TY - JOUR
T1 - Gla-rich protein is involved in the cross-talk between calcification and inflammation in osteoarthritis
AU - Cavaco, Sofia
AU - Viegas, Carla S. B.
AU - Rafael, Marta S.
AU - Ramos, Acacio
AU - Magalhes, Joana
AU - Blanco, Francisco J.
AU - Vermeer, Cees
AU - Simes, Dina C.
PY - 2016/3
Y1 - 2016/3
N2 - 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-1 beta results in an increased expression of COX2 and MMP13 and up-regulation of GRP. Importantly, while treatment of articular cells with gamma-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 gamma-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.
AB - 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-1 beta results in an increased expression of COX2 and MMP13 and up-regulation of GRP. Importantly, while treatment of articular cells with gamma-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 gamma-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.
KW - Osteoarthritis
KW - Gla-rich protein
KW - ECM mineralization
KW - Gamma-carboxylated GRP
KW - Inflammation
U2 - 10.1007/s00018-015-2033-9
DO - 10.1007/s00018-015-2033-9
M3 - Article
SN - 1420-682X
VL - 73
SP - 1051
EP - 1065
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
IS - 5
ER -