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 November 4, 2019
Citation Information: J Clin Invest. 2019;129(12):5357-5373. https://doi.org/10.1172/JCI125212.
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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 5

RARB is an upstream regulator that promotes TNAP expression in AS MSCs.

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RARB is an upstream regulator that promotes TNAP expression in AS MSCs. ...
(A) Differential gene expression of transcription factors between AS MSCs and control MSCs under osteogenic induction at the indicated days. (B–E) Expression of transcription factors RARB and LEF1 in AS and control MSCs measured by RT-qPCR (B and C) and immunoblotting (D and E). (F and G) RT-qPCR (F) and immunoblot analyses (G) showing reduced TNAP expression in AS or control MSCs transduced with 2 shRNAs against RARB at day 7 under osteogenic induction compared with the effects of shCtrl. (H) ARS staining of mineralization in AS or control MSCs expressing shRARB or shCtrl under osteogenic induction with quantification (I). All experiments were done in the AS patient group using AS MSCs (derived from A1, A2, and A3 with experimental triplicates) and/or in the control group using control MSCs (derived from C1, C2, and C3 with experimental triplicates). Data are the mean ± SEM. *P < 0.05; **P < 0.01; ****P < 0.0001 by 1-way ANOVA, followed by Tukey’s HSD test. Representative immunoblots from AS (A1) MSCs and control (C3) MSCs are shown in G and H. Scale bar: 200 μm (H).