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.
Highlights
Artificial joint replacement has emerged as an effective treatment for severe joint degeneration.[1]
The results showed that osteolysis was significantly increased in the vehicle group compared with sham control, while DFO injection with 10 mg/kg or 30 mg/kg daily could significantly prevent from ultrahigh-molecular-weight polyethylene (UHMWPE) particles-induced osteolysis (Figures 1c–e)
Consistent with the histological results, the calvarias culture results confirmed that DFO significantly dampened particles-induced inflammatory responses, as the increased IL-1β (Figure 2b), IL-6 (Figure 2c) and tumor necrosis factor-α (TNF-α) (Figure 2d) expression in the particles group were all abundantly decreased after DFO treatment
Summary
Artificial joint replacement has emerged as an effective treatment for severe joint degeneration.[1] much effort has been made to improve the efficacy of artificial joint replacement, ultrahigh-molecular-weight polyethylene (UHMWPE) wear particles-induced osteolysis still remains the leading cause of early implant loosening in endoprosthetic surgery.[2,3,4] the underlying mechanisms by which UHMWPE wear particles promoted-osteolysis are not fully elucidated, studies have showed that osteolysis at the periprosthetic site is dominantly due to the enhanced osteoclastic resorption activity.[5,6]. HO-1 dampens early differentiation of osteoclast precursors into osteoclasts, but not acts on mature osteoclasts.[19,20] In addition to the cytokines and growth factors, it is reported that iron homeostasis may contribute to fine-turning of the RANKL-induced osteoclast development.[21,22] In general, inhibitions of osteoclasts formation and/or function by modulating microenvironmental cytokines, growth factors, HO-1 and/or iron homeostasis may be critical for preventing from wear particles-induced osteolysis and pathological bone loss
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