CNP inhibits T3 - induced hypertrophic growth in H9c2 cells: Impact of HDAC inhibitor.

Artesunate ameliorates leflunomide low-response against bone destruction in rheumatoid arthritis via cGMP-PKG signalling.

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.

Although CNP (C-type natriuretic peptide) was first identified in brain tissue, its systemic expression and release is mainly located to the endothelial lining of the vasculature. As such, CNP should not be viewed as a classic blood-borne hormone but rather as a local factor that supports the integrity of vascular function. Albeit CNP is structurally related to both ANP and BNP (A- and B-type natriuretic peptide), the main signaling pathway is through a specific membrane-bound receptor without crosstalk from endocrine ANP and BNP. CNP expression and CNP-mediated effects can thus be uniquely targeted without interference from the related cardiac NPs. In this perspective, we present the CNP system as a largely overlooked target for potential intervention in cardiometabolic disease, hypertension, and diabetes before onset of complications and overt heart failure. To fully unleash this potential, with this perspective, we hope to fuel renewed interest with a focus on use of human invitro and exvivo systems as well as experimental medical approaches and human cohort data.

Children with craniopharyngioma exhibit a notably high incidence of normal-accelerated growth before and/or after neurosurgery/hypophysectomy despite confirmed panhypopituitarism, this constituting what is known as the growth without GH syndrome, which, to date, remains an unsolved mystery. Most cases involve suprasellar tumor extension, suggesting a factor intrinsic to tumor localization apart from neurosurgical sequelae alone. Patients need mineralocorticoid therapy post surgery, at least until GH replacement therapy is initiated, implying elevated natriuretic peptides inducing secondary mineralocorticoid deficiency. Elevated natriuretic peptides, and in particular C-type natriuretic peptide (CNP), may serve as a compensatory growth mediator in the absence of GH, acting as local regulator of endochondral ossification through natriuretic peptide receptor B (NPR-B) by promoting chondrocyte proliferation and hypertrophy, rescuing skeletal growth in GH-insensitive contexts, and as also demonstrated by the therapeutic efficacy of the CNP analog vosoritide in achondroplasia. A comprehensive research approach unraveling the role of CNP in growth may redefine our understanding of growth and management of short stature.

Osteogenesis imperfecta (OI) is a heterogenous type 1 collagenopathy characterized by recurrent fractures, decreased bone mass, and shorter stature. Bisphosphonates reduce fracture incidence in children with OI but do not improve growth velocity. C-type natriuretic peptide (CNP) is produced in the growth plate (also in the brain and heart) and positively regulates linear bone growth; people with OI have been shown to have a reduced serum level of CNP. This pilot study evaluated whether a CNP analog combined with alendronate (ALN) improves growth and bone mineral density in oim/oim (OIM) mice, a model of moderate-to-severe Type III OI. Two-week-old OIM and WT mice received weekly ALN and one of three CNP regimens: 10 μg/kg three days/week (low), 20 μg/kg three days/week (medium), or 20 μg/kg five days/week (high). Controls received saline. Faxitron images were taken at two, eight, and 14 weeks (sacrifice) to assess fracture incidence and measure femoral length and vertebral height. Microcomputed tomography (micro-CT) was used to assess bone microstructural parameters of the femur ex vivo. The high-dose group had no fractures post-sacrifice; one fracture each was observed in the low and medium dose groups. Femoral length increased in all treated groups, with the high dose group showing the greatest increase (8.2%, significant) in OIM mice. Vertebral height increased in all treated groups; low and high dose groups had greater, comparable increases than the medium group in OIM mice. All treated groups showed increased trabecular bone mineral density (BMD). Cortical tissue mineral density (TMD), BMD, and thickness were also elevated in all treated groups compared to controls. In conclusion, CNP analog adjuvant treatment enhanced linear growth and bone quality without compromising fracture reduction, providing benefits not seen with bisphosphonates alone. These results will inform optimal dosing for future studies. A full murine study is planned to further evaluate therapeutic potential for translation to humans.

