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


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.


  1. Goldring, S. R. & Goldring, M. B. Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage-bone crosstalk. Nat. Rev. Rheumatol. 12, 632–644 (2016).

    Article  Google Scholar 

  2. Martel-Pelletier, J. et al. Osteoarthritis. Nat. Rev. Dis. Prim. 2, 16072 (2016).

    Article  Google Scholar 

  3. Peat, G., McCarney, R. & Croft, P. Knee pain and osteoarthritis in older adults: a review of community burden and current use of primary health care. Ann. Rheum. Dis. 60, 91–97 (2001).

    Article  CAS  Google Scholar 

  4. Han, S. B., Seo, I. W. & Shin, Y. S. Intra-articular injections of hyaluronic acid or steroids associated with better outcomes than platelet-rich plasma, adipose mesenchymal stromal cells, or placebo in knee osteoarthritis: a network meta-analysis. Arthroscopy 37, 292–306 (2021).

    Article  CAS  Google Scholar 

  5. Jones, I. A., Togashi, R., Wilson, M. L., Heckmann, N. & Vangsness, C. T. Jr. Intra-articular treatment options for knee osteoarthritis. Nat. Rev. Rheumatol. 15, 77–90 (2019).

    Article  Google Scholar 

  6. Brittberg, M. et al. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N. Engl. J. Med. 331, 889–895 (1994).

    Article  CAS  Google Scholar 

  7. Wakitani, S. et al. Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months. J. Tissue Eng. Regen. Med. 5, 146–150 (2011).

    Article  Google Scholar 

  8. Wei, C. C., Lin, A. B. & Hung, S. C. Mesenchymal stem cells in regenerative medicine for musculoskeletal diseases: bench, bedside, and industry. Cell Transplant. 23, 505–512 (2014).

    Article  Google Scholar 

  9. Yubo, M. et al. Clinical efficacy and safety of mesenchymal stem cell transplantation for osteoarthritis treatment: a meta-analysis. PLoS ONE 12, e0175449 (2017).

    Article  Google Scholar 

  10. Jo, C. H. et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a 2-year follow-up study. Am. J. Sports Med 45, 2774–2783 (2017).

    Article  Google Scholar 

  11. Chiang, E. R. et al. Allogeneic mesenchymal stem cells in combination with hyaluronic acid for the treatment of osteoarthritis in rabbits. PLoS ONE 11, e0149835 (2016).

    Article  Google Scholar 

  12. Murphy, J. M., Fink, D. J., Hunziker, E. B. & Barry, F. P. Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum. 48, 3464–3474 (2003).

    Article  Google Scholar 

  13. Kamei, G. et al. Articular cartilage repair with magnetic mesenchymal stem cells. Am. J. Sports Med 41, 1255–1264 (2013).

    Article  Google Scholar 

  14. McHugh, J. A drug delivery system with sting. Nat. Rev. Rheumatol. 16, 248 (2020).

    Article  Google Scholar 

  15. Cheung, C. S., Lui, J. C. & Baron, J. Identification of chondrocyte-binding peptides by phage display. J. Orthop. Res 31, 1053–1058 (2013).

    Article  CAS  Google Scholar 

  16. Rothenfluh, D. A., Bermudez, H., O’Neil, C. P. & Hubbell, J. A. Biofunctional polymer nanoparticles for intra-articular targeting and retention in cartilage. Nat. Mater. 7, 248–254 (2008).

    Article  CAS  Google Scholar 

  17. Chen, W. H. et al. In vitro stage-specific chondrogenesis of mesenchymal stem cells committed to chondrocytes. Arthritis Rheum. 60, 450–459 (2009).

    Article  CAS  Google Scholar 

  18. Charafe-Jauffret, E. et al. Immunophenotypic analysis of inflammatory breast cancers: identification of an ‘inflammatory signature’. J. Pathol. 202, 265–273 (2004).

    Article  Google Scholar 

  19. Stockwell, R. A. Changes in the acid glycosaminoglycan content of the matrix of ageing human articular cartilage. Ann. Rheum. Dis. 29, 509–515 (1970).

    Article  CAS  Google Scholar 

  20. Deng, M. W. et al. Cell therapy with G-CSF-mobilized stem cells in a rat osteoarthritis model. Cell Transplant. 24, 1085–1096 (2015).

    Article  Google Scholar 

  21. Singh, A. et al. Enhanced lubrication on tissue and biomaterial surfaces through peptide-mediated binding of hyaluronic acid. Nat. Mater. 13, 988–995 (2014).

