Genetic and pharmacological targeting of transcriptional repression in resistance to thyroid hormone alpha.

Background Thyroid hormones act in bone and cartilage via thyroid hormone receptor α (TRα). In the absence of 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 α (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. We 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. Methods We determined the skeletal phenotypes of (i) Thra1PV/+ mice, a well characterized model of RTHα, (ii) Ncor1ΔID/ΔID mice, which express an NCoR1 mutant that fails to interact with TRα, and (iii) Thra1PV/+Ncor1ΔID/ΔID double mutant adult mice. Wild-type, Thra1PV/+, Ncor1ΔID/ΔID, and Thra1PV/+Ncor1ΔID/ΔID double mutant mice were also treated with SAHA to determine whether HDAC inhibition results in amelioration of skeletal abnormalities. Results Thra1PV/+ mice had a severe skeletal dysplasia characterized by short stature, abnormal bone morphology and increased bone mineral content. Despite normal bone length, Ncor1ΔID/ΔID mice displayed increased cortical bone mass, mineralization and strength. Thra1PV/+Ncor1ΔID/ΔID double mutant mice displayed only a small improvement of skeletal abnormalities compared to Thra1PV/+ 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. Conclusions 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.