Abstract
BackgroundProgesterone receptor (PR) affects immunomodulation, and lack of PR in osteoprogenitor cells primarily affects pathways associated with immunomodulation, especially in males. In this study, we selectively deleted PR from osteoprogenitor cells using Prx1-Cre to evaluate the tissue-specific effects of PR on the pathegenesis of inflammatary arthritis (IA).MethodsCollagen-induced arthritis (CIA) was used as an IA animal model. Both male and female PRΔPrx1 mice and their wild-type (WT) littermates were immunized with collagen II (CII) emulsified complete Freund’s adjuvant (CFA). Joint erosion, inflammation, and cartilage damage were assessed using a semiquantitative histologic scoring system. Bone volume and erosions in knee and ankle joints were quantitated using microCT and histology.ResultsBone erosions developed in both paw joints in 37.5% and 41.7% of the WT and PRΔPrx1 female mice and in 45.4 and 83.3% of the WT and PRΔPrx1 male mice, respectively. Also, both joint damage and subchondral bone erosions were significantly more severe in male PRcKO-CIA mice than in male WT-CIA mice. Female PRΔPrx1 mice also developed higher bone loss in the knee joints than the KO-normal or WT-CIA females although with less severity compared to the male mice.ConclusionsThe presence of PR in osteoprogenitor cells decreased the development of collagen-induced arthritis and might help to explain the sex differences observed in human inflammatory arthritis.
Highlights
Rheumatoid arthritis (RA) is a systemic autoimmune disease that can affect many organ systems, and inflammation of synovial tissue causes activation of inflammatory cytokines that destroy both cartilage and periarticularLiu et al Arthritis Research & Therapy (2020) 22:165 therapy [5, 9, 10]
Mice with Progesterone receptor (PR) conditionally knocked out in osteoprogenitor cells (OPC) had higher systemic activation of T cells and showed higher incidence of arthritis We found very low levels of circulating activated T cells marked by CD3e+, CD69+, and CD25+ in the WT-Collagen-induced arthritis (CIA) controls, especially in the female WT-CIA mice, at proximately 0.1% of the total mononuclear cells
Total bone volume did not differ in WT-CIA mice compared to their WT-non-CIA controls, but was reduced significantly in male PRΔPrx1-CIA mice compared to the PRΔPrx1-non-CIA male controls (Fig. 2a)
Summary
Rheumatoid arthritis (RA) is a systemic autoimmune disease that can affect many organ systems, and inflammation of synovial tissue causes activation of inflammatory cytokines that destroy both cartilage and periarticularLiu et al Arthritis Research & Therapy (2020) 22:165 therapy [5, 9, 10]. Since the lack of PR signaling in the osteoprogenitor cells (OPC) regulated immunomodulation pathways [34], we performed this study to evaluate the role of PR in the PRΔPrx mice using a CIA model. We selectively deleted PR from osteoprogenitor cells using Prx1-Cre to evaluate the tissue-specific effects of PR on the pathegenesis of inflammatary arthritis (IA). Methods: Collagen-induced arthritis (CIA) was used as an IA animal model Both male and female PRΔPrx mice and their wild-type (WT) littermates were immunized with collagen II (CII) emulsified complete Freund’s adjuvant (CFA). Results: Bone erosions developed in both paw joints in 37.5% and 41.7% of the WT and PRΔPrx female mice and in 45.4 and 83.3% of the WT and PRΔPrx male mice, respectively. Female PRΔPrx mice developed higher bone loss in the knee joints than the KO-normal or WT-CIA females with less severity compared to the male mice
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