Hypothyroidism in young leads to irreversible growth failure. Hyt/hyt mice have a non-functional TSH receptor (TSHR) and are severely hypothyroid but growth retardation was not observed in adult mice. We found that epiphyseal cartilage as well as cultured chondrocytes expressed functional TSHR at levels comparable to that seen in the thyroid, and that addition of TSH to cultured chondrocytes suppressed expression of chondrocyte - differentiation marker genes, such as Sox-9 and type IIa collagen. Next, we compared the long bone phenotypes of two distinct mouse models of hypothyroidism: a thyroidectomized (THYx) mice and hyt/hyt mice. Although both THYx and hyt/hyt mice were in severely hypothyroid and had similar serum Ca²⁺ and growth hormone levels, the tibia was shorter and the proliferating and hypertrophic zones in growth plate was significantly narrower in THYx mice than in hyt/hyt mice. Supplementation of hyt/hyt mice thyroid hormone resulted in a wider growth plate when compared with that of wild-type mice. Expression of chondrocyte- differentiation marker genes, Sox-9 and type IIa collagen, in growth plate from THYx mice were 52% and 60% lower than those of hyt/hyt mice, respectively. High serum TSH causes abnormal skeletal development in young mice with hypothyroidism via suppressive effects on the growth plate.