Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.

Human Chondrocyte Behaviour During In Vitro Over Expression of Normal and Mutated HFE, the Hemochromatosis Gene.

Martelli1,  Vanessa, Di Battista1,  John A., Panopalis1,  Pantelis, Antoniou2,  John, Sebag1,  Michael, Gilfix1,  Brian, Menard1,  Henri A.

McGill University Health Center, Montreal, QC
Jewish General Hospital, Montreal, QC


Clinical hereditary hemochromatosis type I (HH-I) is defined as the progressive accumulation of iron in organs and is caused by missense mutations in the HFE gene. In population studies, there are two prevalent mutations the C282Y and the H63D. Rheumatic complaints of the osteoarthritis (HHOA) phenotype are the leading clinical manifestations of HH-I. Yet, little is known about the expression in chondrocytes of proteins regulating iron metabolism. Our study verified their presence and explored variations of OA-related biomarkers in normal vs. HFE-mutation-carrying cultured human chondrocytes and, in normal chondrocytes transfected with normal or mutated HFE under basal conditions or cytokine stimulations in a variable culture medium/serum iron environment.


Cultured chondrocytes were derived from tissues obtained at total knee replacement (TKR) of patients not carrying (OA) or carrying mutations (HHOA).Levels of MMP-1, MMP-3, MMP-13, iNOS and COX-2 (referred to as an "activation profile") were measured in normal chondrocytes transfected with plasmids containing normal or mutated HFE.


Ferroportin, Divalent Metal Transporter 1, ferritin and transferrin receptor 1 were all identified by PCR in human chondrocytes. In vivo mutated chondrocytes spontaneously expressed in vitro, significantly higher levels of the "activation profile" compared with cells obtained from age-matched patients with idiopathic primary OA. The in vitro transfection of a construct expressing the wild type (normal) HFE gene into normal donor-derived chondrocytes had similar effects on basal or cytokine-induced MMP-13 or COX-2 expression as cells transfected with an empty vector or under mock transfection conditions. However, transfecting plasmids with HFE containing the mutations, generated through site directed mutagenesis, resulted in a 3 to 7-fold increase in MMP-1/MMP-13/COX-2/iNOS expression levels under basal and cytokine-induced conditions. Those effects were similar in the presence of normal vs. elevated iron concentrations in the culture medium.


These data albeit preliminary, constitute the first attempt to define in chondrocytes the molecular mechanisms driving the characteristic HHOA and the role that HFE mutant genotypes may play in this regard. Our companion clinical observations as well as published population-based data suggest that many patients with the so-called "silent" H63D HFE mutation have early rheumatic symptoms while presenting a normal biochemical phenotype. It follows that given its high frequency that mutation may be a major, still insufficiently recognized, genetic risk factor for OA. We are currrently trying to repair in vitro the HHOA phenotype of the chondrocytes using normal HFE gene therapy.

To cite this abstract, please use the following information:
Martelli, Vanessa, Di Battista, John A., Panopalis, Pantelis, Antoniou, John, Sebag, Michael, Gilfix, Brian, et al; Human Chondrocyte Behaviour During In Vitro Over Expression of Normal and Mutated HFE, the Hemochromatosis Gene. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1803

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