C-type natriuretic peptide (CNP) has therapeutic potential in heart failure with preserved ejection fraction (HFpEF) due to its broad range of beneficial effects on cardiovascular structure and function. This study presents the design of a CNP analogue (65) for once-weekly subcutaneous administration. The design of 65 incorporated five strategic substitutions and an engineered fatty acid protractor to enhance the chemical stability, improve the pharmacokinetics, and lower the isoelectric point (pI). Low pI was found to be essential for minimizing injection site reactions and improving subcutaneous bioavailability. 65 demonstrated a promising pharmacokinetic profile for once-weekly treatment and an improved bioavailability compared to high pI CNP analogs. Furthermore, 65 was engineered for solubility at pH 6.5 to enable stability in liquid formulation. In vivo assessments supported the therapeutic potential in HFpEF of fatty acid-derivatized low pI CNP analogues. 65 is currently under clinical investigation in Phase 1.

BackgroundMammalian follicular development is regulated by endocrine and paracrine factors, and apoptosis of granulosa cells represents a major cause of follicular atresia. C-type natriuretic peptide (CNP), a paracrine factor in follicular fluid, maintains meiotic arrest of oocytes through activation of the NPR2–cGMP pathway. Protein kinase G (PKG) is a principal downstream effector of cGMP, but its function in granulosa cell apoptosis has not been fully characterized.MethodsBovine granulosa cells were treated with CNP, cGMP or the PKG inhibitor KT5823. Transcriptomic analysis was performed to identify differentially expressed genes and signaling pathways. The effects of CNP on apoptosis were further evaluated in mural granulosa cells, cumulus–oocyte complexes (COCs), and oocytectomized complexes (OOXs). Apoptosis was examined by TUNEL assay, and expression of apoptosis-related genes and proteins was determined by RT-qPCR and Western blotting. The influence of PKG inhibition on oocyte developmental competence was assessed during in vitro maturation (IVM).ResultsCNP treatment downregulated multiple apoptosis-related pathways, including TNF, IL-17, and NF-κB signaling. CNP reduced apoptosis in both granulosa and cumulus cells, and this effect was not affected by PKG inhibition. Overexpression of PKG increased apoptosis, suggesting a pro-apoptotic role of PKG in granulosa cells. Addition of KT5823 during IVM decreased apoptosis in cumulus cells and improved blastocyst development and ICM cell numbers in bovine and ovine oocytes.ConclusionsCNP suppresses apoptosis of granulosa cells through a PKG-independent mechanism involving transcriptional downregulation of apoptosis-related pathways. PKG appears to promote, rather than mediate, apoptosis in this system. Inhibition of PKG during IVM may improve oocyte quality and provide a useful reference for optimization of in vitro maturation systems.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13048-025-01879-w.

Oviduct-derived C-type natriuretic peptide improves bovine preimplantation embryo development in vitro by attenuating oxidative damage.

BackgroundSmall cell lung cancer (SCLC) represents an aggressive malignancy characterized by marked heterogeneity and neuroendocrine differentiation. Despite its clinical significance, the functional landscape of neuroendocrine function, while neuroactive-signaling-related genes (NRGs) in SCLC pathogenesis remains poorly characterized. Therefore, the aim of this study is to classify SCLC based on neuroactive signaling networks and to analyze the characteristics of these classifications in relation to the immune microenvironment.MethodsThrough integrated analysis of bulk transcriptomic profiling from 79 primary SCLC tumors and single-cell transcriptomic profiling from 11 SCLC tumors, we employed a consensus clustering algorithm to deconvolute transcriptional programs underlying neuroactive signaling networks. Molecular functions and tumor-infiltrated immune cells were estimated from bulk transcriptomes using bioinformatics methods. Single-cell transcriptomic analysis was implemented for cross-validation and cellular characterization.ResultsBulk-seq analyses reported that the transcriptional variability of three major clusters of tumors were associated with different clinical outcomes and biological pathways. Clinical, genomic, and immunological characteristics were observed among three clusters. Furthermore, the key genes module of cluster with the worst survival were identified as neuroactive-signaling-related signature (NRS) and used to classify tumor samples into two distinct intra-tumoral subtypes (H-NRS and L-NRS) with single-cell transcriptomic data. At single-cell level, malignant cells in H-NRS tumor were in later cell state and had more frequent cellular communication. And NRS subsequently was identified as a biomarker correlated with better prognosis for patients receiving chemoimmunotherapy. It was found that Natriuretic Peptide C (NPPC), as one of the key genes in NRS, was overexpressed in SCLC tumor cells and correlated with poor prognosis. Treatment with C-type natriuretic peptide (CNP) facilitates cellular migration and metastatic potential.ConclusionsThis study proposes a novel molecular taxonomy for SCLC grounded in neuroactive signaling networks, suggests a potential prognostic biomarker to aid in therapeutic stratification, and identifies NPPC as a candidate therapeutic target worthy of further investigation in metastatic SCLC. Our findings may help bridge gaps in understanding between neuroendocrine biology and tumor microenvironment (TME) dynamics during SCLC evolution.

