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

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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.

Key messages

  • Serum level of CFHR5 is elevated and positively correlated with high CRP group of AS patients.

  • Recombinant CFHR5 protein contributes to pathological bone formation in in vivo model of AS.

  • CFHR5 is highly expressed in AS-osteoprogenitors compared to disease control.

  • Recombinant CFHR5 protein increased bone mineralization accompanied by MMP13 in vitro model of AS.

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Data availability

The datasets generated and analyzed during the current study are not publicly available but are available from the corresponding author upon reasonable request.

Abbreviations

AS:

Ankylosing spondylitis

HC:

Healthy controls

CFHR5:

Complement factor H-related protein-5

H&E:

Hematoxylin and eosin

CRP:

C-reactive protein

SO:

Safranin O

ALP:

Alkaline phosphatase

ARS:

Alizarin red S

VON:

Von Kossa

HA:

Hydroxyapatite

MMP13:

Matrix metallopeptidase 13

OCN:

Osteocalcin

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Funding

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (Grant number 2021R1F1A1060970 to Chang-Nam Son, 2019R1A2C2004214 and 2021R1A6A1A03038899 to Tae-Hwan Kim, and 2020R1A2C1102386 to Sungsin Jo), the Korea Healthy Industry Development Institute (Grant number HI23C0661 to Tae-Hwan Kim), and the Medi-Start Up Program through Daegu-Gyeongbuk Medical Innovation Foundation funded by Daegu Metropolitan (Grant number B-A-H-21–02 to Chang-Nam Son).

Author information

Author notes

  1. Ji-Hyun Lee and Seung Hoon Lee contributed equally to this work.

Authors and Affiliations

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

    Ji-Hyun Lee & Chang-Nam Son

  2. Rheumarker Bio Inc, Daegu, Republic of Korea

    Ji-Hyun Lee & Chang-Nam Son

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

    Seung Hoon Lee, Chanhyeok Jeon, Sungsin Jo & Tae-Hwan Kim

  4. Gencurix Inc, Seoul, Republic of Korea

    Jinil Han

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

    Sang-Hyon Kim

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

    Jeehee Youn

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

    Ye-Soo Park

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

    Tae-Jong Kim

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

    Jong-Seo Kim

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

    Jong-Seo Kim

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

    Sungsin Jo

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

    Tae-Hwan Kim

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  1. Ji-Hyun Lee
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  2. Seung Hoon Lee
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  4. Jinil Han
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  9. Jong-Seo Kim
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  10. Sungsin Jo
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  11. Tae-Hwan Kim
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  12. Chang-Nam Son
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S Jo, J-H Lee, J-S Kim, T-H Kim, and C-N Son contributed to the study design and conception. S Jo, J-H Lee, SH Lee, and C Jeon performed and assisted with experiments. S–H Kim, Y-S Park, T-J Kim, T-H Kim, and C-N Son provided serum, PBMC, and surgical samples from patients with AS. J Youn provided SKG mice. J Han performed statistical analysis. S Jo and C-N Son drafted the manuscript. S Jo, J-H Lee, SH Lee, T-H Kim, and C-N Son wrote the revised version of the manuscript. C-N Son and T-H Kim supervised this study. All authors have read and approved the publication.

Corresponding authors

Correspondence to Sungsin Jo, Tae-Hwan Kim or Chang-Nam Son.

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Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University Hanyang University Hospital (2014–05-002) and approved by the Animals Ethics Screening Committee of Hanyang University (2021-0229A).

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Competing interests

Ji-Hyun Lee and Jinil Han are employed by Rheumarker Bio Inc. and Gencurix Inc., respectively. Chang-Nam Son is the chief executive officer (CEO) of Rheumarker Bio Inc. Other authors declare no conflicts of interest.

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Lee, JH., Lee, S.H., Jeon, C. et al. The complement factor H-related protein-5 (CFHR5) exacerbates pathological bone formation in ankylosing spondylitis. J Mol Med 102, 571–583 (2024). https://doi.org/10.1007/s00109-024-02428-6

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

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