engleski

Increased expression of Notch receptors on osteoclast progenitors induced by rheumatoid arthritis

As Notch signaling has been implicated in osteoclast differentiation and activation, we investigated the expression of Notch receptors and ligands on osteoclast progenitors (OCP) in rheumatoid arthritis (RA) patients and mouse collagen-induced arthritis model. Peripheral blood mononuclear cells (PBMC) of RA patients and controls were phenotyped by flow cytometry, and an increase in Notch receptors on OCP was observed. During osteoclast differentiation in culture, there is an increase in Notch1, Notch3, Jag1 and DLL1 relative mRNA level in OCP, specifically in RA patients. By comparing the gene expression levels of Notch system components in sorted progenitors vs PBMC or synovial fluid cells we concluded that Notch receptors are generally more abundantly expressed on OCP, with an increase of Notch3 and DLL1 in arthritis. Likewise, in mice there is a significant increase in all the Notch receptors on flow cytometry, both in periarticular bone marrow (PBM) and spleen OCP. Although with initially higher levels of Notch1 and Notch2, during osteoclast differentiation levels of Notch3 and Notch4 as well as DLL4 mRNA increased in arthritic mice. Compared with controls, arthritic mice express more Notch2 mRNA in PBM. Immunohistochemistry of mice hind paws confirmed Notch receptor expression, with Notch1 and Notch2 on chondrocytes and synovial tissue, as well as Notch2 in PBM. Osteoclastogenic culture of sorted progenitors in wells coated with Notch ligands showed Jag1 inhibited, while DLL1 stimulated osteoclast formation. In conclusion, there is an increase in Notch expression on OCPs which may contribute to enhanced bone resorption in arthritis.

osteoclast progenitors ; colagen-induced arthritis ; rheumatoid arthritis ; notch

The work has been supported by Croatian Science Foundation projects IP-2018-01-2414, UIP-2017-05- 1965 and DOK-2018-09-4276.