HLA-B27–mediated activation of TNAP phosphatase promotes pathogenic syndesmophyte formation in ankylosing spondylitis
Chin-Hsiu Liu, … , Shih-Chieh Hung, Kuo-I Lin
Chin-Hsiu Liu, … , Shih-Chieh Hung, Kuo-I Lin
Published December 2, 2019; First published November 4, 2019
Citation Information: J Clin Invest. 2019;129(12):5357-5373. https://doi.org/10.1172/JCI125212.
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Categories: Research Article Autoimmunity Bone biology

HLA-B27–mediated activation of TNAP phosphatase promotes pathogenic syndesmophyte formation in ankylosing spondylitis

Abstract

Ankylosing spondylitis (AS) is a type of axial inflammation. Over time, some patients develop spinal ankylosis and permanent disability; however, current treatment strategies cannot arrest syndesmophyte formation completely. Here, we used mesenchymal stem cells (MSCs) from AS patients (AS MSCs) within the enthesis involved in spinal ankylosis to delineate that the HLA-B27–mediated spliced X-box–binding protein 1 (sXBP1)/retinoic acid receptor-β (RARB)/tissue-nonspecific alkaline phosphatase (TNAP) axis accelerated the mineralization of AS MSCs, which was independent of Runt-related transcription factor 2 (Runx2). An animal model mimicking AS pathological bony appositions was established by implantation of AS MSCs into the lumbar spine of NOD-SCID mice. We found that TNAP inhibitors, including levamisole and pamidronate, inhibited AS MSC mineralization in vitro and blocked bony appositions in vivo. Furthermore, we demonstrated that the serum bone-specific TNAP (BAP) level was a potential prognostic biomarker to predict AS patients with a high risk for radiographic progression. Our study highlights the importance of the HLA-B27–mediated activation of the sXBP1/RARB/TNAP axis in AS syndesmophyte pathogenesis and provides a new strategy for the diagnosis and prevention of radiographic progression of AS.

Authors

Chin-Hsiu Liu, Sengupta Raj, Chun-Hsiung Chen, Kuo-Hsuan Hung, Chung-Tei Chou, Ing-Ho Chen, Jui-Teng Chien, I-Ying Lin, Shii-Yi Yang, Takashi Angata, Wen-Chan Tsai, James Cheng-Chung Wei, I-Shiang Tzeng, Shih-Chieh Hung, Kuo-I Lin

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Figure 6

HLA-B27 mediates the upregulation of the RARB/TNAP axis in AS MSCs.

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HLA-B27 mediates the upregulation of the RARB/TNAP axis in AS MSCs. (A) ...
(A) ARS staining of mineralization in AS MSCs transduced with shHLA-B or shCtrl under osteogenic induction with quantification (B). (C) Immunoblot analyses showing the expression of RARB and TNAP in AS MSCs expressing shHLA-B or shCtrl at day 7 under osteogenic induction. (D) Immunoblot showing HLA-B27 expressions of control MSCs transduced with pLAS2w or pLAS2w-HLA-B27. (E) ARS staining of control MSCs transduced with control lentiviral vector (pLAS2w) or a vector expressing HLA-B27 (pLAS2w-HLA-B27) with quantification (F). (G) Immunoblot analyses showing RARB and TNAP expressions in control MSCs transduced with pLAS2w or pLAS2w-HLA-B27. All experiments done in the AS patient group and the control group are from AS MSCs (A1, A2, and A3) and control MSCs (C1, C2, and C3), respectively, with at least 2–3 experimental repeats. Data are the mean ± SEM. ***P < 0.001; ****P < 0.0001 by 2-tailed Student’s t test (2 groups) or 1-way ANOVA, followed by Tukey’s HSD test. Representative images from AS (A1) MSCs are shown in C. Scale bars: 200 μm (A and E).