engleski

Notch 1 inhibition increases osteoclast progenitor activity in the mouse model of rheumatoid arthritis

Background: Osteoclast progenitor cells (OCPs) are susceptible to regulation through Notch signaling. We previously identified an increased frequency of OCPs expressing Notch receptors in arthritic mice. We aimed to determine the effects of Notch receptor signaling inhibition on OCP activity in murine collagen-induced arthritis (CIA). Methods: Periarticular bone marrow (PBM) and spleen (SPL) were harvested from mice with CIA, additionally treated by i.p. injections of anti-Notch 1 neutralizing antibodies (1mg/kg). FACS sorted OCPs were stimulated by osteoclastogenic factors (M- CSF/RANKL), in Jagged (JAG)1 or Delta-like (DLL)1 coated wells, with or without anti-Notch 1 antibodies. The research was approved by the Ethics Committee. Results: Seeding OCPs on DLL1- coated wells increased, whereas seeding on JAG1- coated wells decreased the number of TRAP+ osteoclasts and expression of osteoclast differentiation genes. Addition of anti-Notch 1 antibodies to ligand-stimulated OCPs resulted in an increased number of TRAP+ osteoclasts, partially reversing Jag1 inhibition. In vivo treatment with anti-Notch 1 antibodies did not affect total OCP frequency, but increased the expression of Notch 4 both in PBM and SPL as seen by flow cytometry. Additionally, anti-Notch 1 treatment stimulated Notch transcription factors HES and HEY. Both PBM and SPL cultured OCPs from anti-Notch 1 treated mice produced a higher number of large TRAP+ osteoclasts and exhibited increased expression of osteoclast differentiation genes. Conclusion: Both in vitro and in vivo anti-Notch 1 neutralizing antibodies enhanced osteoclastogenesis in CIA model, implying an inhibitory role of Notch 1 signaling in osteoclast differentiation.

osteoclast progenitors ; collagen-induced arthritis ; Notch ; Jagged ; Delta-like

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