COMMD1 Regulates Osteoclast Differentiation in Talaromyces marneffei-Induced Osteomyelitis via the NF-κB Pathway

This study investigated the role of copper metabolism MURR1 domain-containing 1 (COMMD1) in Talaromyces marneffei (TM)-induced osteomyelitis (OM) and its regulation of osteoclast differentiation via the NF-κB pathway.

A murine TM infection model was used to assess bone destruction and osteoclast activity via micro-CT, histological analysis, biomechanical testing, qPCR, and Western blot. RNA sequencing was performed to analyze differentially expressed genes. Functional validation was conducted using COMMD1 conditional knockout (cKO) mice and bone marrow-derived monocytes macrophages (BMMs). The NF-κB inhibitor JSH-23 was used to verify pathway dependency.

TM infection significantly upregulated inflammatory cytokines (IL-10, IL-17, TNF-α) and induced severe bone structural damage, characterized by trabecular thinning and reduced mechanical strength. These changes were accompanied by increased osteoclast numbers and elevated expression of osteoclast differentiation-related genes (TRAP, NFATc1, Ctsk, FOS). RNA sequencing revealed downregulation of COMMD1 and activation of the NF-κB pathway in TM-infected mice. COMMD1 deficiency exacerbated bone destruction and osteoclast differentiation, while COMMD1 overexpression suppressed these effects. Mechanistic studies showed that COMMD1 deletion increased P65 phosphorylation and decreased IκBα expression, effects that were reversed by JSH-23 treatment.

COMMD1 protects against TM-induced OM by inhibiting the NF-κB pathway, suggesting it as a potential therapeutic target for bone infections.