Historically considered a skeletal dysplasia characterized by disproportionate short stature, achondroplasia is a condition with multisystemic effects due to the widespread expression of the fibroblast growth factor receptor 3 variant throughout the body, impacting muscle, neurological function, cardiorespiratory health, and health-related quality of life. To evaluate the efficacy, safety, and tolerability of once-weekly navepegritide, an investigational prodrug of C-type natriuretic peptide, while assessing benefits beyond growth that may have important implications for complications and health-related quality of life in children with achondroplasia. Enrollment for this pivotal phase 2b, randomized, double-blind, placebo-controlled trial (APPROACH) was conducted between March and August 2023 at 10 hospitals in Australia, Canada, Denmark, Ireland, New Zealand, Spain, and the US with randomized, blind treatment through 52 weeks and an open-label extension (ongoing). Eligible participants aged 2 to 11 years had achondroplasia confirmed by genetic testing, were naive to treatment with growth-promoting agents, and had their height recorded at least 6 months prior to randomization. Enrolled participants were stratified by age and sex. Those with radiographic evidence of closed growth plates, planned bone surgery, severe untreated sleep apnea, or medical conditions known to affect growth were excluded (n = 2 of 86); of 84 participants enrolled, all were analyzed for safety and efficacy outcomes, including 2 who discontinued treatment. Navepegritide (100 μg/kg/wk) or placebo administered by once-weekly subcutaneous injection. The primary end point was annualized growth velocity at week 52. Other clinically important secondary measures included radiographically assessed skeletal outcomes and health-related quality of life, evaluated using Achondroplasia Child Experience Measures. Safety assessments included adverse events, clinical laboratory assessments, bone age, and immunogenicity. Eighty-four participants were enrolled and assigned randomly in a 2:1 ratio to receive navepegritide (n = 57; mean [SD] age, 5.6 [2.6] years; 31 [54%] male) or placebo (n = 27; mean [SD] age, 6.0 [2.7] years; 14 [52%] male). All randomized participants were included in efficacy and safety analyses, although 2 patients in the navepegritide group discontinued treatment (one at week 26 and the other at week 34). The trial met its primary end point, demonstrating superiority of navepegritide in annualized growth velocity at week 52 vs placebo (least-squares mean treatment difference of 1.49 cm/y; 95% CI, 1.05 to 1.93; P < .001). Treatment resulted in improvements (least-squares mean treatment difference [95% CI]) in tibial-femoral angle (-1.81° [-3.16 to -0.47]), mechanical axis deviation (-2.78 mm [-4.71 to -0.86]), fibula to tibia length ratio (-0.016 [-0.024 to -0.008]), and Achondroplasia Child Experience Measures-Physical Functioning (-11.1 [-21.5 to -0.80] in children younger than 5 years). No serious adverse events were treatment-related, and no deaths occurred. Injection site reaction rates were low, and no symptomatic hypotension or fractures were observed. In this randomized clinical trial, navepegritide treatment resulted in statistically significantly higher annualized growth velocity in children with achondroplasia, with a similar safety and tolerability profile vs placebo. Moreover, navepegritide demonstrated additional potential health benefits beyond growth. ClinicalTrials.gov Identifier: NCT05598320.

