Autoantibodies against Protein Phosphatase Magnesium-Dependent 1A as a Biomarker for Predicting Radiographic Progression in Ankylosing Spondylitis Treated with Anti-Tumor Necrosis Factor Agents

Abstract

Background: Patients with ankylosing spondylitis (AS) have increased levels of protein phosphatase magnesium-dependent 1A (PPM1A) and autoantibodies. We evaluated the usefulness of serum anti-PPM1A antibodies as a biomarker for AS. Methods: Serum samples from 58 AS patients were obtained from a multicenter registry prior to the initiation of anti-TNF agents. The serum levels of anti-PPM1A antibodies were measured using ELISA. Spinal radiographic progression was defined as an increase in the modified stoke ankylosing spondylitis spinal score (mSASSS) by ≥2 units or a newly developed syndesmophyte. The role of exogenous PPM1A on bone mineralization was evaluated using primary osteoprogenitors acquired from patients with AS and non-inflammatory controls. Results: The baseline levels of anti-PPM1A antibodies and mSASSS were higher in the radiographic progression group than in the non-progression group. In logistic regression analysis, baseline mSASSS and serum anti-PPM1A antibodies were associated with a higher risk of progression. The level of anti-PPM1A antibodies for predicting progression had an AUC of 0.716 (cut-off value: 43.77 ng/mL). PPM1A stimulation increased matrix mineralization in AS-osteoprogenitors but not in controls. Conclusion: Along with mSASSS, the serum levels of anti-PPM1A antibodies might be useful as a predictor of radiographic progression after treatment with anti-TNF agents.

Extracellular PPM1A promotes mineralization of osteoblasts differentiation in ankylosing spondylitis via the FOXO1A‐RUNX2 pathway

“…We previously reported that exogenous PPM1A treatment promotes matrix mineralization in AS‐osteoprogenitor cells 18 . In consistent with the previous reports, exogenous PPM1A treatment significantly enhanced matrix mineralization of AS‐osteoprogenitor cells (Figure 2A‐C).…”

“…Our study focused on bone formation in AS with elevated serum PPM1A levels 16 . As a result, exogenous PPM1A treatment increased matrix mineralization in human AS‐osteoprogenitor cells suggesting PPM1A could be a serum biomarker for excessive osteoblast differentiation in AS 18 . Functionally, PPM1A has been reported to dephosphorylate AMPK or transforming growth factor beta (TGFβ) and BMPs‐activated smad1/2/3/5 proteins 10,12,14 .…”

“…Although exogenous PPM1A treatment induced matrix mineralization in AS‐osteoprogenitor cells was previously reported, 18 the regulatory mechanism remains to be established. In this study, we investigate the underlying molecular mechanism of PPM1A‐induced matrix mineralization of AS‐osteoprogenitor cells during osteoblast differentiation.…”

“…Macrophage‐specific PPM1A deficiency mice showed increased osteoclast differentiation by inducing RANK expression 17 . Moreover, in AS patients treated with TNF inhibitor, a high level of anti‐PPM1A autoantibodies was a risk factor for radiographic progression and in vitro, exogenous PPM1A treatment increased matrix mineralization of primary osteoprogenitor during osteoblast differentiation 18 . These findings suggest that PPM1A may contribute to dynamic bone metabolism and formation in AS leading to spinal ankylosis.…”

Emerging Roles of Long Non-Coding RNAs in Ankylosing Spondylitis

“…AS mostly presents before the age of 45. Although AS has no known specific cause, individuals harbouring HLA-B27 (one among hundreds of different forms the HLA-B gene) are at a much greater risk ( 9 , 10 ). The molecular pathogenesis is complex and involves genetic, immunological, microbial (e.g., high abundance of Klebsiella pneumoniae in the gut microbiome) and hormonal (e.g., sex hormone disturbance, glucocorticoid deficiency) components ( 11 ).…”