IL-3 Differentially Regulates Membrane and Soluble RANKL in Osteoblasts through Metalloproteases and the JAK2/STAT5 Pathway and Improves the RANKL/OPG Ratio in Adult Mice
| Autor: | Suhas T. Mhaske, Vikrant Piprode, Amruta Barhanpurkar-Naik, Kanupriya Singh, Mohan R. Wani |
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| Rok vydání: | 2016 |
| Předmět: |
musculoskeletal diseases
0301 basic medicine Immunology Gene Expression Osteoclasts Mice Transgenic Bone remodeling 03 medical and health sciences Mice Osteoprotegerin Downregulation and upregulation Osteoclast medicine STAT5 Transcription Factor Immunology and Allergy Animals Cells Cultured Osteoblasts biology Receptor Activator of Nuclear Factor-kappa B Chemistry Mesenchymal stem cell RANK Ligand Osteoblast Janus Kinase 2 Coculture Techniques Matrix Metalloproteinases Cell biology 030104 developmental biology medicine.anatomical_structure RANKL biology.protein Interleukin-3 Signal Transduction |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 200(2) |
| ISSN: | 1550-6606 |
| Popis: | Bone remodeling comprises balanced activities between osteoclasts and osteoblasts, which is regulated by various factors, including hormones and cytokines. We previously reported that IL-3 inhibits osteoclast differentiation and pathological bone loss. IL-3 also enhances osteoblast differentiation and bone formation from mesenchymal stem cells. However, the role of IL-3 in regulation of osteoblast–osteoclast interactions and underlying mechanisms is not yet delineated. In this study, we investigated the role of IL-3 on the regulation of osteoblast-specific molecules, receptor activator of NF-κB ligand (RANKL), and osteoprotegerin (OPG) that modulate bone homeostasis. We found that IL-3 increases RANKL expression at both the transcriptional and translational levels, and it showed no effect on OPG expression in calvarial osteoblasts. The increased RANKL expression by IL-3 induces mononuclear osteoclasts; however, it does not induce multinuclear osteoclasts. Interestingly, IL-3 decreases soluble RANKL by reducing ectodomain shedding of membrane RANKL through downregulation of metalloproteases mainly a disintegrin and metalloproteinase (ADAM)10, ADAM17, ADAM19, and MMP3. Moreover, IL-3 increases membrane RANKL by activating the JAK2/STAT5 pathway. Furthermore, IL-3 enhances RANKL expression in mesenchymal stem cells of wild-type mice but not in STAT5a knockout mice. Interestingly, IL-3 restores RANKL expression in adult mice by enhancing bone-specific RANKL and decreasing serum RANKL. Furthermore, IL-3 increases the serum OPG level in adult mice. Thus, our results reveal, to our knowledge for the first time, that IL-3 differentially regulates two functional forms of RANKL through metalloproteases and the JAK2/STAT5 pathway, and it helps in restoring the decreased RANKL/OPG ratio in adult mice. Notably, our studies indicate the novel role of IL-3 in regulating bone homeostasis in important skeletal disorders. |
| Databáze: | OpenAIRE |
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