Leitch Victoria D, Di Cosmo Caterina, Liao Xiao-Hui, O'Boy Sam, Galliford Thomas M, Evans Holly, Croucher Peter I, Boyde Alan, Dumitrescu Alexandra, Weiss Roy E, Refetoff Samuel, Williams Graham R, Bassett J H Duncan
Molecular Endocrinology Laboratory, Department of Medicine, Hammersmith Campus, Imperial College London, London W12 0NN, United Kingdom.
Department of Medicine, The University of Chicago, Chicago, Illinois 60637.
Endocrinology. 2017 Sep 1;158(9):3055-3066. doi: 10.1210/en.2017-00399.
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.
T3是骨骼发育和成人骨骼维持的重要调节因子。甲状腺激素发挥作用需要T4和T3有效转运至靶细胞。我们推测，由X染色体上的Mct8编码的单羧酸转运蛋白（MCT）8是骨骼中一种重要的甲状腺激素转运蛋白。为验证这一假设，我们确定了雄性Mct8基因敲除小鼠（Mct8KO）和Mct8D1D2KO复合突变体的幼年和成年骨骼表型，后者还缺乏将甲状腺激素原T4转化为活性激素T3的能力。Mct8KO和Mct8D1D2KO小鼠的产前骨骼发育均正常，而Mct8KO和Mct8D1D2KO小鼠的出生后软骨内成骨和线性生长均延迟。此外，成年Mct8KO和Mct8D1D2KO小鼠的骨量和矿化程度降低，复合突变体的骨强度也降低。Mct8KO和Mct8D1D2KO小鼠骨骼发育和成熟延迟，这与生长板软骨细胞中甲状腺激素作用降低一致，尽管血清T3浓度升高，而低骨量和骨质疏松则反映出由于全身T3水平升高，成年骨骼中甲状腺激素作用增强。这些研究确定了软骨细胞中MCT8的一项基本生理需求，并证明了其他转运蛋白在成年骨骼维持过程中在其他骨骼细胞中的作用。
