The role of mTORC1 in mediating thyroid hormone actions on bone and bone cell metabolism

• Applicant: Dr. Franziska Brinkmann
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 455890087

By accelerating bone turnover, hyperthyroidism is an established cause of secondary osteoporosis and increased bone fragility. At the cellular level, thyroid hormones (TH) promote osteoblast differentiation and activity via the bone morphogenetic (BMP) pathway, amongst others, and further stimulate osteoclastogenesis and bone resorption indirectly. Increased cellular activity consumes higher amounts of energy, however, studies characterizing the metabolic fluxes and ways of energy production in TH-treated osteoblasts are still lacking. Preliminary data suggest that pathways centered on the energy and nutrient sensor mTORC1 are activated at the transcriptional level in osteoblasts and osteocytes challenged with TH, indicating a mTORC1-induced metabolic reprogramming of these bone cells to meet increased energy needs. Whether these changes are mediated by the thyroid hormone receptors THRA or/and THRB as well as the BMP signaling pathway and whether mTORC1-driven osteoblast/osteocyte metabolism also links to increased osteoclast activity and bone resorption under hyperthyroid conditions is unknown. This project will provide novel and detailed insights into the molecular actions of TH in bone cell metabolism, in particular the involvement of mTORC1, THRA/THRB, and BMPs in TH-activated osteoblast/osteocyte metabolism, which may improve our understanding of hyperthyroidism-driven osteoporosis.

• DFG Programme: Research Grants