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

Abstract

As wear particles-induced osteolysis still remains the leading cause of early implant loosening in endoprosthetic surgery, and promotion of osteoclastogenesis by wear particles has been confirmed to be responsible for osteolysis. Therapeutic agents targeting osteoclasts formation are considered for the treatment of wear particles-induced osteolysis. In the present study, we demonstrated for the first time that desferrioxamine (DFO), a powerful iron chelator, could significantly alleviate osteolysis in an ultrahigh-molecular-weight polyethylene (UHMWPE) particles-induced mice calvaria osteolysis model. Furthermore, DFO attenuated calvaria osteolysis by restraining enhanced inflammatory osteoclastogenesis induced by UHMWPE particles. Consistent with the in vivo results, we found DFO was also able to inhibit osteoclastogenesis in a dose-dependent manner in vitro, as evidenced by reduction of osteoclasts formation and suppression of osteoclast specific genes expression. In addition, DFO dampened osteoclasts differentiation and formation at early stage but not at late stage. Mechanistically, the reduction of osteoclastogenesis by DFO was due to increased heme oxygenase-1 (HO-1) expression, as decreased osteoclasts formation induced by DFO was significantly restored after HO-1 was silenced by siRNA, while HO-1 agonist COPP treatment enhanced DFO-induced osteoclastogenesis inhibition. In addition, blocking of p38 mitogen-activated protein kinase (p38MAPK) signaling pathway promoted DFO-induced HO-1 expression, implicating that p38 signaling pathway was involved in DFO-mediated HO-1 expression. Taken together, our results suggested that DFO inhibited UHMWPE particles-induced osteolysis by restraining inflammatory osteoclastogenesis through upregulation of HO-1 via p38MAPK pathway. Thus, DFO might be used as an innovative and safe therapeutic alternative for treating wear particles-induced aseptic loosening.

Could Hesperidin and Iron chelator be a new Therapeutic approach in Gentamicin induced Acute Kidney Injury in Rats?

“…Furthermore, iron chelators suppress oxidative stress by inhibiting the activity of NADPH oxidase and suppressed expression of its subunit p22 phox [40]. Additionally, DFO induces HO-1 expression by blocking of p38 signaling pathway [41]. The decreased IL6 by DFO was in agreement with Demetrios Vlahakos et al [42].…”

<p>Zn-Incorporated TiO2 Nanotube Surface Improves Osteogenesis Ability Through Influencing Immunomodulatory Function of Macrophages</p>

“…TGF-beta accelerates the formation of fibrous wraps and separates inflamed tissue from normal tissue, to reduce the formation of inflammatory granulation tissue, 70 while the increase of HO-1 can effectively inhibit the excessive action of osteoclasts. [71][72][73] Macrophages of the M1 and M2 phenotypes are indispensable in osteogenesis. Therefore, some scholars suggested that the key factor in determining macrophage-induced osteogenic or osteoclastic effects is the macrophage switch pattern rather than the specific macrophage phenotype.…”

Shikimic Acid Inhibits Osteoclastogenesis in Vivo and in Vitro by Blocking RANK/TRAF6 Association and Suppressing NF-κB and MAPK Signaling Pathways

“…The over-activation of osteoclasts leads to an imbalance in bone resorption, which results in osteoclast-related diseases such as postmenopausal osteoporosis [15,16]. We therefore examined whether shikimic acid affected ovariectomy-induced osteoporosis in mice.…”