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 3

TNAP blockade inhibits new bony appositions induced by AS MSCs in NOD-SCID mice.

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TNAP blockade inhibits new bony appositions induced by AS MSCs in NOD-SC...
(A, C, and D) Representative images of lumbar spine micro-CT of NOD-SCID mice implanted with AS MSCs (derived from A1, A2, and A3 with triplicates in each group) or control MSCs (derived from C1, C2, and C3 with triplicates in each group) in the artificial cortical defect of the right lamina of lumbar spine segment L4–5 (A); with AS MSCs (derived from A1, A2, and A3 with triplicates in each group) transduced with shCtrl or shTNAP (C); or with AS MSCs (derived from A1, A2, and A3 with triplicates in each group) plus daily oral administration of H2O (n = 9), levamisole (10 mg/kg) (n = 9), beryllium sulfate (7.5 mg/kg) (n = 9), or pamidronate (0.3 mg/kg) (n = 9) (D). Images were taken 3 weeks after implantation. Longitudinal view over L4–6 (left), longitudinal view at high magnification over L4 (middle), and cross-sectional view over L4 (right) are shown. New bony appositions are highlighted by a red rectangle (middle) and white arrow (right). (B) Representative H&E staining images showing MSC-implanted sites (arrowhead-dotted areas) in the spinal tissues. AS MSCs (A1) formed new woven bone apposition (asterisks) bridging with host bone (HB), with some osteochondral-like tissues surrounding the newly formed bone (white arrow), while control MSCs (C3) formed fibrous-like tissues (black arrow) in direct contact with host bone. Higher-magnification views of areas in red rectangles in upper panels are shown in lower panels (scale bars: 200 μm). (E) The quantitative volumes of new bony appositions (mm3) between groups (A, C, and D). Data are the mean ± SEM (n = 9 in E). ****P < 0.0001 by 2-tailed Student’s t test (2 groups) or 1-way ANOVA, followed by Tukey’s HSD test.