DKK-1 and Its Influences on Bone Destruction: A Comparative Study in Collagen-Induced Arthritis Mice and Rheumatoid
Di Zhao1,2, Lisheng Wu1,2, Mukeng Hong1,2
1Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Abstract:
Dickkopf-1 (DKK-1) has been considered a master regulator of bone remodeling. As precursors of osteoclasts (OCs), myeloid-derived suppressor cells (MDSCs) were previously shown to participate in the process of bone destruction in rheumatoid arthritis (RA). However, the role of DKK-1 and MDSCs in RA is not yet fully understood. We investigated the relevance between the level of DKK-1 and the expression of MDSCs in different tissues and joint destruction in RA patients and collagen-induced arthritis (CIA) mouse models. Furthermore, the CIA mice were administered recombinant DKK-1 protein. The arthritis scores, bone destruction, and the percentage of MDSCs in the peripheral blood and spleen were monitored. In vitro, the differentiation of MDSCs into OCs was intervened with recombinant protein and inhibitor of DKK-1. The number of OCs differentiated and the protein expression of the Wnt/β-catenin signaling pathway were explored. The level of DKK-1 positively correlates with the frequency of MDSCs and bone erosion in RA patients and CIA mice. Strikingly, recombinant DKK-1 intervention significantly exacerbated arthritis scores and bone destruction, increasing the percentage of MDSCs in the peripheral blood and spleen in CIA mice. In vitro experiments showed that recombinant DKK-1 promoted the differentiation of MDSCs into OCs, reducing the expression of β-catenin and TCF4 and increasing the expression of CyclinD1. In contrast, the DKK-1 inhibitor had the opposite effect. Our findings highlight that DKK-1 promoted MDSCs expansion in RA and enhanced the differentiation of MDSCs into OCs via targeting the Wnt/β-catenin pathway, aggravating the bone destruction in RA.
Insights
Dickkopf-1 (DKK-1) promotes myeloid-derived suppressor cells (MDSCs) expansion and osteoclast differentiation in rheumatoid arthritis (RA). This exacerbates joint destruction by targeting the Wnt/β-catenin pathway, highlighting DKK-1 as a therapeutic target for RA bone erosion.
Area of Science:
- Immunology
- Rheumatology
- Molecular Biology
Background:
- Dickkopf-1 (DKK-1) is a key regulator of bone remodeling.
- Myeloid-derived suppressor cells (MDSCs) contribute to bone destruction in rheumatoid arthritis (RA).
- The specific roles of DKK-1 and MDSCs in RA pathogenesis remain unclear.
Purpose of the Study:
- To investigate the correlation between DKK-1 levels and MDSC expression in RA patients and a collagen-induced arthritis (CIA) mouse model.
- To elucidate the mechanism by which DKK-1 influences MDSC differentiation into osteoclasts (OCs).
Main Methods:
- Correlative analysis of DKK-1 levels, MDSC frequency, and joint destruction in RA patients and CIA mice.
- Administration of recombinant DKK-1 protein to CIA mice to assess effects on arthritis severity, bone erosion, and MDSC populations.
- In vitro studies using recombinant DKK-1 and its inhibitor to examine MDSC differentiation into OCs and Wnt/β-catenin pathway signaling.
Main Results:
- DKK-1 levels positively correlated with MDSC frequency and bone erosion in both RA patients and CIA mice.
- Recombinant DKK-1 administration worsened arthritis scores and bone destruction, increasing MDSC percentages in CIA mice.
- In vitro, DKK-1 promoted MDSC differentiation into OCs, altering Wnt/β-catenin pathway components (reduced β-catenin/TCF4, increased CyclinD1).
Conclusions:
- DKK-1 promotes MDSC expansion and differentiation into osteoclasts in RA.
- DKK-1 exacerbates bone destruction in RA by targeting the Wnt/β-catenin pathway.
- DKK-1 represents a potential therapeutic target for mitigating bone damage in rheumatoid arthritis.
