title: Ferritin ferroxidase activity: a potent inhibitor of osteogenesis.
abstract: Hemochromatosis is a known cause of osteoporosis, and iron overload has deleterious effects on bone. Although iron overload and its association with osteoporosis has long been recognized, the pathogenesis and exact role of iron have been undefined. Bone is an active tissue with constant remodeling capacity. Osteoblast (OB) development and maturation are under the influence of core binding factor alpha-1 (CBF-alpha1), which induces expression of OB-specific genes, including alkaline phosphatase, an important enzyme in early osteogenesis, and osteocalcin, a noncollagenous protein deposited within the osteoid. This study investigates the mechanism by which iron inhibits human OB activity, which in vivo may lead to decreased mineralization, osteopenia, and osteoporosis. We demonstrate that iron-provoked inhibition of OB activity is mediated by ferritin and its ferroxidase activity. We confirm this notion by using purified ferritin H-chain and ceruloplasmin, both known to possess ferroxidase activity that inhibited calcification, whereas a site-directed mutant of ferritin H-chain lacking ferroxidase activity failed to provide any inhibition. Furthermore, we are reporting that such suppression is not restricted to inhibition of calcification, but OB-specific genes such as alkaline phosphatase, osteocalcin, and CBF-alpha1 are all downregulated by ferritin in a dose-responsive manner. This study corroborates that iron decreases mineralization and demonstrates that this suppression is provided by iron-induced upregulation of ferritin. In addition, we conclude that inhibition of OB activity, mineralization, and specific gene expression is attributed to the ferroxidase activity of ferritin.
authors.affiliation: Department of Medicine, University of Debrecen, 4012 Debrecen, Hungary.
authors.forename: Abolfazl
authors.initials: A
authors.lastname: Zarjou
authors.forename: Viktória
authors.initials: V
authors.lastname: Jeney
authors.forename: Paolo
authors.initials: P
authors.lastname: Arosio
authors.forename: Maura
authors.initials: M
authors.lastname: Poli
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Zavaczki
authors.forename: György
authors.initials: G
authors.lastname: Balla
authors.forename: József
authors.initials: J
authors.lastname: Balla
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D001052:Apoferritins / Q000378:metabolism; D002113:Calcification, Physiologic / Q000187:drug effects; D002460:Cell Line; D002570:Ceruloplasmin / Q000378:metabolism* / Q000494:pharmacology; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005293:Ferritins / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007501:Iron / Q000494:pharmacology; D009928:Organ Specificity / Q000187:drug effects; D010006:Osteoblasts / Q000378:metabolism; D015675:Osteocalcin / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D010710:Phosphates / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D010710:Phosphates; D015675:Osteocalcin; D005293:Ferritins; D001052:Apoferritins; D007501:Iron; D002570:Ceruloplasmin; D000469:Alkaline Phosphatase