Endocrine Abstracts

The type 3 deiodinase enzyme (D3) inactivates T₃ and prevents activation of T₄ to protect the fetus from premature exposure to thyroid hormones. Rapidly falling levels of D3 activity and rising levels of T₃ at birth initiate the onset of cell differentiation and organ maturation during the post-natal period. Congenital hypothyroidism causes delayed ossification with reduced bone mineral deposition and short stature. We hypothesize that increased T₃ availability in bone forming chondrocytes and osteoblasts initiates the acceleration of postnatal linear growth and bone mass accrual to establish the structure of the mature skeleton. Thus, to investigate the role of T₃ availability during bone development, we generated transgenic mice that over-express D3 following excision of a floxed stop cassette (pCCALL2/D3) and crossed them with mice expressing cre-recombinase only in chondrocytes (COL2cre) or osteoblasts (OCcre). Restricted D3 over-expression in either chondrocytes or osteoblasts did not affect circulating T₃ or T₄ levels. Consistent with high levels of endogenous D3 in utero, mice over-expressing the enzyme in chondrocytes (COL2D3) and osteoblasts (OCD3) displayed normal endochondral and intramembranous ossification at post-natal day P1. However, at P21 COL2D3 mice had grossly abnormal epiphyses, absent secondary ossification centres and severe growth retardation. Short stature persisted throughout adulthood. By contrast, OCD3 mice had no abnormality of ossification or linear growth. Quantitative Faxitron micro-radiography of adult COL2D3 mice at 10 micron pixel resolution revealed the persistence of gross morphological abnormalities that were accompanied by reduced peak bone mass and the presence of low bone mineral content even at P366. No abnormalities were observed in OCD3 mice. These data demonstrate that local availability of T₃ in chondrocytes is essential for normal post-natal bone development, accrual of peak bone mass and establishment of the adult skeleton. By contrast, T₃ action in osteoblasts does not play a major role during skeletal development.