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

Abstract

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...

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

“…D2-mediated T4-to-T3 conversion mitigates the adverse effects of T3 deficiency on bone mineralization, whereas the reduced D2 activity in osteoblasts limits the detrimental effects of thyroid hormone excess. D2KO mice have low bone turnover and impaired osteoblast activity with a reduced mineralized surface, resulting in bones which are brittle and have reduced fracture resistance (57). The authors speculate that the absence of D2 in these mice results in intracellular hypothyroidism in the osteoblast despite a normal circulating T3.…”

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…Such parameters in the mouse are at the limits of spatial resolution by micro-CT. Detailed analysis of bone microarchitecture and micromineralization density can be analyzed using specialist back scattered electron-scanning electron microscopy (BSE-SEM) techniques (725)(726)(727)(729)(730)(731). The effects of altered thyroid status on linear growth and bone structural parameters are significant and readily determined using these methods, although specialist equipment and data analysis methods are required.…”

“…19). Bone mineral content, bone length, and cortical bone measurements are determined in long bones and vertebrae from adults aged 12 weeks onwards by Faxitron digital point projection x-ray microradiography (725). Bone microarchitecture and volumetric parameters require sophisticated imaging and can be obtained by high resolution micro-CT (to a maximum nominal resolution of 0.5-2 lm).…”

“…Neonatal P1 mice and limbs from animals aged between P21 and P42 should be stained with alizarin red (bone) and alcian blue (cartilage) to investigate intrauterine skeletal development and the progress of postnatal bone formation. Measurement of skull dimensions, fontanelles, and suture areas provide an assessment of intramembranous ossification; measures of bone length and growth plate histomorphometry are accurate and sensitive indicators of the progression of endochondral ossification (725)(726)(727)(728)(729)(730)(731).…”

Potential of Human Fetal Chorionic Stem Cells for the Treatment of Osteogenesis Imperfecta

“…Sixteen bit DICOM images were converted to 8-bit Tiff images using ImageJ and the image histogram stretched between the polyester (gray level 0) to steel (gray level 255) standards. Bone mineralization densities were represented by a pseudocolor scheme representing 16 equal intervals [25].…”