Abstract
T3 is an important regulator of skeletal development and adult bone maintenance. Thyroid hormone action requires efficient transport of T4 and T3 into target cells. We hypothesized that monocarboxylate transporter (MCT) 8, encoded by Mct8 on the X-chromosome, is an essential thyroid hormone transporter in bone. To test this hypothesis, we determined the juvenile and adult skeletal phenotypes of male Mct8 knockout mice (Mct8KO) and Mct8D1D2KO compound mutants, which additionally lack the ability to convert the prohormone T4 to the active hormone T3. Prenatal skeletal development was normal in both Mct8KO and Mct8D1D2KO mice, whereas postnatal endochondral ossification and linear growth were delayed in both Mct8KO and Mct8D1D2KO mice. Furthermore, bone mass and mineralization were decreased in adult Mct8KO and Mct8D1D2KO mice, and compound mutants also had reduced bone strength. Delayed bone development and maturation in Mct8KO and Mct8D1D2KO mice is consistent with decreased thyroid hormone action in growth plate chondrocytes despite elevated serum T3 concentrations, whereas low bone mass and osteoporosis reflects increased thyroid hormone action in adult bone due to elevated systemic T3 levels. These studies identify an essential physiological requirement for MCT8 in chondrocytes, and demonstrate a role for additional transporters in other skeletal cells during adult bone maintenance.
Highlights
Thyroid hormone is an important regulator of skeletal development, linear growth, and adult bone mass and strength [1]
We identified an essential role for MCT8 in the skeleton by analyzing [1] mice that lack Mct8 alone (Mct8KO) and [2] mice that lack both Mct8 and the ability to convert T4 to the active hormone T3 (Mct8D1D2KO)
Skeletal thyroid hormone deficiency and excess in Mct8KO and Mct8D1D2KO mice In WT mice Mct8 is expressed in the skeleton at high levels in utero but declines at birth and remains stable thereafter
Summary
Thyroid hormone is an important regulator of skeletal development, linear growth, and adult bone mass and strength [1]. We hypothesized that MCT8 is an essential thyroid hormone transporter required for bone development, mineralization, and strength To test this hypothesis, we determined the skeletal consequences of deletion of Mct in Mct82/y knockout (KO) mice (Mct8KO) compared with wild-type (WT) mice. To investigate the possibility that other thyroid hormone transporters could contribute to thyroid hormone uptake, we compared Mct8KO mice to triple KO Mct82/yDio12/2Dio22/2 mice, which are deprived of the intracellularly generated active T3 as they lack both thyroid hormone–activating enzymes and Mct (Mct8D1D2KO). In these studies, an abnormal skeletal phenotype in Mct8KO mice would indicate an essential physiological role for MCT8 in bone. An equivalent phenotype in Mct8D1D2KO mice would identify MCT8 as the sole thyroid hormone transporter in the skeleton, whereas a more severe skeletal phenotype in Mct8D1D2KO mice would suggest an additional transporter contributes to thyroid hormone uptake in bone
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