Ankylosing spondylitis (AS) is characterized by the formation of syndesmophytes and occurs more frequently in HLA-B27+ individuals, but whether these two phenomena are related has been uncertain. According to the results of a new study, HLA-B27 misfolding is directly linked to syndesmophyte formation via tissue-nonspecific alkaline phosphatase (TNAP), in a process that can be targeted therapeutically.
“We derived mesenchymal stem cells (MSCs) from the entheses of patients with AS to address if there is any abnormality in AS-derived MSCs,” explains co-corresponding author Kuo-I Lin. “We did not find any significant differences in the production of the cytokines or chemokines that we tested in AS-derived MSCs as compared with control MSCs, but AS-derived MSCs did show accelerated mineralization upon osteogenic induction.”
The researchers were surprised to discover that this enhanced mineralization was not regulated by the transcription factor RUNX2, which is usually associated with this process, but was instead regulated by TNAP via the transcription factor RARβ. Further in vitro investigations revealed that unfolded HLA-B27 causes the upregulation of TNAP in AS-derived MSCs via the IRE1α–sXBP1 pathway of the unfolded protein response. Crucially, serum concentrations of bone-specific TNAP were increased in patients with AS compared with healthy individuals from two different cohorts and correlated with disease progression.
“We also implanted AS-derived MSCs near the mechanically eroded lumber spine of NOD-SCID mice to test whether they show enhanced bone formation in vivo,” says co-corresponding author Shih-Chieh Hung. “This new animal model seems to mimic the development of new bony appositions in patients.”
“unfolded HLA-B27 causes the upregulation of TNAP in AS-derived MSCs”
Interestingly, treatment of these mice with the TNAP inhibitors levamisole (an anti-helminthic drug) or pamidronate (a bisphosphonate) substantially reduced syndesmophyte formation. “In the future, we hope to identify new drug candidates, as currently available TNAP inhibitors may have some adverse effects,” concludes Lin.
Liu, C.-H. et al. HLA-B27–mediated activation of TNAP phosphatase promotes pathogenic syndesmophyte formation in ankylosing spondylitis. J. Clin. Invest. https://doi.org/10.1172/JCI125212 (2019)
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Clarke, J. HLA-B27-related pathway mediates syndesmophyte formation in AS. Nat Rev Rheumatol 16, 3 (2020). https://doi.org/10.1038/s41584-019-0343-2