Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration

Hongwei Ma, Fan Yang, Michael R. Butler, Joshua Belcher, T. Michael Redmond, Andrew T. Placzek, Thomas (Tom) Scanlan, Xi Qin Ding

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and metabolism. Recent studies have implicated TH signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we demonstrated that antithyroid drug treatment and targeting iodothyronine deiodinases (DIOs) to suppress cellular tri-iodothyronine (T3) production or increase T3 degradation preserves cones. In this work, we investigated the effectiveness of inhibition of the TH receptor (TR). Two genes, THRA and THRB, encode TRs; THRB2 has been associated with cone viability. Using TR antagonists and Thrb2 deletion, we examined the effects of TR inhibition. Systemic and ocular treatment with the TR antagonists NH-3 and 1-850 increased cone density by 30–40% in the Rpe652/2 mouse model of Leber congenital amaurosis and reduced the number of TUNEL+ cells. Cone survival was significantly improved in Rpe652/2 and Cpfl1 (a model of achromatopsia with Pde6c defect) mice with Thrb2 deletion. Ventral cone density in Cpfl1/Thrb22/2 and Rpe652/2/Thrb22/2 mice was increased by 1- to 4-fold, compared with age-matched controls. Moreover, the expression levels of TR were significantly higher in the cone-degeneration retinas, suggesting locally elevated TR signaling. This work shows that the effects of antithyroid treatment or targeting DIOs were likely mediated by TRs and that suppressing TR protects cones. Our findings support the view that inhibition of TR locally in the retina is a therapeutic strategy for retinal degeneration management.—Ma, H., Yang, F., Butler, M. R., Belcher, J., Redmond, T. M., Placzek, A. T., Scanlan, T. S., Ding, X.-Q. Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration.

Original languageEnglish (US)
Pages (from-to)3425-3438
Number of pages14
JournalFASEB Journal
Volume31
Issue number8
DOIs
StatePublished - Aug 1 2017

Fingerprint

Thyroid Hormone Receptors
Retinal Degeneration
Retina
Cones
erbA Genes
Retinal Cone Photoreceptor Cells
Iodide Peroxidase
Thyroid Hormones
Leber Congenital Amaurosis
Color Vision Defects
Therapeutics
Antithyroid Agents
In Situ Nick-End Labeling
Drug Delivery Systems
Cell Differentiation
Drug therapy
Cell Count
Cell Proliferation
Cell proliferation
Metabolism

Keywords

  • Cone degeneration
  • Cone dystrophy
  • Leber congenital amaurosis
  • TR antagonist

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Ma, H., Yang, F., Butler, M. R., Belcher, J., Redmond, T. M., Placzek, A. T., ... Ding, X. Q. (2017). Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration. FASEB Journal, 31(8), 3425-3438. https://doi.org/10.1096/fj.201601166RR

Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration. / Ma, Hongwei; Yang, Fan; Butler, Michael R.; Belcher, Joshua; Redmond, T. Michael; Placzek, Andrew T.; Scanlan, Thomas (Tom); Ding, Xi Qin.

In: FASEB Journal, Vol. 31, No. 8, 01.08.2017, p. 3425-3438.

Research output: Contribution to journalArticle

Ma, H, Yang, F, Butler, MR, Belcher, J, Redmond, TM, Placzek, AT, Scanlan, TT & Ding, XQ 2017, 'Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration', FASEB Journal, vol. 31, no. 8, pp. 3425-3438. https://doi.org/10.1096/fj.201601166RR
Ma, Hongwei ; Yang, Fan ; Butler, Michael R. ; Belcher, Joshua ; Redmond, T. Michael ; Placzek, Andrew T. ; Scanlan, Thomas (Tom) ; Ding, Xi Qin. / Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration. In: FASEB Journal. 2017 ; Vol. 31, No. 8. pp. 3425-3438.
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abstract = "Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and metabolism. Recent studies have implicated TH signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we demonstrated that antithyroid drug treatment and targeting iodothyronine deiodinases (DIOs) to suppress cellular tri-iodothyronine (T3) production or increase T3 degradation preserves cones. In this work, we investigated the effectiveness of inhibition of the TH receptor (TR). Two genes, THRA and THRB, encode TRs; THRB2 has been associated with cone viability. Using TR antagonists and Thrb2 deletion, we examined the effects of TR inhibition. Systemic and ocular treatment with the TR antagonists NH-3 and 1-850 increased cone density by 30–40{\%} in the Rpe652/2 mouse model of Leber congenital amaurosis and reduced the number of TUNEL+ cells. Cone survival was significantly improved in Rpe652/2 and Cpfl1 (a model of achromatopsia with Pde6c defect) mice with Thrb2 deletion. Ventral cone density in Cpfl1/Thrb22/2 and Rpe652/2/Thrb22/2 mice was increased by 1- to 4-fold, compared with age-matched controls. Moreover, the expression levels of TR were significantly higher in the cone-degeneration retinas, suggesting locally elevated TR signaling. This work shows that the effects of antithyroid treatment or targeting DIOs were likely mediated by TRs and that suppressing TR protects cones. Our findings support the view that inhibition of TR locally in the retina is a therapeutic strategy for retinal degeneration management.—Ma, H., Yang, F., Butler, M. R., Belcher, J., Redmond, T. M., Placzek, A. T., Scanlan, T. S., Ding, X.-Q. Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration.",
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