific D2 activity was identified in whole bone and differentiated MC3T3 osteoblastic cells in one study (17). Using a sensitive and highly specific HPLC-based assay, we showed D2 is restricted to mature primary osteoblasts but is undetectable in chondrocytes and osteoclasts (19).…”

mentioning

confidence: 99%

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Optimal bone strength and mineralization requires the type 2 iodothyronine deiodinase in osteoblasts

Bassett

Boyde

Howell

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

129

135

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Hypothyroidism and thyrotoxicosis are each associated with an increased risk of fracture. Although thyroxine (T4) is the predominant circulating thyroid hormone, target cell responses are determined by local intracellular availability of the active hormone 3,5,3′-L-triiodothyronine (T3), which is generated from T4 by the type 2 deiodinase enzyme (D2). To investigate the role of locally produced T3 in bone, we characterized mice deficient in D2 (D2KO) in which the serum T3 level is normal. Bones from adult D2KO mice have reduced toughness and are brittle, displaying an increased susceptibility to fracture. This phenotype is characterized by a 50% reduction in bone formation and a generalized increase in skeletal mineralization resulting from a local deficiency of T3 in osteoblasts. These data reveal an essential role for D2 in osteoblasts in the optimization of bone strength and mineralization.thyroid hormone metabolism | fracture | hypothyroidism | bone formation | skeleton T hyroid hormones are essential for linear growth and peak bone mass acquisition. In adults, thyrotoxicosis results in high bone turnover osteoporosis and increased susceptibility to fracture, whereas hypothyroidism reduces bone turnover (1-3). In previous studies, we identified thyroid hormone receptor α (TRα) as the critical mediator of 3,5,3′-L-triiodothyronine (T3) action in bone (4-7). The aim of this study is to investigate the role of the type 2 iodothyronine deiodinase (D2) as a local prereceptor modulator of T3 action in the skeleton.Thyroid hormone actions are determined by local availability of T3 to its nuclear receptor (8). D2 catalyzes removal of an outer ring 5′-iodine atom from the major circulating hormone thyroxine (T4) to generate the active metabolite T3. Conversely, the type 3 deiodinase (D3) inactivates both T4 and T3 by removal of an inner ring 5-iodine atom. Thus, D2 and D3, in conjunction with serum-derived T3, are important local modulators of thyroid hormone action in vivo. Expression of D2 and D3 is regulated in a temporo-spatial and tissue-specific manner, resulting in varying levels of T3 action in individual tissues despite relatively constant serum thyroid hormone levels (8).Mice deficient in D2 (D2KO) exhibit pituitary resistance to feedback regulation by T4 characterized by a 3-fold increase in serum thyroid-stimulating hormone (TSH), a 27% increase in the serum T4 level, but a normal T3 level. The increased TSH and T4 levels are evident as early as postnatal day (PD)10 (9). These changes are accompanied by cold intolerance, impaired hearing, and reduced brain T3 content (10). The type 1 deiodinase (D1) is widely believed to catalyze conversion of T4 to T3 in tissues such as liver and kidney, predominantly for export to plasma. Like the D2KO mice, D1/D2KO double-mutant mice exhibit increases in serum T4 and TSH and have a normal serum T3 level (10).The roles of D1 and D2 in regulating T3 action in the skeleton have not been studied, although limited information regarding growth is available. A minor and trans...

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Section: Discussionsupporting

confidence: 71%

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confidence: 72%

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confidence: 99%

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Optimal bone strength and mineralization requires the type 2 iodothyronine deiodinase in osteoblasts

Bassett

Boyde

Howell

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

129

135

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“…Weight gain and growth, however, were normal in D1KO-and in DIO1-deficient C3H/HeJ mice and in combined C3H/HeJ D2KO mutants with DIO1 and DIO2 deficiency (Berry et al 1993, Schoenmakers et al 1993, Schneider et al 2006, Christoffolete et al 2007). We and others showed that DIO1 is not expressed in bone and cartilage (LeBron et al 1989, Dreher et al 1998, Gouveia et al 2005, Williams et al 2008, indicating that DIO1 does not directly influence T 3 action in bone.…”

Section: Role Of Dio2 In the Skeletonmentioning

confidence: 75%

Local control of thyroid hormone action: role of type 2 deiodinase

Williams

Bassett²

2011

Journal of Endocrinology

117

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“…(21) D2 is essential for the local production of T 3 through deiodination of triiodothyroxine (T 4 ). Although earlier studies on the role and functional expression of iodothyronine deiodinase enzymes in the skeleton have been equivocal, (12,14,(22)(23)(24)(25) a recent study reported normal growth in mice with deficiencies in D1 and D2, indicating that D2 may not be critical in skeletal development. (26) This notion was supported in a recent study that demonstrated that D2 activity is restricted to mature osteoblasts, suggesting a possible role for D2 in mature osteoblast function.…”

Section: Introductionmentioning

confidence: 97%

The type 2 deiodinase Thr92Ala polymorphism is associated with increased bone turnover and decreased femoral neck bone mineral density

Heemstra

Hoftijzer

Deure

et al. 2010

Journal of Bone and Mineral Research

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The role of type 2 deiodinase (D2) in the human skeleton remains unclear. The D2 polymorphism Thr92Ala has been associated with lower enzymatic activity, which could result in lower local triiodothyronine (T 3 ) availability in bone. We therefore hypothesized that the D2 Thr92Ala polymorphism may influence bone mineral density (BMD) and bone turnover. We studied 154 patients (29 men, 125 women: 79 estrogen-replete, 46 estrogen-deficient) with cured differentiated thyroid carcinoma. BMD and bone turnover markers [bone-specific alkaline phosphatase (BAP), cross-linking terminal C-telopeptide of type I collagen (CTX), procollagen type 1 aminoterminal propeptide (P1NP), and cross-linked N-telopeptide of type I collagen (NTX)] were measured. Effects of the D2 Thr92Ala polymorphism on BMD and bone turnover markers were assessed by a linear regression model, with age, gender, estrogen state, body mass index (BMI), serum calcium, 25-hydroxyvitamin D, parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), and free triiodothyroxine (T 4 ) as covariables. Sixty patients were wild type (Thr/Thr), 66 were heterozygous (Thr/Ala), and 28 were homozygous (Ala/Ala) for the D2 polymorphism. There were no significant differences in any covariables between the three genotypes. Subjects carrying the D2 Thr92Ala polymorphism had consistently lower femoral neck and total hip densities than wild-type subjects ( p ¼ .028), and this was accompanied by significantly higher serum P1NP and CTX and urinary NTX/creatinine levels. We conclude that in patients with cured differentiated thyroid carcinoma, the D2 Thr92Ala polymorphism is associated with a decreased femoral neck BMD and higher bone turnover independent of serum thyroid hormone levels, which points to a potential functional role for D2 in bone. ß

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Thyroid hormone 5′-deiodinase activity, nuclear binding, and effects on mitogenesis in umr-106 osteoblastic osteosarcoma cells

Cited by 48 publications

References 44 publications

Optimal bone strength and mineralization requires the type 2 iodothyronine deiodinase in osteoblasts

Optimal bone strength and mineralization requires the type 2 iodothyronine deiodinase in osteoblasts

Local control of thyroid hormone action: role of type 2 deiodinase

The type 2 deiodinase Thr92Ala polymorphism is associated with increased bone turnover and decreased femoral neck bone mineral density

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