Irreversible inhibition of RANK expression as a possible mechanism for IL-3 inhibition of RANKL-induced osteoclastogenesis

• Published in: Biochemical and biophysical research communications 2010-09, Vol.399 (4), p.688-693
• Main Authors: Khapli, Shruti M., Tomar, Geetanjali B., Barhanpurkar, Amruta P., Gupta, Navita, Yogesha, S.D., Pote, Satish T., Wani, Mohan R.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Bone marrow; BONE MARROW CELLS; Bone Marrow Cells - cytology; Cell Differentiation; Cells, Cultured; IL-3; IN VIVO; INHIBITION; Interleukin-3 - metabolism; Interleukin-3 - pharmacology; LIGANDS; LYMPHOCYTES; MACROPHAGES; MAP Kinase Kinase 4 - antagonists & inhibitors; MAP Kinase Kinase 4 - biosynthesis; MICE; NFATC Transcription Factors - metabolism; Osteoclast differentiation; Osteoclasts - cytology; Osteoclasts - metabolism; POPULATIONS; Proto-Oncogene Proteins c-fos - metabolism; RANK Ligand - metabolism; RANK signaling pathways; RANKL; Receptor Activator of Nuclear Factor-kappa B - antagonists & inhibitors; Receptor Activator of Nuclear Factor-kappa B - biosynthesis; RECEPTORS; STEM CELLS; TRANSCRIPTION FACTORS
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2010.07.143

► IL-3 inhibits receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. ► IL-3 inhibits RANKL-induced JNK activation. ► IL-3 down-regulates expression of c-Fos and NFATc1 transcription factors. ► IL-3 down-regulates RANK expression posttranscriptionally and irreversibly. ► IL-3 inhibits in vivo RANK expression. IL-3, a cytokine secreted by activated T lymphocytes, stimulates the proliferation, differentiation and survival of pluripotent hematopoietic stem cells. In this study, we investigated the mechanism of inhibitory action of IL-3 on osteoclast differentiation. We show here that IL-3 significantly inhibits receptor activator of NF-κB (RANK) ligand (RANKL)-induced activation of c-Jun N-terminal kinase (JNK). IL-3 down-regulates expression of c-Fos and nuclear factor of activated T cells (NFATc1) transcription factors. In addition, IL-3 down-regulates RANK expression posttranscriptionally in both purified osteoclast precursors and whole bone marrow cells. Furthermore, the inhibitory effect of IL-3 on RANK expression was irreversible. Interestingly, IL-3 inhibits in vivo RANK expression in mice. Thus, we provide the first evidence that IL-3 irreversibly inhibits RANK expression that results in inhibition of important signaling molecules induced by RANKL.