IL-3 inhibits human osteoclastogenesis and bone resorption through downregulation of c-Fms and diverts the cells to dendritic cell lineage.

Abstract

IL-3 is an important cytokine that regulates hematopoiesis and functions as a link between the immune and the hematopoietic system. In this study, we investigated the role and mechanism of IL-3 action on human osteoclast formation and bone resorption using PBMCs. PBMCs differentiate into functional osteoclasts in the presence of M-CSF and receptor activator of NF-kappaB ligand as evaluated by 23c6 expression and bone resorption. We found that IL-3 dose-dependently inhibited formation of 23c6-positive osteoclasts, bone resorption and C-terminal telopeptide of type I collagen, a collagen degradation product. The inhibitory effect of IL-3 on bone resorption was irreversible. To investigate the mechanism of IL-3 action, we analyzed the effect of IL-3 on the receptor activator of NF-kappaB and c-Fms receptors and c-Fos, PU.1, NFAT cytoplasmic 1, and RelB transcription factors essential for osteoclastogenesis. IL-3 significantly inhibited c-Fms and downregulated both PU.1 and c-Fos at both mRNA and protein level. Furthermore, IL-3-treated cells showed increased expression of dendritic cell markers CD1a and CD80 and decreased expression of monocyte/macrophage marker CD14. Interestingly, IL-3 inhibited formation of human osteoclasts derived from blood monocytes and bone marrow cells of osteoporotic individuals. Thus, IL-3 may have therapeutic potential as an antiosteolytic agent in treatment of osteoporosis.

• Authors: Navita Gupta, Amruta P Barhanpurkar, Geetanjali B Tomar, Rupesh K Srivastava, Supinder Kour, Satish T Pote, Gyan C Mishra, Mohan R Wani
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 185 Issue 4 Pg. 2261-72 (Aug 15 2010) ISSN: 1550-6606 [Electronic] United States
• PMID: 20644169 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-3
• Osteoprotegerin
• RANK Ligand
• Receptors, Interleukin-3
• Receptor, Macrophage Colony-Stimulating Factor

Topics

• Adult
• Aged
• Bone Resorption (prevention & control)
• Cell Differentiation (drug effects)
• Cell Lineage (drug effects)
• Cells, Cultured
• Dendritic Cells (cytology, drug effects, metabolism)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Flow Cytometry
• Gene Expression (drug effects)
• Humans
• Interleukin-3 (pharmacology)
• Middle Aged
• Osteoclasts (cytology, drug effects, metabolism)
• Osteoprotegerin (genetics, metabolism)
• RANK Ligand (pharmacology)
• Receptor, Macrophage Colony-Stimulating Factor (genetics, metabolism)
• Receptors, Interleukin-3 (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Young Adult