TY - JOUR
T1 - Disease modification and symptom relief in osteoarthritis using a mutated GCP-2/CXCL6 chemokine
AU - Caxaria, Sara
AU - Kouvatsos, Nikos
AU - Eldridge, Suzanne
AU - Alvarez-Fallas, Mario
AU - Thorup, Anne-Sophie
AU - Cici, Daniel
AU - Barawi, Aida
AU - Arshed, Ammaarah
AU - Strachan, Danielle
AU - Carletti, Giulia
AU - Huang, Xinying
AU - Bharde, Sabah
AU - Deniz, Melody
AU - Wilson, Jacob
AU - Thomas, Bethan
AU - Pitzalis, Costantino
AU - Cantatore, Francesco Paolo
AU - Sayilekshmy, Manasi
AU - Sikandar, Shafaq
AU - Luyten, Frank
AU - Pap, Thomas
AU - Sherwood, Joanna
AU - Day, Anthony
AU - Dell'Accio, Francesco
PY - 2023/1/11
Y1 - 2023/1/11
N2 - 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.
AB - 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.
KW - CXCL6
KW - GCP-2
KW - chemokine
KW - chondrogenesis
KW - osteoarthritis
U2 - 10.15252/emmm.202216218
DO - 10.15252/emmm.202216218
M3 - Article
C2 - 36507558
SN - 1757-4676
VL - 15
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 1
M1 - e16218
ER -