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 (mCT)
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.