Journal Article

Collagen-binding C-type natriuretic peptide enhances chondrogenesis and osteogenesis

Sawamura, Kenta, Tsukahara, Hirokazu, Matsushita, Osamu, Uchida, Kentaro, Saito, Hiroki, Imagama, Shiro, Kubota, Satoshi, Matsushita, Masaki, Okusha, Yuka, Hirai, Kenta, Hosono, Yasuyuki, Esaki, Ryusaku, Mima, Takehiko, Sawada, Ryusuke, Aoyama, Eriko

2025

Overview

C-type natriuretic peptide (CNP) is known to promote chondrocyte proliferation and bone formation; however, CNP's extremely short half-life necessitates continuous intravascular administration to achieve bone-lengthening effects. Vosoritide, a CNP analog designed for resistance to neutral endopeptidase, allows for once daily administration. Nonetheless, it distributes systemically rather than localizing to target tissues, which may result in adverse effects such as hypotension. To enhance local drug delivery and therapeutic efficacy, we developed a novel synthetic protein by fusing a collagen-binding domain (CBD) to CNP, termed CBD-CNP. This fusion protein exhibited stability under heat conditions and retained the collagen-binding ability and bioactivity as CNP. CBD-CNP localized to articular cartilage in fetal murine tibiae and promoted bone elongation. Spatial transcriptomic analysis revealed that the upregulation of chondromodulin expression may contribute to its therapeutic effects. Treatment of CBD-CNP mixed with collagen powder to a fracture site of a mouse model increased bone mineral content and bone volume rather than CNP-22. Intra-articular injection of CBD-CNP to a mouse model of knee osteoarthritis suppressed subchondral bone thickening. By addressing the limitations of CNP's rapid degeneration, CBD-CNP leverages its collagen-binding capacity to achieve targeted, sustained delivery in collagen-rich tissues, offering a promising strategy for enhancing chondrogenesis and osteogenesis.