AT A GLANCE

A new study published in Journal of Orthopaedic Translation suggests the potential of targeting macrophage pro-inflammatory M1 phenotype in and osteoclastogenesis as an effective strategy for inflammatory arthritis and systemic osteoporosis and positions narirutin (NRT) as a promising therapeutic drug candidate.¹

“Inflammatory arthritis, exemplified by rheumatoid arthritis (RA), represents a prevalent autoimmune-driven inflammatory bone disorder hallmarked by chronic synovitis and progressive bone erosion, culminating in joint dysfunction and systemic osteoporosis,” explain study authors Wang et al. “NRT, a flavonoid glycoside derived from citrus plants, is renowned for its multifaceted bioactivities, including antioxidant, immunomodulatory, and cardioprotective properties.”

Despite these attributes,” they add, “the role of NRT in mitigating macrophage-mediated pro-inflammatory activation and osteoclastogenesis within the context of inflammatory arthritis and osteoporosis remains insufficiently elucidated. This study aimed to evaluate the therapeutic potential of NRT in the context of inflammatory arthritis and osteoporosis.”

Using RAW264.7, THP-1, and bone marrow–derived macrophages (BMMs) in vitro, the authors assessed the phenotypic modulation of macrophages and the osteoclastogenic effects of NRT. A classical collagen-induced arthritis model was also established to investigate the therapeutic effects of NRT administration on inflammatory arthritis and osteoporosis.

Subsequently, the authors assessed macrophage phenotypes and the expression of inflammatory mediators both in vitro and vivo, while high-throughput RNA sequencing and bioinformatics analyses were conducted to identify key downstream signaling pathways.

Finally, histological staining, micro-computed tomography, and immunohistofluorescence staining were used to assess the in vivo amelioration of inflammation and bone destruction, while visceral toxicity was assessed in vivo.

“NRT markedly inhibited lipopolysaccharide-induced macrophage polarization toward the pro-inflammatory M1 phenotype (CD86⁺), while promoting a shift toward the anti-inflammatory M2 phenotype (CD206+),” explain the authors. “This was accompanied by a suppression of pro-inflammatory cytokines, including iNOS, TNF, IL-1β, and IL-6, and an upregulation of immunosuppressive mediators such as IL-10 and Arg-1.”

They add that “RNA sequencing revealed that NRT attenuates the activation of the NOD-like receptor signaling pathway and downstream inflammasome activation. Additionally, osteoclast differentiation was also significantly inhibited, as evidenced by the suppression of NF-κB and MAPK signaling pathways.”

Finally, they observed that NRT substantially alleviated the severity of inflammatory arthritis and mitigated systemic osteoporosis in vivo.

“These findings demonstrated that NRT mitigates inflammatory arthritis and osteoporosis through modulating macrophage phenotype and osteoclastogenesis via NOD-like receptor signaling pathway induced inflammasome activation and NF-κB and MAPK signaling pathways, respectively,” the authors conclude. “These findings highlight the potential of targeting macrophage pro-inflammatory M1 phenotype in and osteoclastogenesis as an effective strategy for inflammatory arthritis and systemic osteoporosis and … NRT may serve as a promising therapeutic drug candidate.”

Reference

1.     Wang Q, Peng X, Xu H, et al. Narirutin mitigates inflammatory arthritis and osteoporosis through modulating macrophage phenotype and osteoclastogenesis. J Orthop Translat. 2025:54:115–130.