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 a-1 (CBF-a1), 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 ironprovoked inhibition of OB activity is mediated by ferritin and its ferroxidase activity. We confirm this notion by using purified ferritin Hchain 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-a1 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. ß

Inhibitory effects of iron on bone morphogenetic protein 2–induced osteoblastogenesis

“…Our results support recent reports showing that iron and ferritin suppress osteoblast-specific genes such as ALP and osteocalcin in a dose-dependent manner. (21,22) Although the ferroxidase activity of the ferritin was shown to inhibit calcification, (21) our data indicate that iron itself possesses the most pronounced inhibitory effects on ALP as well as mineralization. ALP activity is critical to the initiation of mineralization, (23,24) and inhibitors of ALP were shown to suppress vascular calcification.…”

Osteoblast-released Matrix Vesicles, Regulation of Activity and Composition by Sulfated and Non-sulfated Glycosaminoglycans

“…Furthermore, with FTH1, a potential inhibitor of osteogenesis, a protein also corresponding to the cluster of metabolic enzymes was downregulated in our findings. The repressing effect on the development of the osteoblastic phenotype could be attributed to its ferroxidase activity (89). In sum, this lead to a more efficient maturing of hBMSC to osteoblasts, a stronger interaction of cells and released MVs with the ECM, and a stronger ECM mineralization as observed in vitro after sHA1 exposition.…”

Predictors of osteoclast activity in patients with sickle cell disease

“…[6][7][8] An increased amount of iron has been associated with reduced in vitro osteoblast proliferation 9 and extracellular calcium deposition. 10 In a mouse model, iron dextran injection increased the osteoclast population in the bone structure and reduced the number and thickness of trabeculae. 11 Another study in mice indicated that osteoclast differentiation and mitochondria biogenesis are regulated by iron: increased iron stimulated osteoclast activity while iron chelation both inhibited osteoclast-mediated bone resorption and protected against bone loss.…”