Gla-rich protein is involved in the cross-talk between calcification and inflammation in osteoarthritis.
Osteoarthritis (OA) is a whole-joint disease characterized by articular cartilage loss, tissue inflammation, abnormal bone formation and extracellular matrix (ECM) mineralization. Disease-modifying treatments are not yet available and a better understanding of osteoarthritis pathophysiology should lead to the discovery of more effective treatments. Gla-rich protein (GRP) has been proposed to act as a mineralization inhibitor and was recently shown to be associated with OA in vivo. Here, we further investigated the association of GRP with OA mineralization-inflammation processes. Using a synoviocyte and chondrocyte OA cell system, we showed that GRP expression was up-regulated following cell differentiation throughout ECM calcification, and that inflammatory stimulation with IL-1β results in an increased expression of COX2 and MMP13 and up-regulation of GRP. Importantly, while treatment of articular cells with γ-carboxylated GRP inhibited ECM calcification, treatment with either GRP or GRP-coated basic calcium phosphate (BCP) crystals resulted in the down-regulation of inflammatory cytokines and mediators of inflammation, independently of its γ-carboxylation status. Our results strengthen the calcification inhibitory function of GRP and strongly suggest GRP as a novel anti-inflammatory agent, with potential beneficial effects on the main processes responsible for osteoarthritis progression. In conclusion, GRP is a strong candidate target to develop new therapeutic approaches.
Centre of Marine Sciences (CCMAR), University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal.
Sofia
S
Cavaco
Centre of Marine Sciences (CCMAR), University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal.|GenoGla Diagnostics, Centre of Marine Sciences (CCMAR), University of Algarve, Faro, Portugal.
Carla S B
CS
Viegas
Centre of Marine Sciences (CCMAR), University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal.
Marta S
MS
Rafael
Department of Orthopedics and Traumatology, Algarve Medical Centre (CHAlgarve), Faro, Portugal.
Acácio
A
Ramos
Grupo de Bioingeniería Tisular y Terapia Celular (GBTTC-CHUAC), Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidad de A Coruña (UDC), A Coruña, Spain.|Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain.
Joana
J
Magalhães
Grupo de Bioingeniería Tisular y Terapia Celular (GBTTC-CHUAC), Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidad de A Coruña (UDC), A Coruña, Spain.
Francisco J
FJ
Blanco
VitaK, Maastricht University, Maastricht, The Netherlands.
Cees
C
Vermeer
Centre of Marine Sciences (CCMAR), University of Algarve, Campus de Gambelas, 8005-139, Faro, Portugal. dsimes@ualg.pt.|GenoGla Diagnostics, Centre of Marine Sciences (CCMAR), University of Algarve, Faro, Portugal. dsimes@ualg.pt.
Dina C
DC
Simes
D002114:Calcinosis / Q000150:complications / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010003:Osteoarthritis / Q000150:complications / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000032:analysis / Q000276:immunology / Q000378:metabolism*
D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C528959:Ucma protein, human
ECM mineralization; Gamma-carboxylated GRP; Gla-rich protein; Inflammation; Osteoarthritis