Deiodinase 2 upregulation demonstrated in osteoarthritis patients cartilage causes cartilage destruction in tissue-specific transgenic rats

Nagase, Hiroyuki; Nagasawa, Yasuo; Tachida, Yuki; Sakakibara, Satoshi; Okutsu, Junichi; Suematsu, Naoya; Arita, Susila; Shimada, Kohei

doi:10.1016/j.joca.2012.12.013

Cited by 29 publications

(33 citation statements)

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“…However, the effect of these hormones - particularly of T3 - on articular chondrocytes and their subsequent matrix synthesis has not been well studied. Specifically, investigation into the de-iodinase receptor profile of osteoarthritic articular chondrocytes has shown their ability to promote the conversion of T4 to T3 [36]. In addition, differential responses of articular chondrocytes from different zones have been demonstrated [37], but are limited to gene expression and focused on mineralization, and do not evaluate functional properties.…”

Section: Discussionmentioning

confidence: 99%

Thyroid hormones enhance the biomechanical functionality of scaffold-free neocartilage

Lee¹,

Gegg²,

Hu³

et al. 2015

Arthritis Res Ther

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IntroductionThe aim of this study was to investigate the effects of thyroid hormones tri-iodothyronine (T3), thyroxine (T4), and parathyroid hormone (PTH) from the parathyroid glands, known to regulate the developing limb and growth plate, on articular cartilage tissue regeneration using a scaffold-free in vitro model.MethodsIn Phase 1, T3, T4, or PTH was applied during weeks 1 or 3 of a 4-week neocartilage culture. Phase 2 employed T3 during week 1, followed by PTH during week 2, 3, or weeks 2 to 4, to further enhance tissue properties. Resultant neotissues were evaluated biochemically, mechanically, and histologically.ResultsIn Phase 1, T3 and T4 treatment during week 1 resulted in significantly enhanced collagen production; 1.4- and 1.3-times untreated neocartilage. Compressive and tensile properties were also significantly increased, as compared to untreated and PTH groups. PTH treatment did not result in notable tissue changes. As T3 induces hypertrophy, in Phase 2, PTH (known to suppress hypertrophy) was applied sequentially after T3. Excitingly, sequential treatment with T3 and PTH reduced expression of hypertrophic marker collagen X, while yielding neocartilage with significantly enhanced functional properties. Specifically, in comparison to no hormone application, these hormones increased compressive and tensile moduli 4.0-fold and 3.1-fold, respectively.ConclusionsThis study demonstrated that T3, together with PTH, when applied in a scaffold-free model of cartilage formation, significantly enhanced functional properties. The novel use of these thyroid hormones generates mechanically robust neocartilage via the use of a scaffold-free tissue engineering model.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0541-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Thyroid hormones enhance the biomechanical functionality of scaffold-free neocartilage

Lee¹,

Gegg²,

Hu³

et al. 2015

Arthritis Res Ther

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“…D2 up-regulation and D3 down-regulation causes locally increased levels of T3 in chondrocytes. This promotes the expression of the metalloproteinase ADAMTS5, which degrades the cartilage in joints (Nagase et al, 2013). The SNP rs225014 upstream of D2 has been associated with risk of osteoarthritis and carriers of this allele show defective epigenetic silencing of D2 in chondrocytes (Bomer et al, 2015).…”

Section: The Deiodinasesmentioning

confidence: 99%

New insights into thyroid hormone action

Mendoza

Hollenberg

2017

Pharmacology & Therapeutics

182

136

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Thyroid hormones (TH) are endocrine messengers essential for normal development and function of virtually every vertebrate. The hypothalamic-pituitary-thyroid axis is exquisitely modulated to maintain nearly constant TH (T4 and T3) concentrations in circulation. However peripheral tissues and the CNS control the intracellular availability of TH, suggesting that circulating concentrations of TH are not fully representative of what each cell type sees. Indeed, recent work in the field has identified that TH transporters, deiodinases and thyroid hormone receptor coregulators can strongly control tissue-specific sensitivity to a set amount of TH. Furthermore, the mechanism by which the thyroid hormone receptors regulate target gene expression can vary by gene, tissue and cellular context. This review will highlight novel insights into the machinery that controls the cellular response to TH, which include unique signaling cascades. These findings shed new light into the pathophysiology of human diseases caused by abnormal TH signaling.

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“…In the studies of Nagase et al 13 , microarray analyses of human cartilage showed that DIO2 was expressed at levels of more than 2-fold higher in OA samples compared to healthy controls, whereas DIO1 was not detected and DIO3 was not significantly different. Also, they showed that Dio2 was expressed at higher levels than other deiodinase genes in articular cartilage of 8-week-old rats and that T3 treatment of cultured chondrocytes and cartilage explants isolated from these rats increased the gene expression of markers associated with chondrocyte hypertrophy and endochondral ossification, including alkaline phosphatase, type X collagen, osteocalcin, and Runx2, as reported previously by others 21–23 .…”

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confidence: 97%

“…The subject of a recent report byNagase et al 13 , the OA susceptibility gene DIO2, encodes the deiodinase type 2 protein (D2), which is responsible for catalyzing the conversion of intracellular inactive thyroid hormone (T4) to its active form (T3). During normal growth plate development, active T3 subsequently signals the terminal maturation of the chondrocytes leading to cell hypertrophy, degradation and mineralization of the cartilage matrix, and bone formation 14,15 .…”

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confidence: 99%

Insight into the function of DIO2, a susceptibility gene in human osteoarthritis, as an inducer of cartilage damage in a rat model: is there a role for chondrocyte hypertrophy?

Goldring

2013

Osteoarthritis and Cartilage

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Deiodinase 2 upregulation demonstrated in osteoarthritis patients cartilage causes cartilage destruction in tissue-specific transgenic rats

Abstract: Our findings demonstrate that upregulated expression of DIO2 in OA patient cartilage might be responsible for OA pathogenesis by enhancing the chondrocyte hypertrophy and inflammatory response.

Cited by 29 publications

References 50 publications

Thyroid hormones enhance the biomechanical functionality of scaffold-free neocartilage

Thyroid hormones enhance the biomechanical functionality of scaffold-free neocartilage

New insights into thyroid hormone action

Insight into the function of DIO2, a susceptibility gene in human osteoarthritis, as an inducer of cartilage damage in a rat model: is there a role for chondrocyte hypertrophy?

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