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

TL;DR

A new protein that binds to collagen improves bone growth and joint health by targeting specific tissues.

Contribution

A collagen-binding CNP fusion protein was developed to enable targeted delivery and improved therapeutic effects.

Findings

CBD-CNP localized to articular cartilage and promoted bone elongation in fetal murine tibiae.

CBD-CNP mixed with collagen powder enhanced bone mineral content and volume in a fracture model.

CBD-CNP injection reduced subchondral bone thickening in a knee osteoarthritis model.

Abstract

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 potentially 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 compared with CNP-22. Intraarticular 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.

Collagen-binding C-type natriuretic peptide localized to collagen-rich tissues and promoted bone elongation and fracture healing, and mitigated joint degradation.

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