title: Deferoxamine Suppresses Collagen Cleavage and Protease, Cytokine, and COL10A1 Expression and Upregulates AMPK and Krebs Cycle Genes in Human Osteoarthritic Cartilage.
abstract: This study reports the effects of the iron chelator deferoxamine (DFO) on collagen cleavage, inflammation, and chondrocyte hypertrophy in relation to energy metabolism-related gene expression in osteoarthritic (OA) articular cartilage. Full-depth explants of human OA knee articular cartilage from arthroplasty were cultured with exogenous DFO (1-50μM). Type II collagen cleavage and phospho-adenosine monophosphate-activated protein kinase (pAMPK) concentrations were measured using ELISAs. Gene expression studies employed real-time PCR and included AMPK analyses in PBMCs. In OA explants collagen cleavage was frequently downregulated by 10-50μM DFO. PCR analysis of 7 OA patient cartilages revealed that 10μM DFO suppressed expression of MMP-1, MMP-13, IL-1β, and TNFαand a marker of chondrocyte hypertrophy, COL10A1. No changes were observed in the expression of glycolysis-related genes. In contrast, expressions of genes associated with the mitochondrial Krebs cycle (TCA), AMPK, HIF1α, and COL2A1 were upregulated. AMPK gene expression was reduced in OA cartilage and increased in PBMCs from the same patients compared to healthy controls. Our studies demonstrate that DFO is capable of suppressing excessive collagenase-mediated type II collagen cleavage in OA cartilage and reversing phenotypic changes. The concomitant upregulation of proanabolic TCA-related gene expressions points to a potential for availability of energy generating substrates required for matrix repair by end-stage OA chondrocytes. This might normally be prevented by high whole-body energy requirements indicated by elevated AMPK expression in PBMCs of OA patients.
authors.affiliation: Immunology and Molecular Biology Laboratory, Nasonova Research Institute of Rheumatology, Moscow, Russia.
authors.forename: Elena V
authors.identifier: 0000-0001-7312-2349
authors.initials: EV
authors.lastname: Tchetina
authors.affiliation: Immunology and Molecular Biology Laboratory, Nasonova Research Institute of Rheumatology, Moscow, Russia.
authors.forename: Galina A
authors.initials: GA
authors.lastname: Markova
authors.affiliation: Department of Surgery, McGill University, Montreal, QC, Canada.
authors.forename: A Robin
authors.initials: AR
authors.lastname: Poole
authors.affiliation: Jewish General Hospital, McGill University, Montreal, QC, Canada.
authors.forename: David J
authors.initials: DJ
authors.lastname: Zukor
authors.affiliation: Jewish General Hospital, McGill University, Montreal, QC, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Antoniou
authors.affiliation: Surgery Department, Nasonova Research Institute of Rheumatology, Moscow, Russia.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Makarov
authors.affiliation: Forensic Medicine Service, Moscow City Health Department, Moscow, Russia.
authors.forename: Aleksandr N
authors.initials: AN
authors.lastname: Kuzin