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Collagen-binding peptides for the enhanced imaging, lubrication and regeneration of osteoarthritic articular cartilage

Nature Biomedical Engineering volume 6, pages 1105–1117 (2022)Cite this article

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Abstract

Treatments for osteoarthritis would benefit from the enhanced visualization of injured articular cartilage and from the targeted delivery of disease-modifying drugs to it. Here, by using ex vivo human osteoarthritic cartilage and live rats and minipigs with induced osteoarthritis, we report the application of collagen-binding peptides, identified via phage display, that are home to osteoarthritic cartilage and that can be detected via magnetic resonance imaging when conjugated with a superparamagnetic iron oxide. Compared with the use of peptides with a scrambled sequence, hyaluronic acid conjugated with the collagen-binding peptides displayed enhanced retention in osteoarthritic cartilage and better lubricated human osteoarthritic tissue ex vivo. Mesenchymal stromal cells encapsulated in the modified hyaluronic acid and injected intra-articularly in rats showed enhanced homing to osteoarthritic tissue and improved its regeneration. Molecular docking revealed WXPXW as the consensus motif that binds to the α1 chain of collagen type XII. Peptides that specifically bind to osteoarthritic tissue may aid the diagnosis and treatment of osteoarthritic joints.

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Fig. 1: Intravital imaging of the binding capability of C5-24 peptides to OA cartilage.
Fig. 2: C5-24 peptides in early OA diagnosis.
Fig. 3: C5-24 peptides in joint lubrication.
Fig. 4: C5-24 peptides increase HA retention in OA cartilage.
Fig. 5: C5-24 peptides in OA regeneration.
Fig. 6: Identification of the binding protein of C5-24 peptides.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are available for research purposes from the corresponding authors on reasonable request. Source data are provided with this paper.

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Acknowledgements

We thank C.-C. Lin and the Core Facility of the Institute of Cellular and Organismic Biology (ICOB), Academia Sinica, for their assistance with C5-24, scrambled-peptide synthesis and biotin conjugation. This work was supported by the Drug Development Center, China Medical University, from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. We thank W.-T. Juan and G.-Y. Zhuo, from the Two photon core facility, China Medical University, for their assistance. This work was financially supported by the Minister of Science and Technology (MOST 106-2321-B-039-003; 109-2321-B-039 -003; 108-2221-E-039-006-MY3; 111-2326-B-039 -001), China Medical University (Grant Nos. CMU110-S-26 and CMU110-MF-83) and China Medical University Hospital (Grant No. DMR-110-228). The funding sources had no involvement in study design, in the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the article for publication.

Author information

Author notes

  1. These authors contributed equally: Chin-Yu Lin, Yung-Li Wang.

Authors and Affiliations

  1. Drug Development Center, Institute of Translational Medicine and New Drug Development, School of Medicine, China Medical University, Taichung, Taiwan

    Chin-Yu Lin, Yung-Li Wang, Long Yi Chan & Shih-Chieh Hung

  2. Integrative Stem Cell Center, China Medical University Hospital, Taichung, Taiwan

    Yu-Jen Chen, Chun-Te Ho & Shih-Chieh Hung

  3. Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan

    Yi-Hsuan Chi & Han-Chung Wu

  4. Molecular Science Center, GGA Corporation, Taipei, Taiwan

    Guan-Wen Chen

  5. Department of Medicine, School of Medicine, China Medical University, Taichung, Taiwan

    Horng-Chaung Hsu

  6. Department of Orthopaedics, China Medical University Hospital, Taichung, Taiwan

    Horng-Chaung Hsu & Shih-Chieh Hung

  7. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    Dennis W. Hwang

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Contributions

H.-C.W. and S.-C.H. conceptualized the study and acquired funds. C.-Y.L., Y.-L.W., Y.-J.C., C.-T.H., Y.-H.C. and L.Y.C. conducted experiments. C.-Y.L., Y.-L.W., Y.-J.C., C.-T.H., Y.-H.C., L.Y.C., D.W.H. and S.-C.H. carried out data analyses. G.-W.C. carried out computational analyses. D.W.H. carried out the MRI studies. C.-Y.L., H.-C.W. and S.-C.H. wrote and edited the manuscript.

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Correspondence to Han-Chung Wu or Shih-Chieh Hung.

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Nature Biomedical Engineering thanks Jeffrey Weiss and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data

Extended Data Fig. 1 Biopanning of phage clones targeting OA cartilage.

The OA articular cartilage specimens of knee joints from patients who received total knee joint replacement were separated into two parts, cell lysates and square pieces, for screening a phage peptide display library to identify clones targeting OA cartilage. a, Preparation of clinical cartilage tissues for phage clones biopanning. b, Biopanning of cartilage lysate. c, Biopanning of cartilage pieces.

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Lin, CY., Wang, YL., Chen, YJ. et al. Collagen-binding peptides for the enhanced imaging, lubrication and regeneration of osteoarthritic articular cartilage. Nat. Biomed. Eng 6, 1105–1117 (2022). https://doi.org/10.1038/s41551-022-00948-5

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