Emerging NPR-B agonists for cartilage and bone: from CNP biology to translational compound design

Disorders affecting cartilage and bone development frequently originate from disrupted endochondral ossification within growth-plate cartilage. Nonetheless, few therapeutic interventions directly target the local signaling pathways governing this process. This review explores the C-type natriuretic peptide (CNP)/natriuretic peptide receptor B (NPR-B) axis as a mechanism-based therapeutic approach addressing issues in cartilage and bone, including skeletal dysplasias, genetic short-stature conditions, and acquired ailments such as bone fractures. It summarizes the production and processing of CNP in vivo, elucidates how NPR-B activation induces cyclic guanosine monophosphate signaling in chondrocytes, and discusses how this pathway functionally antagonizes FGFR3-driven MAPK signaling in achondroplasia. Additionally, it traces the progression from native, rapidly cleared CNP peptides to engineered agonists optimized for enhanced stability, prolonged systemic exposure, or tissue retention, emphasizing exposure design. Clinically approved agents, such as vosoritide and navepegritide, exemplify how NPR-B agonism has become a viable treatment strategy for pediatric achondroplasia. Both U.S. approvals were accelerated, with final-height confirmation required. Emerging long-acting analogs, sustained-release prodrugs, matrix-binding constructs, Fc-fusion proteins, and elastin-like polypeptide fusion platforms demonstrate the potential for molecular design adaptations to meet various therapeutic objectives. The scope of potential applications now extends to hypochondroplasia, several non-achondroplasia genetic short-stature disorders, acquired growth-plate impairments, fracture healing, and osteoarthritis-related cartilage strategies. Overall, NPR-B agonism signifies a transition from systemic endocrine-driven growth promotion to the controlled modulation of skeletal growth and repair. Future developments will necessitate long-term evidence concerning final height, skeletal proportions, functional outcomes, joint health, quality of life, and safety.