Introduction: C-type natriuretic peptide (CNP) is an endogenous paracrine mediator released by endothelial cells and cardiomyocytes during inflammation and cardiac stress. CNP is known to regulate various aspects of myocardial structure and function including myocyte contractility, coronary vascular reactivity and fibrosis. However, an intrinsic role for the peptide in offsetting the pathogenesis of heart failure with preserved ejection fraction (HFpEF) remains unsubstantiated. Aim: To investigate whether endogenous CNP preserves diastolic function in the setting of HFpEF by maintaining cardiac structure, reducing myocardial fibrosis, and dampening inflammation. Methods: Endothelial (ecCNP -/- ) and cardiomyocyte (cmCNP -/- ) -restricted CNP knockout and natriuretic peptide receptor-C (NPR-C -/- ) knockout mice were subjected to a high fat diet (HFD) plus N G -nitro-L-arginine methyl-ester (L-NAME; 100mg/kg/day; p.o.) ‘two-hit’ model of HFpEF. Echocardiography was performed at baseline and endpoint to assess cardiac structure and function. Blood pressure, heart weight and lung wet weight were determined, and cardiac sections processed to establish fibrotic burden and immune cell infiltration. Results: ecCNP -/- animals developed a more severe HFpEF phenotype in comparison to WT littermates, as illustrated by greater diastolic dysfunction (e.g. isovolumetric relaxation time, IVRT; myocardial performance index, MPI) and greater myocardial immune cell infiltration. In contrast, whilst cmCNP -/- animals did not exhibit any overt deficiency in diastolic function in experimental HFpEF, myocardial fibrosis was exacerbated in these mice. Interestingly, diastolic dysfunction (e.g. IVRT, MPI, E/e’) and fibrotic burden were also significantly greater in mice lacking the cognate receptor NPR-C suggesting it is this NPR subtype that underpins the combined beneficial actions of endothelial and cardiomyocyte -derived CNP. Conclusions: Endogenous CNP, of endothelial and cardiomyocyte origin, plays an important role in mitigating the development of diastolic dysfunction, inflammation and ventricular stiffening in HFpEF; this salutary action is underpinned by activation of NPR-C. Targeting CNP/NPR-C signalling may therefore be of therapeutic benefit in this disorder. Funding: British Heart Foundation Programme Grant (RG/F/23/110123) and Biotechnology and Biological Sciences Research Council CASE PhD studentship (BB/W509991/1).

C-type natriuretic peptide (CNP), belonging to the natriuretic peptide group, has recently emerged as a potential modulator of feeding behavior in mammalian species. This study aimed to examine the impact of central infusion of CNP-22 on feeding behavior in neonatal broilers and to elucidate its interaction with the dopaminergic, malanocortinergic, and neuropeptide Y (NPY) systems. Across ten separate experiments, broilers were systematically allocated into four different treatment groups for each experiment. In the initial experiment, neonatal chickens (Ross-308) received ICV injections of saline or CNP-22 at escalating doses (0.75, 1.5, and 3 nmol). Subsequent experiments assessed the interplay between CNP-22 (3 nmol); L-DOPA, a precursor of dopamine; 6-hydroxydopamine (6-OHDA), a neurotoxin targeting dopaminergic neurons; SCH23390, an antagonist of D1 dopamine receptors; AMI-193, an antagonist of D2 dopamine receptors; SHU9119, an antagonist of melanocortin 3 and 4 receptors; HS 024, a selective melanocortin 4 receptor antagonist; BMS193885, an antagonist of the neuropeptide Y1 receptor; CYM9484, an antagonist of the neuropeptide Y2 receptor; and L-152,804, which functions as an antagonist at neuropeptide Y5 receptors. Treatments included individual injections and simultaneous co-administrations of CNP-22 with these pharmacological agents. Feed consumption was measured for 120min post-infusion. When CNP-22 was administered at concentrations of 1.5 and 3 nmol, a progressive decline in meal consumption was observed, correlating with increasing dosage (P < 0.05). Co-infusion of BMS193885 + CNP-22 enhanced the anorexigenic effect induced by CNP-22 (P < 0.05). However, simultaneous infusion of 6-OHDA, SCH23390, and SHU9119 with CNP-22 markedly decreased CNP-22-induced anorexia (P < 0.05). The data indicate that CNP-22 administration suppresses feeding behavior in young broiler chickens, a process potentially mediated via the D1, MC3/MC4, and NPY1 receptors pathways.

