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Macrophage migration inhibitory factor is essential for osteoclastogenic mechanisms in vitro and in vivo mouse model
Ran Gu1, Leilani L Santos1, Devi Ngo1
1Centre for Inflammatory Disease, Monash University, Clayton, Australia.
Abstract:
Macrophage migration inhibitory factor (MIF) enhances activation of leukocytes, endothelial cells and fibroblast-like synoviocytes (FLS), thereby contributing to the pathogenesis of rheumatoid arthritis (RA). A MIF promoter polymorphism in RA patients resulted in higher serum MIF concentration and worsens bone erosion; controversially current literature reported an inhibitory role of MIF in osteoclast formation. The controversial suggested that the precise role of MIF and its putative receptor CD74 in osteoclastogenesis and RA bone erosion, mediated by locally formed osteoclasts in response to receptor activator of NF-κB ligand (RANKL), is unclear. We reported that in an in vivo K/BxN serum transfer arthritis, reduced clinical and histological arthritis in MIF(-/-) and CD74(-/-) mice were accompanied by a virtual absence of osteoclasts at the synovium-bone interface and reduced osteoclast-related gene expression. Furthermore, in vitro osteoclast formation and osteoclast-related gene expression were significantly reduced in MIF(-/-) cells via decreasing RANKL-induced phosphorylation of NF-κB-p65 and ERK1/2. This was supported by a similar reduction of osteoclastogenesis observed in CD74(-/-) cells. Furthermore, a MIF blockade reduced RANKL-induced osteoclastogenesis via deregulating RANKL-mediated NF-κB and NFATc1 transcription factor activation. These data indicate that MIF and CD74 facilitate RANKL-induced osteoclastogenesis, and suggest that MIF contributes directly to bone erosion, as well as inflammation, in RA.
Insights
Macrophage migration inhibitory factor (MIF) and its receptor CD74 promote osteoclast formation, worsening bone erosion in rheumatoid arthritis (RA). Blocking MIF reduces inflammation and bone damage by inhibiting osteoclastogenesis.
Area of Science:
- Immunology
- Rheumatology
- Molecular Biology
Background:
- Macrophage migration inhibitory factor (MIF) contributes to rheumatoid arthritis (RA) pathogenesis.
- The role of MIF and its receptor CD74 in osteoclast formation and RA bone erosion is debated.
- Previous studies suggest conflicting roles for MIF in osteoclastogenesis.
Purpose of the Study:
- To clarify the precise role of MIF and CD74 in osteoclastogenesis and RA bone erosion.
- To investigate the mechanism by which MIF influences osteoclast formation.
- To evaluate the therapeutic potential of MIF blockade in RA.
Main Methods:
- Utilized K/BxN serum transfer arthritis model in wild-type, MIF(-/-), and CD74(-/-) mice.
- Performed in vitro osteoclast differentiation assays using MIF(-/-) and CD74(-/-) cells.
- Analyzed RANKL-induced signaling pathways, including NF-κB and ERK1/2 phosphorylation.
- Assessed the effect of MIF blockade on osteoclastogenesis.
Main Results:
- MIF(-/-) and CD74(-/-) mice exhibited reduced arthritis severity and significantly fewer osteoclasts.
- In vitro, MIF deficiency or CD74 deficiency markedly reduced osteoclast formation and related gene expression.
- MIF blockade inhibited RANKL-induced osteoclastogenesis by disrupting NF-κB and NFATc1 activation.
- Reduced phosphorylation of NF-κB-p65 and ERK1/2 was observed in MIF(-/-) cells.
Conclusions:
- MIF and CD74 are crucial facilitators of RANKL-induced osteoclastogenesis.
- MIF directly contributes to bone erosion and inflammation in rheumatoid arthritis.
- Targeting MIF presents a potential therapeutic strategy for mitigating RA-associated bone damage.
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