Tumor necrosis factor alpha (TNF-)-induced osteoclastogenesis have profound effects in states of inflammatory osteolysis such as rheumatoid arthritis, periprosthetic implant loosening, and periodontitis. However, the exact mechanisms by which TNF-alpha promotes RANKL-induced osteoclast formation remains poorly understood. B lymphocyte-induced maturation protein-1 (Blimp1) is a transcriptional repressor that plays crucial roles in the differentiation and/or function of various kinds of cells including osteoclasts. A novel mechanism was identified where TNF-alpha-mediated Blimp1 expression, which contributed to RANKL-induced osteoclastogenesis. It is shown that TNF-alpha could promote the level of Blimp1 expression during osteoclast differentiation. Silencing of Blimp1 in osteoclast precursor cells obviously attenuated the stimulatory effect of TNF-alpha on osteoclastogenesis. Mechanistically, TNF-alpha-induced Blimp1 expression was markedly rescued by blocking the PI3K/Akt signaling pathway, which suggested that PI3K/Akt signaling was involved in the regulation of TNF-alpha-stimulated Blimp1 expression. Taken together, the results established a molecular mechanism of TNF--induced osteoclasts differentiation, and provided insights into the potential contribution of Blimp1 in the regulation of osteoclastogenesis by TNF-alpha. J. Cell. Biochem. 118: 1308-1315, 2017. (C) 2016 Wiley Periodicals, Inc.