Rickets in VDR null mice is secondary to decreased apoptosis of hypertrophic chondrocytes.

Both vitamin D deficiency and the absence of a functional vitamin D receptor (VDR) lead to a growth plate abnormality known as rickets. Prevention of abnormal mineral ion homeostasis by early institution of dietary therapy in VDR null mice prevents rickets, demonstrating that the VDR is not required for normal growth plate maturation. We, therefore, hypothesized that rickets, in the absence of a functional VDR, is due to impaired mineral ion homeostasis. Analyses of growth plate morphology in VDR null mice demonstrated normal resting and proliferating chondrocyte layers; however an expansion of the hypertrophic chondrocyte layer was present by 24 days of age. Because extracellular calcium has been shown to play a role in chondrocyte maturation, we addressed the hypothesis that hypocalcemia led to impaired chondrocyte differentiation. However, in situ hybridization analyses revealed normal expression of hypertrophic chondrocyte markers in the tibial growth plate of 24 day old VDR null mice, suggesting that the increase in the hypertrophic chondrocyte layer was not secondary to impaired differentiation. We then addressed whether expansion of the hypertrophic chondrocyte layer was secondary to increased proliferation or decreased apoptosis. BrdU labeling failed to demonstrate an increase in chondrocyte proliferation in the VDR null mice; however, apoptosis was markedly diminished in the late hypertrophic chondrocytes of the VDR null mice, suggesting that impairment in programmed cell death of these cells leads to the characteristic findings of rickets.