A STUDY OF ZINC CONCENTRATION IN HAIR AS AN INDICATION OF ZINC IMBALANCES

Trace metal imbalances have been implicated in several disease and nutritional states. There is mounting concern to identify the nutritional balance of the trace metals needed for growth, mental acuity and physical functioning. These two factors, diseases in which trace metals show involvement and nutritional balance, have made it necessary to be able to accurately describe the trace metal balances of an individual. Although several investigators have measured the concentration of trace metals in the hair and related those observed concentrations to various disease and nutritional states, no one has satisfactorily answered the questions of whether hair is useful to determine trace metal imbalances, whether the concentrations found in hair reflect tissue or serum concentrations of the trace metals, or whether any tissue accurately reflects body status of the trace metals.^ Male mice were used to examine several tissues, heart, liver, kidney, spleen, intestine, brain, bone, hair and serum for copper and zinc concentrations. The environment and dietary intake of the animals were carefully controlled, so that environmental and physical variables were minimized. Dietary intake of zinc was varied while copper intake was held constant. Each experimental diet group was matched with a pair fed control group.^ Of the tissues examined, only the serum was indicative of an early state of zinc imbalance. Neither hair nor the other tissues examined for copper and zinc concentrations were indicative of an acute zinc imbalance in a normal mature mouse. Zinc deficiencies or excesses may manifest themself differently in the chronic imbalance state or in the weanling, aged or traumatized mouse. The tissue response to zinc imbalance may vary in these cases. ^

Osterix inhibits bone destruction in osteosarcoma through transcriptional repression of Interleukin-1alpha expression

Osteosarcoma, a malignant bone tumor, rapidly destroys the cortical bone. We demonstrated that mouse K7M2 osteosarcoma cells were deficient in osterix (osx), a zinc finger-containing transcription factor required for osteoblasts differentiation and bone formation. These cells formed lytic tumors when injected into the tibia. The destruction of bone is mediated by osteoclasts in osteosarcoma. The less expression of osterix with osteolytic phenotype was also observed in more tumor cell lines. Replacement of osterix in K7M2 cells suppressed lytic bone destruction, inhibited tumor growth in vitro and in vivo, and suppressed lung metastasis in vivo and the migration of K7M2 to lung conditioned medium in vitro. By contrast, inhibiting osterix by vector-based small interfering RNA (siRNA) in two cell lines (Dunn and DLM8) that expressed high levels of osterix converted osteoblastic phenotype to lytic. Recognizing and binding of Receptor Activator of NF-κB (RANK) on osteoclast precursors by its ligand RANKL is the key osteoclastogenic event. Increased RANKL results in more osteoclast activity. We investigated whether K7M2-mediated bone destruction was secondary to an effect on RANKL. The conditioned medium from K7M2 could upregulate RANKL in normal osteoblast MC3T3, which might lead to more osteoclast formation. By contrast, the conditioned medium from K7M2 cells transfected with osx-expressing plasmid did not upregulate RANKL. Furthermore, Interleukin-1alpha (IL-1α) was significantly suppressed following osx transfection. IL-1α increased RANKL expression in MC3T3 cells, suggesting that osx may control RANKL via a mechanism involving IL-1α. Using a luciferase reporter assay, we demonstrated that osx downregulated IL-1α through a transcription-mediated mechanism. Following suppression of osterix in Dunn and DLM8 cells led to enhanced IL-1α promoter activity and protein production. Site-directed mutagenesis and Chromatin immunoprecipitation (ChIP) indicated that osterix downregulated IL-1α through a Sp1-binding site on the IL-1α promoter. These data suggest that osterix is involved in the lytic phenotype of osteosarcoma and that this is mediated via transcriptional repression of IL-1α. ^