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Ferritin ferroxidase activity: A potent inhibitor of osteogenesis
Author(s) -
Zarjou Abolfazl,
Jeney Viktória,
Arosio Paolo,
Poli Maura,
Zavaczki Erzsébet,
Balla György,
Balla József
Publication year - 2010
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.091002
Subject(s) - ceruloplasmin , ferritin , osteocalcin , osteoblast , chemistry , calcification , alkaline phosphatase , endocrinology , medicine , transferrin , osteoid , osteoporosis , biochemistry , biology , enzyme , in vitro
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 α‐1 (CBF‐α1), 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‐α1 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. © 2010 American Society for Bone and Mineral Research

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