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

Area of Science:

• Biomedical Science
• Immunology
• Pharmacology

Background:

• Osteomyelitis is a bone infection characterized by inflammation and bone destruction.
• Methyltransferase 3 (METTL3) is implicated in inflammatory processes.
• Targeting METTL3 may offer a novel therapeutic strategy for osteomyelitis.

Purpose of the Study:

• To investigate the therapeutic potential of a METTL3 inhibitor, STM2457, in osteomyelitis.
• To elucidate the molecular mechanisms underlying STM2457's effects on inflammation and bone remodeling in osteomyelitis.

Main Methods:

• Isolated bone marrow cells (BMs) and peripheral blood mononuclear cells (PBMCs) from osteomyelitis patients.
• Pretreated primary BM-derived macrophages (BMDMs) with STM2457 and stimulated with LPS, poly(I:C), or PAM3CSK4.
• Established a murine osteomyelitis model by injecting S. aureus and treated with STM2457.
• Assessed body weight, micro-CT analyses, bacterial burden, and inflammatory cytokine levels (IL-6, TNF-α).

Main Results:

• Elevated METTL3 expression was observed in BMs and PBMCs of osteomyelitis patients.
• STM2457 inhibited LPS- and PAM3CSK4-induced IL-6 and TNF-α secretion in BMDMs.
• STM2457 treatment in mice improved body weight, reduced bone damage, decreased bacterial load, and lowered IL-6 and TNF-α levels.
• STM2457 downregulated Myeloid Differentiation Factor 88 (MyD88) and NF-κB pathway molecules in LPS-stimulated BMDMs.

Conclusions:

• STM2457 demonstrates significant therapeutic efficacy in an experimental osteomyelitis model.
• The mechanism involves the downregulation of MyD88 and NF-κB signaling pathways in macrophages.
• METTL3 inhibition presents a promising therapeutic avenue for managing osteomyelitis.