Iron Chelation Inhibits Osteoclastic Differentiation In Vitro and in Tg2576 Mouse Model of Alzheimer’s Disease

Abstract

Patients of Alzheimer’s disease (AD) frequently have lower bone mineral density and higher rate of hip fracture. Tg2576, a well characterized AD animal model that ubiquitously express Swedish mutant amyloid precursor protein (APPswe), displays not only AD-relevant neuropathology, but also age-dependent bone deficits. However, the underlying mechanisms remain poorly understood. As APP is implicated as a regulator of iron export, and the metal chelation is considered as a potential therapeutic strategy for AD, we examined iron chelation’s effect on the osteoporotic deficit in Tg2576 mice. Remarkably, in vivo treatment with iron chelator, clinoquinol (CQ), increased both trabecular and cortical bone-mass, selectively in Tg2576, but not wild type (WT) mice. Further in vitro studies showed that low concentrations of CQ as well as deferoxamine (DFO), another iron chelator, selectively inhibited osteoclast (OC) differentiation, without an obvious effect on osteoblast (OB) differentiation. Intriguingly, both CQ and DFO’s inhibitory effect on OC was more potent in bone marrow macrophages (BMMs) from Tg2576 mice than that of wild type controls. The reduction of intracellular iron levels in BMMs by CQ was also more dramatic in APPswe-expressing BMMs. Taken together, these results demonstrate a potent inhibition on OC formation and activation in APPswe-expressing BMMs by iron chelation, and reveal a potential therapeutic value of CQ in treating AD-associated osteoporotic deficits.

Desferrioxamine reduces ultrahigh-molecular-weight polyethylene-induced osteolysis by restraining inflammatory osteoclastogenesis via heme oxygenase-1

“…37 Besides of exerting the anti-osteolysis function like bisphosphonates, IL-1 antagonists and Denosumab by inhibiting the process of osteoclastogenesis, 38 DFO has been shown to increase angiogenesis via the hypoxia inducible factor (HIF) pathway. The HIF pathway activates angiogenesis as a regulator of response to hypoxia whose activation is also seen in skeletal repair.…”

“…As studies have revealed that MAPKs (including p38MAPK, JNK and ERK) and NF- κ B are critical for RANKL-induced osteoclastogenesis, 50 and our results in Figure 7 have demonstrated that DFO significantly dampens the activation of MAPKs and NF- κ B induced by RANKL. In addition, it has been reported that clinoquinol, another iron chelator, impairs RANKL-driven AKT phosphorylation and NFATC1 activation in the process of osteoclastogenesis, 38 both AKT and NFATC1 are required for efficient osteoclastogenesis and osteoclast activation. 52, 53, 54 Except of p38MAPK, we predict that DFO inhibits osteoclastogenesis may also by regulating RANKL-induced ERK, JNK, AKT or NFATC1 activation.…”

Wnt5a is a key target for the pro-osteogenic effects of iron chelation on osteoblast progenitors

“…In osteoclasts, iron excess stimulates osteoclastogenesis by supporting mitochondrial respiration, [18][19][20] while sequestering iron from osteoclasts inhibits their maturation and function. [21][22] In contrast, osteoblast function is suppressed by iron excess in osteoblast cell lines, [23][24][25] while iron chelation using deferoxamine (DFO) seems to exert positive effects on osteoblast maturation. [26][27][28] In addition, bone regeneration during distraction osteogenesis and after radiation therapy has been shown to be promoted in the presence of DFO.…”

Deletion of ferroportin in murine myeloid cells increases iron accumulation and stimulates osteoclastogenesis in vitro and in vivo

“…Moreover, iron overload in mice leads to increased bone resorption and oxidative stress that exacerbate estrogen-deficiency bone loss (54,55). In contrast, iron chelation inhibits generation of osteoclasts in vitro and prevents bone loss in ovariectomized mice (14,56). Iron functioning together with PGC1␤ regulate mitochondrial biogenesis and promote osteoclast differentiation (14).…”