A METTL3 Inhibitor Alleviates the Onset of Osteomyelitis in a Mouse Model by Targeting MyD88.

Abstract

We aimed to study the effects of a methyltransferase 3 (METTL3) inhibitor on osteomyelitis. Bone marrow cells (BMs) and peripheral blood mononuclear cells (PBMCs) were isolated from osteomyelitis patients at our hospital. Primary BM-derived macrophages (BMDMs) were incubated with lipopolysaccharide (LPS), poly(I:C), or PAM3CSK4 after pretreatment with STM2457. S. aureus was injected into the intramedullary canal to construct an osteomyelitis C57BL/6 mice model, which was then treated with STM2457. Body weights, μCT three-dimensional analyses, and bacterial burdens of the mice were obtained. Up-regulated METTL3 expression was found in both BMs and PBMCs of osteomyelitis patients. LPS and PAM3CSK4-induced IL-6 and TNF-α secretion in BMDMs could be inhibited by STM2457 pretreatment, while STM2457 pretreatment did not affect the relative expression of NOS2, IL-6, and TNF-α after incubation with poly(I:C). STM2457 alleviated the symptoms of osteomyelitis in mice with increased body weights, diminished reactive bone formation and cortical bone loss, increased bacterial burdens, and decreased IL-6 and TNF-α secretion. STM2457 pretreatment down-regulated the relative expression of myeloid differentiation factor 88 (MyD88), p-TAK, and p-IKKα/β in LPS-stimulated BMDMs, while it did not show any effect on poly(I:C)-stimulated BMDMs. STM2457 alleviates the onset of osteomyelitis in mice by down-regulating the relative expression of MyD88 and NF-κB relevant inflammation molecules in macrophages.