Bone marrow stromal cell proliferation in mice lacking NFATc1 in mature osteoclasts

Abstract

The transcription factor Nuclear factor of activated T cells c1 (NFATc1) is a master regulator of osteoclastogenesis. Previous knockout studies have shown that global NFATc1 deletion in younger mice leads to poor osteoclastogenesis and osteopetrosis. Here we show that the cathepsin k-cre mediated deletion of NFATc1 in mature osteoclasts leads to a phenotype with notable differences including the presence of abnormally large, multinucleate, TRAP-positive osteoclasts and the effacement of the bone marrow by stromal cells resembling a fibrotic reaction. We characterize this phenotype in a multitude of ways. We show that the fibrosis phenotype: (1) presents between age E15.5 and P5, (2) is dependent on the presence of osteoclasts and is downstream of RANK, the cell surface receptor that triggers osteoclast differentiation (3) and is not likely an osteoblast lineage-intrinsic phenotype. We hypothesized that NFATc1 in osteoclasts negatively regulates a secreted stromal lineage proliferative factor that functions in coupling. Our in-vitro assays using media conditioned by cultured wild-type or knockout osteoclasts were unable to show differences in neither BMSC proliferation nor differentiation. Last, we identify genes that are highly upregulated in NFATc1 knock-out osteoclasts and describe those that may function in regulation of stromal-lineage differentiation or proliferation.