Endocrine Abstracts

Similar to thyroid hormones, the calcineurin/NFAT pathway regulates bone mass via its actions in osteoblasts and by indirect effects on osteoclast function. Calcineurin is a calcium- and calmodulin-activated phosphatase that dephosphorylates the transcription factor NFAT enabling its translocation to the nucleus. RCAN2 is an inhibitor of calcineurin that is stimulated by T₃ in brain, heart and skeletal muscle although its expression in bone has not been studied. Thus, RCAN2 is proposed to mediate target tissue responses to T₃ by inhibiting calcineurin activity. To investigate the role of RCAN2 in bone, we characterized RCAN2^−/− knockout mice. In juveniles, intramembranous ossification was delayed whereas endochondral ossification and growth were unaffected. Bone mineral content was reduced in RCAN2^−/− compared to wild-type mice at 4 weeks of age but no difference was evident in adults at 16 weeks. Cortical bone width, bone microarchitecture and trabecular bone mineralization density were similar in adult RCAN2^−/− and wild-type mice but cortical bone mineralization was increased in RCAN2^−/− mice. Examination of bone surfaces by back-scattered electron scanning electron microscopy and analysis of osteoclast parameters by histomorphometry revealed no differences between RCAN2^−/− and wild-type mice. Thus, RCAN2^−/− mice display delayed intramembranous ossification during skull development, reduced bone mineral content during growth but increased cortical bone mineralization in adulthood. This phenotype does not result from abnormal endochondral ossification or a defect in osteoclast function, but is consistent with an isolated impairment of osteoblast function that results in delayed intramembranous ossification and reduced bone mineral deposition during growth but increased cortical bone mineralization in adult bone. The findings are similar to the discrete osteoblast defect observed in mice lacking the type 2 deiodinase enzyme, which generates T₃ in thyroid hormone responsive target cells. We hypothesize that RCAN2 mediates some of the actions of T₃ in osteoblasts by inhibiting calcineurin/NFAT signaling.