C-type natriuretic peptide suppresses VEGFa gene expression by attenuating IL6-STAT3 signal pathway in primary synovial fibroblasts from rat knee

Riko Yamashita; Iori Nozawa; Shoichi Hasegawa; Yusuke Nakagawa; Kazumasa Miyatake; Hiroki Katagiri; Tomomasa Nakamura; Hideyuki Koga; Ichiro Sekiya; Toshitaka Yoshii; Kunikazu Tsuji

doi:10.1016/j.bbrc.2025.151290

C-type natriuretic peptide suppresses VEGFa gene expression by attenuating IL6-STAT3 signal pathway in primary synovial fibroblasts from rat knee

Biochem Biophys Res Commun. 2025 Jan 20:749:151290. doi: 10.1016/j.bbrc.2025.151290. Online ahead of print.

Affiliations

¹ Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
² Department of Cartilage Regeneration, Tokyo Medical and Dental University, Tokyo, Japan.
³ Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
⁴ Department of Orthopaedic Surgery, Tokyo Medical and Dental University, Tokyo, Japan.
⁵ Department of Orthopaedic Surgery, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: tsuji.orj@tmd.ac.jp.

PMID: 39855042
DOI: 10.1016/j.bbrc.2025.151290

Abstract

C-type natriuretic peptide (CNP) can be a new disease-modifying anti-osteoarthritis drug (DMOAD) candidate because intraarticular injection of CNP attenuates both articular cartilage degradation and persistent pain in a rat knee arthritis model. This study aimed to elucidate the underlying molecular mechanisms by which CNP protects the knee joint from osteoarthritic changes. Gene expression analyses indicated that CNP did not interfere with the expression of IL1β -responsive genes in rat primary synovial fibroblasts or the monocytic cell line, RAW264.7 cells. In contrast, total RNA sequence analyses indicated that CNP negatively regulated the IL6-STAT3 signaling pathway and VEGFa gene expression in rat synovial fibroblasts. As previously indicated, IL6 induced phosphorylation of ⁷⁰⁵Tyr residue of STAT3 and its nuclear translocation to activate VEGFa gene expression; however, in this study, we showed that CNP induced phosphorylation of ⁷²⁷Ser residue and inhibited IL6-induced nuclear translocation of STAT3. Since the IL6 pathway has been shown to accelerate articular cartilage degradation and induce knee pain, our data suggest that CNP can act as a DMOAD by negatively regulating IL6-mediated proinflammatory signals in the knee joint.

Keywords: CNP (C-type natriuretic peptide); DMOAD (disease modifying anti-osteoarthritis drug); IL6; STAT3; Synovial fibroblasts; VEGFa.