Oral Presentation 30th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2020

An essential physiological role for MCT8 in bone in male mice (#6)

Victoria D Leitch 1 2 , Caterina Di Cosmo 3 , Xiao-Hui Liao 3 , Sam O'Boy 2 , Thomas M Galliford 2 , Holly Evans 4 , Peter I Croucher 5 , Alan Boyde 6 , Alexandra Dumitrescu 3 , Roy E Weiss 7 , Samuel Refetoff 3 , Graham R Williams 2 , JH Duncan Bassett 2
  1. RMIT Centre for Additive Manufacturing, RMIT, Melbourne, VIC, Australia
  2. Department of Medicine, Imperial College London, London, UK
  3. The University of Chicago, Chicago, Illinois, USA
  4. Sheffield Myeloma Research Team, University of Sheffield, Sheffield, UK
  5. Bone Biology Laboratory, Garvan Institute of Medical Research, Sydney, NSW, Australia
  6. Oral BioEngineering, Queen Mary University of London, London, UK
  7. University of Miami, Miami, Florida, USA

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-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 also lack the ability to convert the prohormone T4 to the active hormone T3. Mct8KO mice have mild central resistance to thyroid hormone with decreased T4 concentrations and slightly elevated T3 concentrations. By contrast, Mct8D1D2KO mice have severe central resistance to thyroid hormone with systemic hyperthyroidism. Intrauterine 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 (P<0.05) and normalised by 12 weeks of age. This growth delay was accompanied by abnormal mineral content in Mct8KO and Mct8D1D2KO mice between 2 and 16 weeks of age (P<0.001). Adult Mct8KO and Mct8D1D2KO mice had decreased bone mass and mineralisation but only compound mutants had reduced bone strength with decreased yield and maximum loads (P<0.05). Bone resorption was increased in Mct8D1D2KO mice whereas bone formation parameters were not changed in either Mct8KO or Mct8D1D2KO mice. 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 demonstrate an essential role for the thyroid hormone transporter MCT8 in chondrocytes during skeletal development, and reveal the importance of other transporters in adult bone maintenance.