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

Abstract

Postmenopausal osteoporosis is characterized by an imbalance of bone resorption exceeding bone formation, resulting in a net loss of bone mineral density (BMD). Estrogen deficiency is known to promote bone resorption. However, the causative factors that impair bone formation have not been identified. Women after menopause experience not only estrogen deficiency but also iron accumulation as a result of cessation of menstruation. In this study we investigated whether increased iron plays a role in osteoporosis. By growing primary mouse osteoclast and osteoblast progenitor cells as well as immortalized cell lines in the presence of iron, we found that increased iron had minimal effects on osteoclast cell differentiation. Interestingly, iron, particularly in its inorganic form, and to a lesser extent ferritin and transferrin all suppressed alkaline phosphatase (ALP) activities in osteoblasts. Moreover, iron downregulated mRNA levels of several other osteoblastogenic markers such as Runx2, osterix, osteopontin, and osteocalcin. To further show that this in vitro finding is relevant to the in vivo condition, we demonstrated that iron-accumulated mice with intact ovaries exhibited a significant decrease in BMD. Although iron inhibited preosteoblast cell differentiation, it did enhance preosteoblast cell proliferation, as evidenced by increased cell growth and expression of cell cycle regulator genes such as CDK4, CDK6, cyclin D1, and cyclin D3 and G 2 /M phase cell population. Taken together, our results suggest that increased iron could be a factor that slows down bone formation in postmenopausal women. ß

Running exercise alleviates trabecular bone loss and osteopenia in hemizygous β-globin knockout thalassemic mice

“…Furthermore, iron overload and oxidative stress from iron toxicity commonly found in ␤-thalassemia could suppress osteoblast function (11,17). Iron markedly suppressed alkaline phosphatase activity in osteoblast-like cell lines as well as the expression of several osteoblast-derived bone formation markers, such as runt-related transcription factor 2, osteocalcin, and osteopontin (58). Excessive production of reactive oxygen species after iron overload might also activate the nuclear factor-B signaling pathway, leading to a reduction in osteoblast activity or even apoptosis of osteoblasts (1).…”

Estrogen regulates iron homeostasis through governing hepatic hepcidin expression via an estrogen response element

“…There is an elevated iron level in postmenopausal women compared to premenopausal women (Jian et al, 2009), suggesting that extra iron plays a crucial role in provoking postmenopausal osteoporosis. A variety of studies have demonstrated that extra iron burden would repress osteoblastogenesis, proliferation and mineralization (Messer et al, 2009;Yamasaki and Hagiwara, 2009;Yang et al, 2011), and enhance osteoclast differentiation and provoke osteoclastic function (Ishii et al, 2009). Thus, it could be concluded that iron surplus presumably hampers bone formation and induces bone loss.…”

Excess iron undermined bone load-bearing capacity through tumor necrosis factor-α-dependent osteoclastic activation in mice

“…2A). In contrast to these findings, in their study, Yamasaki et al (8) (9,10). This discrepancy may be due to the in vitro sensitivity of osteoblasts being higher compared to the in vivo, when directly exposed to iron.…”

“…Tsay et al (7) reported that the iron overload (IO)-induced bone loss in mice was correlated with the inflammatory bone resorption and oxidative stress. Using in vitro cell assays, iron treatment was demonstrated to inhibit osteoblast formation, proliferation and mineralization (8)(9)(10), while promoting osteoclast differentiation and increased osteoclastic function (11). Therefore, IO is believed to disrupt bone metabolism and induce bone loss.…”