Intracellular iron uptake is favored in Hfe-KO mouse primary chondrocytes mimicking an osteoarthritis-related phenotype

HFE-hemochromatosis is a disease characterized by a systemic iron overload phenotype mainly associated with mutations in the HFE protein (HFE) gene. Osteoarthritis (OA) has been reported as one of the most prevalent complications in HFE-hemochromatosis patients, but the mechanisms associated with its onset and progression remain incompletely understood. In this study, we have characterized the response to high iron concentrations of a primary culture of articular chondrocytes isolated from newborn Hfe-KO mice and compared the results with that of a similar experiment developed in cells from C57BL/6 wild-type (wt) mice. Our data provide evidence that both wt- and Hfe-KO-derived chondrocytes, when exposed to 50 mu M iron, develop characteristics of an OA-related phenotype, such as an increased expression of metalloproteases, a decreased extracellular matrix production, and a lower expression level of aggrecan. In addition, Hfe-KO cells also showed an increased expression of iron metabolism markers and MMP3, indicating an increased susceptibility to intracellular iron accumulation and higher levels of chondrocyte catabolism. Accordingly, upon treatment with 50 mu M iron, these chondrocytes were found to preferentially differentiate toward hypertrophy with increased expression of collagen I and transferrin and downregulation of SRY (sex-determining region Y)-box containing gene 9 (Sox9). In conclusion, high iron exposure can compromise chondrocyte metabolism, which, when simultaneously affected by an Hfe loss of function, appears to be more susceptible to the establishment of an OA-related phenotype.European Regional Development FundEuropean Union (EU) [EMBRC.PT Alg-01-0145-FEDER-022121, Norte-01-0145-FEDER-000012]Fundacao para a Ciencia e a TecnologiaPortuguese Foundation for Science and Technology [SFRH/BD/77056/2011]Portuguese Foundation for Science and TechnologyPortuguese Foundation for Science and TechnologyPortuguese Science and Technology FoundationPortuguese Foundation for Science and Technologyinfo:eu-repo/semantics/publishedVersio

Oceanization starts at depth during continental rupturing in the Northern Red Sea

We present here 3D seismic reflection and gravity data obtained from an off-axis area of the NW Red Sea, as well as results of a study of gabbroic rocks recovered in the same area both from an oil well below a thick evaporitic-sedimentary sequence, and from a layered mafic complex exposed on the Brothers Islets. These new data provide constraints on the composition, depth of emplacement and age of early syn-rift magma intrusions into the deep crust. The Brothers are part of a series of sub-parallel NW-striking topographic highs associated with SW-dipping extensional fault blocks with significant footwall uplift during rifting that brought early syn-rift deep crustal rocks up to the seafloor. Assuming an important role played by magmatism in the evolution of narrow rifts helps to solve the controversy on the nature of the crust in the northern/central Red Sea (i.e., the crust outside the axial oceanic cells is either oceanic or it consists of melt-intruded extended continental crust). Gabbros show petrologic and geochemical signatures similar to those of MORB-type gabbroic cumulates and are compatible with their having been emplaced either in a continental or in an oceanic context. We explored the different hypotheses proposed to explain the lack of magnetic anomalies in the presence of oceanic crust in the northern Red Sea. Our results, combined with a review of all the geophysical and geological data in the area, suggest a stretched and thinned continental crust with few isolated sites of basaltic injections, in line with a model whereby asthenospheric melt intrusions contribute to weaken the lower crust enabling some decoupling between upper and lower crust, protracting upper crust extension and delaying crustal breakup. Our findings show that continental rupture in the northern Red Sea is preceded by intrusion of basaltic melts with MORB-type elemental and isotopic signature, that cooled forming gabbros at progressively shallower crustal depths as rifting progressed toward continental separation