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Negative Regulation of Osteoclast Commitment by Intracellular Protein Phosphatase Magnesium-Dependent 1A

 Oh Chan Kwon 1  ;  Bongkun Choi 2  ;  Eun-Jin Lee 2  ;  Ji-Eun Park 2  ;  Eun-Ju Lee 2  ;  Eun-Young Kim 2  ;  Sang-Min Kim 2  ;  Min-Kyung Shin 2  ;  Tae-Hwan Kim 3  ;  Seokchan Hong 2  ;  Chang-Keun Lee 2  ;  Bin Yoo 2  ;  William H Robinson 4  ;  Yong-Gil Kim 2  ;  Eun-Ju Chang 2 
 ARTHRITIS & RHEUMATOLOGY, Vol.72(5) : 750-760, 2020-05 
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Adult ; Animals ; Cell Differentiation* ; Female ; Humans ; Male ; Mice ; Mice, Knockout ; Osteoclasts / physiology* ; Protein Phosphatase 2C / physiology* ; RANK Ligand / physiology
Objective: Increased protein phosphatase magnesium-dependent 1A (PPM1A) 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 PPM1A to osteoclast differentiation by generating conditional gene-knockout (PPM1Afl/fl ;LysM-Cre) mice and evaluating their bone phenotype. Methods: The bone phenotypes of LysM-Cre mice (n = 6) and PPM1Afl/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 PPM1A, 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 PPM1Afl/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 PPM1A function in osteoclast precursors in PPM1Afl/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. PPM1A 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 PPM1A in peripheral blood mononuclear cells from patients with axial spondyloarthritis (SpA) (γ = -0.7072, P < 0.0001). Conclusion: The loss of PPM1A function in osteoclast precursors driven by inflammatory signals contributes to osteoclast lineage commitment and differentiation by elevating RANK expression, reflecting a potential role of PPM1A in dynamic bone metabolism in axial SpA.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kwon, Oh Chan(권오찬)
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