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Unravelling the Mystery of Ankylosing Spondylitis

Understanding the activation of TNAP gene by HLA-B27 in the pathogenesis of Ankylosing Spondylitis (AS) for development of diagnosis strategies.

In a collaborative research led by Dr. Lin Kuo-I of the Genomics Research Centre at Academia Sinica analysed clinical data form Taiwan and the United Kingdom (UK) to uncover molecular mechanisms of disease pathogenesis of AS.

AS is a form of arthritis that predominantly affects the spine, it causes inflammation of the vertebrae which can lead to severe, chronic pain and discomfort for the patient. This usually results in stiffness and bending of the spine making it hard for the patient to straighten their backs, this condition is commonly known as “bamboo spine”. AS affects men more commonly and the early symptoms usually manifest as chronic lower back pains at a young age.

At present, there is little knowledge of the mechanisms causing the inflammation and what causes the formation of syndesmophytes in the vertebrae. Dr. Liu Chin-Hsiu, first author of the study is also a physician in the Division of Allergy, Immunology, and Rheumatology of the Taipei Tzu Chi Hospital joined Dr. Lin Kuo-I’s team in hopes of finding a cure to help AS patients. Treatments of AS currently only counter the inflammatory symptoms with many patients still developing a bony growth causing pain and stiffness.

To better understand how syndesmophytes are formed, the team studied the development of it from mesenchymal stem cells (MSCs). With the engagement of Dr. Chen In-Ho from the Hualien Tzu Chi Hospital, they were able to obtain sample biopsies after spinal surgeries. Dr. Hung Shih-Chieh of the China Medical University in Taichung and adjunct research fellow at the Institute of Biomedical Science (IBMS), Academia Sinica, specialises in MSC research worked with the team as a co-corresponding author of the study.

Harvesting the MSCs from the biopsied tissue, they were injected into immunodeficient mice to observe how the human MSCs develop. After three weeks since injection, irregular bone-like structures formed on the spines of the mice. The HLA-B27 gene is known to be associated with AS pathogenesis but the mechanism is still unclear. Through this study, the team was able to demonstrate that the HLA-B27 gene triggers misfolding of proteins, activating a signalling pathway that will eventually cause the increased activation of the TNAP gene, causing the formation of syndesmophytes. From this, they were able to test three drugs that showed promising results in the inhibition of the TNAP gene.

The team also worked with Dr. Sengupta Raj from the Royal National Hospital for Rheumatic Disease in the UK to collect serum samples from British AS patients. When analysed they found that serum levels of bone-specific TNAP known as BAP was a potential prognostic biomarker for AS.

“This is a work with combined effort from a variety of research disciplines, especially from several physicians at different hospitals and different regions. With the pathway unveiled, finding better drugs to treat Ankylosing Spondylitis is more than realistic. We are hoping this study will lead to a new therapy for patients.” Commented Dr. Lin.

Their work was published online in the Journal of Clinical Investigation in November 2019 with an accompanying review by Nature Reviews Rheumatology shortly after. [APBN]