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New Insights for RANKL as a Proinflammatory Modulator in Modeled Inflammatory Arthritis.
New Insights for RANKL as a Proinflammatory Modulator in Modeled Inflammatory Arthritis.
- Source :
-
Frontiers in immunology [Front Immunol] 2019 Feb 05; Vol. 10, pp. 97. Date of Electronic Publication: 2019 Feb 05 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- Receptor activator of nuclear factor-κB ligand (RANKL), a member of the Tumor Necrosis Factor (TNF) superfamily, constitutes the master regulator of osteoclast formation and bone resorption, whereas its involvement in inflammatory diseases remains unclear. Here, we used the human TNF transgenic mouse model of erosive inflammatory arthritis to determine if the progression of inflammation is affected by either genetic inactivation or overexpression of RANKL in transgenic mouse models. TNF-mediated inflammatory arthritis was significantly attenuated in the absence of functional RANKL. Notably, TNF overexpression could not compensate for RANKL-mediated osteopetrosis, but promoted osteoclastogenesis between the pannus and bone interface, suggesting RANKL-independent mechanisms of osteoclastogenesis in inflamed joints. On the other hand, simultaneous overexpression of RANKL and TNF in double transgenic mice accelerated disease onset and led to severe arthritis characterized by significantly elevated clinical and histological scores as shown by aggressive pannus formation, extended bone resorption, and massive accumulation of inflammatory cells, mainly of myeloid origin. RANKL and TNF cooperated not only in local bone loss identified in the inflamed calcaneous bone, but also systemically in distal femurs as shown by microCT analysis. Proteomic analysis in inflamed ankles from double transgenic mice overexpressing human TNF and RANKL showed an abundance of proteins involved in osteoclastogenesis, pro-inflammatory processes, gene expression regulation, and cell proliferation, while proteins participating in basic metabolic processes were downregulated compared to TNF and RANKL single transgenic mice. Collectively, these results suggest that RANKL modulates modeled inflammatory arthritis not only as a mediator of osteoclastogenesis and bone resorption but also as a disease modifier affecting inflammation and immune activation.
- Subjects :
- Animals
Bone Resorption
Disease Models, Animal
Humans
Immunomodulation
Mice
Mice, Transgenic
Osteogenesis genetics
Osteopetrosis genetics
Proteomics
RANK Ligand metabolism
Tumor Necrosis Factor-alpha metabolism
Arthritis immunology
Inflammation immunology
Myeloid Cells immunology
RANK Ligand genetics
Tumor Necrosis Factor-alpha genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1664-3224
- Volume :
- 10
- Database :
- MEDLINE
- Journal :
- Frontiers in immunology
- Publication Type :
- Academic Journal
- Accession number :
- 30804932
- Full Text :
- https://doi.org/10.3389/fimmu.2019.00097