1 Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, United Kingdom.
2 Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Thyroid. 2019 May;29(5):726-734. doi: 10.1089/thy.2018.0399. Epub 2019 Mar 14.
Thyroid hormones act in bone and cartilage via thyroid hormone receptor alpha (TRα). In the absence of triiodothyronine (T3), TRα interacts with co-repressors, including nuclear receptor co-repressor-1 (NCoR1), which recruit histone deacetylases (HDACs) and mediate transcriptional repression. Dominant-negative mutations of TRα cause resistance to thyroid hormone alpha (RTHα; OMIM 614450), characterized by excessive repression of T3 target genes leading to delayed skeletal development, growth retardation, and bone dysplasia. Treatment with thyroxine has been of limited benefit, even in mildly affected individuals, and there is a need for new therapeutic strategies. It was hypothesized that (i) the skeletal manifestations of RTHα are mediated by the persistent TRα/NCoR1/HDAC repressor complex containing mutant TRα, and (ii) treatment with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) would ameliorate these manifestations. The skeletal phenotypes of (i) mice, a well characterized model of RTHα; (ii) mice, which express an NCoR1 mutant that fails to interact with TRα; and (iii) double-mutant adult mice were determined. Wild-type, , , and double-mutant mice were also treated with SAHA to determine whether HDAC inhibition results in amelioration of skeletal abnormalities. mice had a severe skeletal dysplasia, characterized by short stature, abnormal bone morphology, and increased bone mineral content. Despite normal bone length, mice displayed increased cortical bone mass, mineralization, and strength. double-mutant mice displayed only a small improvement of skeletal abnormalities compared to mice. Treatment with SAHA to inhibit histone deacetylation had no beneficial or detrimental effects on bone structure, mineralization, or strength in wild-type or mutant mice. These studies indicate treatment with SAHA is unlikely to improve the skeletal manifestations of RTHα. Nevertheless, the findings (i) confirm that TRα1 has a critical role in the regulation of skeletal development and adult bone mass, (ii) suggest a physiological role for alternative co-repressors that interact with TR in skeletal cells, and (iii) demonstrate a novel role for NCoR1 in the regulation of adult bone mass and strength.
甲状腺激素通过甲状腺激素受体 α（TRα）在骨骼和软骨中发挥作用。在没有三碘甲状腺原氨酸（T3）的情况下，TRα 与共抑制因子相互作用，包括核受体共抑制因子-1（NCoR1），其招募组蛋白去乙酰化酶（HDACs）并介导转录抑制。TRα 的显性负突变导致甲状腺激素α抵抗（RTHα；OMIM 614450），其特征是 T3 靶基因的过度抑制导致骨骼发育迟缓、生长迟缓和骨发育不良。尽管在轻度受影响的个体中，甲状腺素治疗的效果有限，但需要新的治疗策略。据推测，（i）RTHα 的骨骼表现是由含有突变 TRα 的持续 TRα/NCoR1/HDAC 抑制复合物介导的，（ii）用 HDAC 抑制剂 suberoylanilide hydroxamic acid（SAHA）治疗会改善这些表现。研究了（i） 小鼠，一种很好表征的 RTHα 模型；（ii） 小鼠，其表达不能与 TRα 相互作用的 NCoR1 突变体；和（iii） 成年双突变鼠的骨骼表型。还对野生型、 、 和 双突变鼠进行了 SAHA 治疗，以确定 HDAC 抑制是否导致骨骼异常的改善。 小鼠表现出严重的骨骼发育不良，表现为身材矮小、骨骼形态异常和骨矿物质含量增加。尽管骨长度正常，但 小鼠表现出皮质骨量、矿化和强度增加。与 小鼠相比， 双突变鼠的骨骼异常仅略有改善。用 SAHA 抑制组蛋白去乙酰化对野生型或突变型小鼠的骨骼结构、矿化或强度均无有益或有害影响。这些研究表明，用 SAHA 治疗不太可能改善 RTHα 的骨骼表现。然而，这些发现（i）证实 TRα1 在骨骼发育和成年骨量的调节中起着关键作用，（ii）表明在骨骼细胞中与 TR 相互作用的替代共抑制因子具有生理作用，（iii）证明了 NCoR1 在调节成年骨量和强度方面的新作用。
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