Regulation of osteoblastic gene expression by lead.
Although it is well recognized that lead accumulates in bone, skeletal tissue is considered primarily a sequestering compartment and not a site of toxic action for lead. However, exposure to lead is associated with impaired skeletal growth in children and reductions in indices of bone formation in laboratory animals. Osteoblastic ROS 17/2.8 cells were used in an effort to better understand the consequences of lead exposure on skeletal homeostasis. Studies on confluent cultures of ROS 17/2.8 cells revealed that lead (2-200 microM) had no effect on cell number or DNA and protein synthesis. However, alkaline phosphatase activity was reduced by lead in a dose- and time-dependent manner. Reductions in steady state alkaline phosphatase mRNA levels paralleled the lead-induced inhibition of enzyme activity. Moreover, lead exposure resulted in similar dose-dependent reductions in steady state type 1 procollagen and bone Gla protein mRNA levels. The effect of lead on osteoblastic gene expression in ROS 17/2.8 cultures, however, was selective in nature, as similar lead exposures resulted in no alterations in beta-actin or glyceraldehyde-3-phosphate dehydrogenase mRNA levels. These data demonstrate that lead, in the absence of over toxicity, specifically restricts the expression of certain aspects of the differentiated osteoblast phenotype. Such alterations in osteoblast function may contribute to the skeletal abnormalities observed in settings of lead intoxication.
Department of Medicine, Oregon Health Sciences University, Portland.
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Klein
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Wiren
D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D007854:Lead / Q000494:pharmacology*; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes / Q000235:genetics; D010006:Osteoblasts / Q000378:metabolism / Q000502:physiology*; D015675:Osteocalcin / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured
D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D015675:Osteocalcin; D007854:Lead; D003094:Collagen; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D000469:Alkaline Phosphatase