4-IPP is an inhibitor of macrophage migration inhibitory factor (MIF).
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Migration inhibitory factor (MIF) is a pleiotropic inflammatory mediator that inhibits macrophage migration in innate and adaptive immunologic responses. 4-IPP is an irreversible MIF inhibitor that binds covalently to MIF to inhibit its activity. It inhibited the viability of bone marrow macrophages (BMMs) with an IC50 value of 104.3µM at 72h. 4-IPP at 5-20µM suppressed the formation of TRAP-positive multinucleated osteoclasts in a dose-dependent manner. 4-IPP treatment at a dose of 20µM also significantly downregulated the expression of genes involved in
BMM precursor fusion (i.e. DC-STAMP), osteoclast maturation (i.e. c-Fos and NFATc1), and bone resorption (i.e. TRAP and CTSK) in BMM-derived osteoclasts. Osteoclasts-treated with 20µM 4-IPP resorbed 3.73±1.24% of the bone discs, whereas the untreated cells resorbed >40% of the total bone area. Incubation of BMMs with 20µM 4-IPP inhibited RANKL-induced NF-κB activation, resulting in the suppression of NFATc1 induction. Treatment with 20µM 4-IPP for 5 days suppressed the formation of TRAP-positive multinucleated osteoclasts in BMMs extracted from wild-type mice but not MIF knockout BMMs. Subcutaneous injection of 4-IPP at a dose of 1 or 5mg/kg every 2 days for 2 weeks reduced the extent of Ti particle-induced bone destruction in mice. Administration of 4-IPP at 1 or 5mg/kg also alleviated the bone loss associated with estrogen deficiency in a mouse model of ovariectomy-induced osteoporosis[1].
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