Title: The complement factor H‑related protein‑5 (CFHR5) exacerbates pathological bone formation in ankylosing spondylitis

Journal: Journal of Molecular Medicine 

Authors: Ji-Hyun Lee^1,2, Seung Hoon Lee³, Chanhyeok Jeon³, Jinil Han⁴, Sang-Hyon Kim⁵, Jeehee Youn⁶, Ye-Soo Park⁷, Tae-Jong Kim⁸, Jong-Seo Kim^9,10, Sungsin Jo^11,12,*, Tae-Hwan Kim^13,14,*, Chang-Nam Son^15,16,*

Affiliations

 ¹ Department of Rheumatology, Eulji Rheumatology Research Institute, Eulji University School of Medicine, 712 Dongil-Ro, Uijeongbu, Gyeonggi-Do, 11759, Republic of Korea

 ² Rheumarker Bio Inc, Daegu, Republic of Korea

 ³ Hanyang University Institute for Rheumatology Research (HYIRR), 222-1 Wangsimni-Ro, Seongdong-Gu, Seoul, 04763, Republic of Korea

 ⁴ Gencurix Inc, Seoul, Republic of Korea

 ⁵ Division of Rheumatology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea

 ⁶ Department of Anatomy & Cell Biology, College of Medicine, Hanyang University, Seoul, Republic of Korea

 ⁷ Department of Orthopedic Surgery, Guri Hospital, Hanyang University College of Medicine, Guri, Gyeonggi-Do, Republic of Korea

 ⁸ Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea

 ⁹ Center for RNA Research, Institute for Basic Science, Seoul, Republic of Korea

 ¹⁰ School of Biological Sciences, Seoul National University, Seoul, Republic of Korea

 ¹¹ Hanyang University Institute for Rheumatology Research (HYIRR), 222-1 Wangsimni-Ro, Seongdong-Gu, Seoul, 04763, Republic of Korea

 ¹² Department of Biology, College of Natural Sciences, Soonchunhyang University, 22 Soonchunhyang-ro, Asan, Chungcheongnam-do, 31358, Republic of Korea

 ¹³ Hanyang University Institute for Rheumatology Research (HYIRR), 222-1 Wangsimni-Ro, Seongdong-Gu, Seoul, 04763, Republic of Korea

 ¹⁴ Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 222-1 Wangsimni-Ro, Seongdong-Gu, Seoul, 04763, Republic of Korea

 ¹⁵ Department of Rheumatology, Eulji Rheumatology Research Institute, Eulji University School of Medicine, 712 Dongil-Ro, Uijeongbu, Gyeonggi-Do, 11759, Republic of Korea

 ¹⁶ Rheumarker Bio Inc, Daegu, Republic of Korea

 ^* Correspondence

Abstract:

Ankylosing spondylitis (AS) is a chronic inflammatory disease, characterized by excessive new bone formation. We previously reported that the complement factor H-related protein-5 (CFHR5), a member of the human factor H protein family, is significantly elevated in patients with AS compared to other rheumatic diseases. However, the pathophysiological mechanism underlying new bone formation by CFHR5 is not fully understood. In this study, we revealed that CFHR5 and proinflammatory cytokines (TNF, IL-6, IL-17A, and IL-23) were elevated in the AS group compared to the HC group. Correlation analysis revealed that CFHR5 levels were not significantly associated with proinflammatory cytokines, while CFHR5 levels in AS were only positively correlated with the high CRP group. Notably, treatment with soluble CFHR5 has no effect on clinical arthritis scores and thickness at hind paw in curdlan-injected SKG, but significantly increased the ectopic bone formation at the calcaneus and tibia bones of the ankle as revealed by micro-CT image and quantification. Basal CFHR5 expression was upregulated in AS-osteoprogenitors compared to control cells. Also, treatment with CFHR5 remarkedly induced bone mineralization status of AS-osteoprogenitors during osteogenic differentiation accompanied by MMP13 expression. We provide the first evidence demonstrating that CFHR5 can exacerbate the pathological bone formation of AS. Therapeutic modulation of CFHR5 could be promising for future treatment of AS.

Keywords: CFHR5, AS, Mineralization, Osteoprogenitors,Pathological bone formation

DOI: https://doi.org/10.1007/s00109-024-02428-6

Published: 29 February 2024