Lack of the Thyroid Hormone Transporter Mct8 in Osteoblast and Osteoclast Progenitors Increases Trabecular Bone in Male Mice

Background: Bone is an important target of thyroid hormones (THs), which require transport into target cells to exert their actions. Recently, the TH-specific monocarboxylate transporter 8 (Mct8) was reported as a regulator of bone mass in male mice. However, its global deletion leads to high 3,3',5-L-triiodothyronine (T3) serum concentrations that may mask direct effects of Mct8-deficiency on bone. In this study, we assessed the bone cell intrinsic function of Mct8 ex vivo and in vivo using conditional Mct8-knockout lines specifically targeting osteoclast and osteoblast progenitors, as well as mature osteoblasts and osteocytes. Materials and Methods: Twelve-week-old male mice with a global Mct8-deficiency or a conditional Mct8-knockout in osteoclast precursors, osteoprogenitors, or mature osteoblasts/osteocytes were analyzed regarding their bone microarchitecture, turnover, and strength. Furthermore, ex vivo studies were conducted to investigate the role of Mct8 in bone cell differentiation and functionality, as well as TH uptake. Results: Global Mct8-knockout mice demonstrated 1.7-fold higher T3 serum concentrations and trabecular bone loss (-28%) likely due to an increased bone turnover as shown by increased osteoblast (+45%) and osteoclast numbers (+41%). However, cortical bone mineral density was increased. Ex vivo cultures of bone marrow-derived osteoblasts and osteoclasts revealed highest expression of Mct8 in mature bone cells. In addition, Mct8-deficiency resulted in a lower mRNA expression of osteoblast and osteoclast differentiation markers, as well as a reduced mineralization capacity and osteoclast numbers, respectively, indicating a bone cell intrinsic role of Mct8. In fact, conditional Mct8-knockout and inhibition of Mct8 in osteoblasts led to an attenuated T3 uptake ex vivo. In vivo, osteoprogenitor-specific Mct8-knockout enhanced trabecular bone volume (+16%) with osteoblast numbers being increased 3.7 fold. Interestingly, Mct8-deficiency in osteoprogenitors and late osteoblasts/osteocytes both resulted in cortical bone loss. Finally, Mct8-deletion in osteoclast progenitors increased trabecular bone volume (+20%) due to reduced osteoclast numbers (-32%), whereas osteoblast numbers were enhanced (+25%). Conclusions: This study confirms that high systemic T3 in global Mct8-knockout mice masks the direct effect of Mct8. Moreover, it identifies Mct8 as a critical regulator of trabecular vs. cortical bone by regulating T3 uptake and highlights its cell intrinsic role in osteoclast and osteoblast progenitors.