Osteolytic diseases are closely associated with osteocyte fate, indicating a more efficient and crucial role of osteocyte-targeting strategy in inhibiting osteoclastogenesis. Here, we investigated the effects of lenalidomide (Lena) on osteocyte fate in order to regulate osteoclastogenesis via effective cascade controlling response. Our data revealed that lenalidomide treatment notably rescued IL-1 beta induced loss of osteocyte viability by inhibiting osteocyte apoptosis with decreased osteoclast-related factors, RANKL and Sclerostin, as demonstrated by the restricted osteoclast formation and reduced bone resorption. Additionally, iTRAQ assay revealed that IL-1 beta induced activation of NF-kappa B inhibitor alpha/beta were remarkably downregulated by lenalidomide, showing that lenalidomide impaired NF-kappa B signaling in osteocytes for inhibiting the expression of osteoclast specific genes in osteoclasts, which was further confirmed by KEGG pathway analysis and Western blot. More interestingly, the in vivo analysis of osteocyte apoptosis and osteoclastogenesis in osteoarthritis mice model indicated a role of lenalidomide in the regulation of osteocyte fate and the consequent inhibition of RANKL-induced osteoclastogenesis. Together, these results suggest that lenalidomide regulates osteocyte fate by attenuating IL-1 beta/NF-kappa B signaling, thereby inhibiting RANKL expression for the attenuated osteoclastogenesis both in vitro and vivo, indicating a more efficient remedy among future anti-osteoclastogenesis approaches. (C) 2018 Elsevier Inc. All rights reserved.