In:
Arthritis & Rheumatology, Wiley, Vol. 72, No. 5 ( 2020-05), p. 750-760
Kurzfassung:
Increased protein phosphatase magnesium‐dependent 1A ( PPM 1A) levels in patients with ankylosing spondylitis regulate osteoblast differentiation in bony ankylosis; however, the potential mechanisms that regulate osteoclast differentiation in relation to abnormal bone formation remain unclear. This study was undertaken to investigate the relationship of PPM 1A to osteoclast differentiation by generating conditional gene‐knockout ( PPM 1A fl/fl ;LysM‐Cre) mice and evaluating their bone phenotype. Methods The bone phenotypes of LysM‐Cre mice (n = 6) and PPM 1A fl/fl ;LysM‐Cre mice (n = 6) were assessed by micro–computed tomography. Osteoclast differentiation was induced by culturing bone marrow–derived macrophages in the presence of RANKL and macrophage colony‐stimulating factor (M‐ CSF ), and was evaluated by counting tartrate‐resistant acid phosphatase–positive multinucleated cells. Levels of messenger RNA for PPM 1A , RANK , and osteoclast‐specific genes were examined by real‐time quantitative polymerase chain reaction, and protein levels were determined by Western blotting. Surface RANK expression was analyzed by fluorescence flow cytometry. Results The PPM 1A fl/fl ;LysM‐Cre mice displayed reduced bone mass ( P 〈 0.001) and increased osteoclast differentiation ( P 〈 0.001) and osteoclast‐specific gene expression ( P 〈 0.05) compared with their LysM‐Cre littermates. Mechanistically, reduced PPM 1A function in osteoclast precursors in PPM 1A fl/fl ;LysM‐Cre mice induced osteoclast lineage commitment by up‐regulating RANK expression ( P 〈 0.01) via p38 MAPK activation in response to M‐ CSF . PPM 1A expression in macrophages was decreased by Toll‐like receptor 4 activation ( P 〈 0.05). The Ankylosing Spondylitis Disease Activity Score was negatively correlated with the expression of PPM 1A in peripheral blood mononuclear cells from patients with axial spondyloarthritis (SpA) (γ = −0.7072, P 〈 0.0001). Conclusion The loss of PPM 1A function in osteoclast precursors driven by inflammatory signals contributes to osteoclast lineage commitment and differentiation by elevating RANK expression, reflecting a potential role of PPM 1A in dynamic bone metabolism in axial SpA.
Materialart:
Online-Ressource
ISSN:
2326-5191
,
2326-5205
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2020
ZDB Id:
2754614-7
