ETA2024 Oral Presentations Oral Session 7: Thyroid hormone mechanisms in diseases (5 abstracts)
Altered skull and bone morphology in hyperthyroid knock-in mice with TSHR M453T and D633H mutations
Kristiina Makkonen 1 , Jorma Määttä 1 , Kaisa Ivaska 1 , Konrad Patyra 2 , Vladyslav Melnyk 3 , Veli Linnossuo 1 , Johanna Ojala 4 , Rowmika Ravi 5 , Holger Jäschke 6 , Julian Undeutsch 2 & Jukka Kero 7
1University of Turku, Finland; 2Research Centre for Integrative Physiology and Pharmacology, Tcdm, Institute of Biomedicine, University of Turku, Turku, Finland; 3University of Turku, Institute of Biomedicine, Turku, Finland; 4University of Turku, Physiology, Pediatrics, Turku, Finland; 5University of Turku, Department of Clinical Sciences, Faculty of Medicine, Turku, Finland; 6University of Turku, Turku, Finland; 7Biomedicine Institute, Physiology, Turku, Finland
Background: Constitutively active thyrotropin receptor (TSHR) mutations are the primary cause of non-autoimmune hyperthyroidism (NAH). The TSHR is a key regulator of thyroid function, which, through thyroid hormones, plays a crucial role in bone formation and resorption. Beyond influencing skeletal bone growth, thyroid hormones also regulate craniofacial development. Furthermore, in addition to thyroid hormones an independent role of TSH on bone development has been proposed. Here we evaluated the impact of constitutively activating mutations (CAM) in TSHR on craniofacial and bone development.
Methods: To understand the role of TSHR CAM in bone development we investigated our previously generated TSHR knock-in (KI) mouse models with patient-derived TSHR D633H and M453T mutations. TSHR D633H homozygous mice present mild transient hyperthyroidism at 2 months of age. TSHR M453T homozygous mice, on the other hand, exhibited a dietary iodine dependent, stronger, hyperthyroid state. Cranium morphometry, micro-computed tomography (µCT) and 3-point bending tests were performed.
Results: Homozygous TSHR D633H and M453T mice showed altered craniofacial morphology, with notable changes in skull dimensions and snout length compared to WTs. Malocclusion incidence was higher in HOM and HET mice compared to WT, independent of sex. TSHR D633H mice showed no significant differences in bone structural or mechanical properties. In contrast TSHR M453T mice showed alterations in BMD and structural characteristics of trabecular bone that were dependent on dietary iodine concentration, with no notable effects observed in cortical bone. No obvious differences in body or tail lengths were observed in TSHR D633H mice. TSHR M453T homozygous mice showed decreased tail length at weaning depending on dietary iodine concentration but the difference disappeared shortly after. No differences in body length were observed.
Conclusion: This is the first in vivo study to reveal NAH effects on bone morphology. Our findings suggest that TSHR CAMs, particularly D633H and M453T mutations, may influence craniofacial morphology and malocclusion incidence in mice. BMD and bone structural characteristics appeared to depend on dietary iodine content in homozygous mice. Further investigations are needed to evaluate more precise mechanisms of TSHR role in skeletal development.
Volume 101
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Endocrine Abstracts
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