    Article  CAS  Google Scholar 

  22. Wu, S. C., Chang, J. K., Wang, C. K., Wang, G. J. & Ho, M. L. Enhancement of chondrogenesis of human adipose derived stem cells in a hyaluronan-enriched microenvironment. Biomaterials 31, 631–640 (2010).

    Article  Google Scholar 

  23. Chung, C. & Burdick, J. A. Influence of three-dimensional hyaluronic acid microenvironments on mesenchymal stem cell chondrogenesis. Tissue Eng. Part A 15, 243–254 (2009).

    Article  CAS  Google Scholar 

  24. Johnson, K., Reynard, L. N. & Loughlin, J. Functional characterisation of the osteoarthritis susceptibility locus at chromosome 6q14.1 marked by the polymorphism rs9350591. BMC Med. Genet. 16, 81 (2015).

    Article  Google Scholar 

  25. Karsdal, M. A. et al. Disease-modifying treatments for osteoarthritis (DMOADs) of the knee and hip: lessons learned from failures and opportunities for the future. Osteoarthr. Cartil. 24, 2013–2021 (2016).

    Article  CAS  Google Scholar 

  26. Shkhyan, R. et al. Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair. Ann. Rheum. Dis. 77, 760–769 (2018).

    Article  CAS  Google Scholar 

  27. Johnson, K. et al. A stem cell-based approach to cartilage repair. Science 336, 717–721 (2012).

    Article  CAS  Google Scholar 

  28. Hollander, A. P. et al. Damage to type II collagen in aging and osteoarthritis starts at the articular surface, originates around chondrocytes, and extends into the cartilage with progressive degeneration. J. Clin. Invest. 96, 2859–2869 (1995).

    Article  CAS  Google Scholar 

  29. Sugrue, S. P. et al. Immunoidentification of type XII collagen in embryonic tissues. J. Cell Biol. 109, 939–945 (1989).

    Article  CAS  Google Scholar 

  30. Benito, M. J., Veale, D. J., FitzGerald, O., van den Berg, W. B. & Bresnihan, B. Synovial tissue inflammation in early and late osteoarthritis. Ann. Rheum. Dis. 64, 1263–1267 (2005).

    Article  CAS  Google Scholar 

  31. Myers, S. L. et al. Synovial inflammation in patients with early osteoarthritis of the knee. J. Rheumatol. 17, 1662–1669 (1990).

    CAS  PubMed  Google Scholar 

  32. Sellam, J. & Berenbaum, F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat. Rev. Rheumatol. 6, 625–635 (2010).

    Article  CAS  Google Scholar 

  33. Deswal, J., Arya, S. K., Raj, A. & Bhatti, A. A case of bilateral corneal perforation in a patient with severe dry eye. J. Clin. Diagn. Res 11, ND01–ND02 (2017).

    PubMed  PubMed Central  Google Scholar 

  34. Rustenburg, C. M. E. et al. Osteoarthritis and intervertebral disc degeneration: quite different, quite similar. JOR Spine 1, e1033 (2018).

    Article  Google Scholar 

  35. Roberts, C. R. & Pare, P. D. Composition changes in human tracheal cartilage in growth and aging, including changes in proteoglycan structure. Am. J. Physiol. 261, L92–L101 (1991).

    CAS  PubMed  Google Scholar 

  36. Wessel, H. et al. Type XII collagen contributes to diversities in human corneal and limbal extracellular matrices. Invest. Ophthalmol. Vis. Sci. 38, 2408–2422 (1997).

    CAS  PubMed  Google Scholar 

  37. Massoudi, D. et al. NC1 long and NC3 short splice variants of type XII collagen are overexpressed during corneal scarring. Invest. Ophthalmol. Vis. Sci. 53, 7246–7256 (2012).

    Article  CAS  Google Scholar 

  38. Liu, N. R., Chen, G. N., Wu, S. S. & Chen, R. Distinguishing human normal or cancerous esophagus tissue ex vivo using multiphoton microscopy. J. Opt. 16, 025301 (2014).

    Article  Google Scholar 

  39. Xu, J. et al. Multiphoton microscopy for label-free identification of intramural metastasis in human esophageal squamous cell carcinoma. Biomed. Opt. Express 8, 3360–3368 (2017).

    Article  CAS  Google Scholar 

  40. Houle, M. A. et al. Analysis of forward and backward second harmonic generation images to probe the nanoscale structure of collagen within bone and cartilage. J. Biophotonics 8, 993–1001 (2015).

    Article  CAS  Google Scholar 

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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.

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Authors and Affiliations



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.

Corresponding authors

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).

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