Disease modification and symptom relief in osteoarthritis using a mutated GCP-2/CXCL6 chemokine

Sara Caxaria, Nikos Kouvatsos, Suzanne Eldridge, Mario Alvarez-Fallas, Anne-Sophie Thorup, Daniel Cici, Aida Barawi, Ammaarah Arshed, Danielle Strachan, Giulia Carletti, Xinying Huang, Sabah Bharde, Melody Deniz, Jacob Wilson, Bethan Thomas, Costantino Pitzalis, Francesco Paolo Cantatore, Manasi Sayilekshmy, Shafaq Sikandar, Frank LuytenThomas Pap, Joanna Sherwood, Anthony Day, Francesco Dell'Accio

Research output: Contribution to journalArticlepeer-review


We showed that the chemokine receptor C-X-C Motif Chemokine Receptor 2 (CXCR2) is essential for cartilage homeostasis. Here, we reveal that the CXCR2 ligand granulocyte chemotactic protein 2 (GCP-2) was expressed, during embryonic development, within the prospective permanent articular cartilage, but not in the epiphyseal cartilage destined to be replaced by bone. GCP-2 expression was retained in adult articular cartilage. GCP-2 loss-of-function inhibited extracellular matrix production. GCP-2 treatment promoted chondrogenesis in vitro and in human cartilage organoids implanted in nude mice in vivo. To exploit the chondrogenic activity of GCP-2, we disrupted its chemotactic activity, by mutagenizing a glycosaminoglycan binding sequence, which we hypothesized to be required for the formation of a GCP-2 haptotactic gradient on endothelia. This mutated version (GCP-2-T) had reduced capacity to induce transendothelial migration in vitro and in vivo, without affecting downstream receptor signaling through AKT, and chondrogenic activity. Intra-articular adenoviral overexpression of GCP-2-T, but not wild-type GCP-2, reduced pain and cartilage loss in instability-induced osteoarthritis in mice. We suggest that GCP-2-T may be used for disease modification in osteoarthritis.

Original languageEnglish
Article numbere16218
JournalEMBO Molecular Medicine
Issue number1
Early online date12 Dec 2022
Publication statusPublished - 11 Jan 2023


  • CXCL6
  • GCP-2
  • chemokine
  • chondrogenesis
  • osteoarthritis


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