Disease modification and symptom relief in osteoarthritis using a mutated GCP‐2/CXCL6 chemokine
Sara Caxaria, Nikolaos Kouvatsos, S. Eldridge, Mario Enrique Alvarèz Fallas, Anne‐Sophie Thorup, Daniela Cici, Aida Barawi, Ammaarah Arshed, Danielle Strachan, Giulia Vittoria Carletti, Xinying Huang, Sabah Bharde, M. Deniz, J. Wilson, B.L. Thomas, Costantino Pitzalis, Francesco Paolo Cantatore, Manasi Sayilekshmy, Shafaq Sikandar, Frank P. Luyten, Thomas Pap, J. Sherwood, Anthony J. Day, Francesco Dell’Accio
Abstract
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.