Nuclear factor of activated T cells 2 is required for osteoclast differentiation and function in vitro but not in vivo.

Abstract

Nuclear factor of activated T cells (NFAT) c2 is important for the immune response and it compensates for NFATc1 for its effects on osteoclastogenesis, but its role in this process is not established. To study the function of NFATc2 in the skeleton, Nfatc2loxP/loxP mice, where the Nfact2 exon 2 is flanked by loxP sequences, were created and mated with mice expressing the Cre recombinase under the control of the Lyz2 promoter. Bone marrow-derived macrophage (BMM) from Lyz2Cre/WT ;Nfatc2Δ/Δ mice cultured in the presence of macrophage-colony stimulating factor and receptor activator of NF-κB ligand exhibited a decrease in the number and size of osteoclasts and a smaller sealing zone when compared to BMMs from Nfatc2loxP/loxP littermate controls. Bone resorption was decreased in osteoclasts from Lyz2Cre/WT ;Nfatc2Δ/Δ mice. This demonstrates that NFATc2 is necessary for optimal osteoclast maturation and function in vitro. Male and female Lyz2Cre/WT ;Nfatc2Δ/Δ mice did not exhibit an obvious skeletal phenotype by microcomputed tomography (μCT) at either 1 or 4 months of age when compared to Nfatc2loxP/loxP sex-matched littermates. Bone histomorphometry confirmed the μCT results, and conditional 4-month-old Lyz2Cre/WT ;Nfatc2Δ/Δ mice did not exhibit changes in parameters of bone histomorphometry. In conclusion, NFATc2 is necessary for optimal osteoclastogenesis in vitro, but its downregulation in the myeloid lineage has no consequences in skeletal remodeling in vivo.