Real-world safety and age-dependent effectiveness of vosoritide in achondroplasia: A single-center retrospective analysis of transition from growth hormone to vosoritide.

Insulin-like growth factor-1 (IGF-1) and C-type natriuretic peptide (CNP) promote endochondral bone growth. We previously reported that vosoritide, a CNP analog, increases annualized growth velocity (AGV) and height standard deviation (SD) in pre-pubertal children with hypochondroplasia (HCH). We hypothesized that IGF-1 and CNP will be inversely associated at baseline and will respond differentially during a single-arm unblinded standardized 12-month Phase II clinical trial of vosoritide in pre-pubertal patients ages 3-11y with HCH and height <-2.25 SD. Subjects were followed for a baseline 6-month observation period and then received a dose of 15μg/kg/day of vosoritide subcutaneous daily injections for 12 months. Anthropometrics, IGF-1 and NTproCNP were measured every 6 months. Longitudinal changes in IGF-1 and NTproCNP as well as the correlations between these 2 analytes and changes in height SD and AGV were analyzed. Baseline IGF-1 values are reduced in children with HCH and increased throughout the study, but IGF-1 SD did not change significantly. NTproCNP was raised at baseline and declined throughout the study, with NTproCNP SD significantly lower at Months 6 and 12 on treatment. Change in height SD or AGV were not correlated to IGF-1 or NTproCNP SD at 12 months. The change in IGF-1 concentrations at 12 months was positively correlated with the change in NTproCNP plasma concentrations (Rho=0.57, p=0.024). In children with HCH, IGF-1 levels are reduced and NTproCNP levels are elevated at baseline. A correlation between changes in these levels during treatment suggests a possible interaction between IGF-1 and CNP signaling.

Disclosure: C. McDonnell: Ascendis Pharma, BioMarin, Pfizer, Inc. H. Hove: Ascendis Pharma, Pfizer, Inc.. J.M. Legare: None. P.M. Campeau: Ascendis Pharma, BioMarin, Ipsen, Pfizer, Inc., Takeda. P.L. Hofman: Eli Lilly & Company, Novo Nordisk. D.G. Hoernschemeyer: BioMarin, Orthopediatrics, Zimvie. J.M. de Bergua Domingo: None. M.J. Abuzzahab: Ascendis Pharma, Endo, Inhale, Lumos, Medtronic, Novo Nordisk, Pfizer, Inc., Rhythm, Soleno. M. Mao: Ascendis Pharma. I. Ballance: Ascendis Pharma. L.C. Freiberg: Ascendis Pharma. L.W. Dalby: Ascendis Pharma. A.D. Shu: Ascendis Pharma. C.A. Bacino: Ascendis Pharma, BioMarin, Ionis Pharmaceuticals Inc., Roche. R. Savarirayan: Ascendis Pharma, BioMarin, BridgeBio.Background: Safety and tolerability are key considerations in assessing the value of emerging therapies that aim to address clinical manifestations and potentially life-threatening complications of achondroplasia (ACH). Navepegritide is an investigational prodrug of C-type natriuretic peptide (CNP), administered SC once weekly and designed to provide a low Cmax through sustained release of active CNP. Continuous exposure to the released CNP stimulates natriuretic peptide receptor B (NPR-B) to counteract the constitutively active fibroblast growth factor receptor 3 (FGFR3) characteristic of ACH. We report safety and tolerability data from ApproaCH, a pivotal, randomized, double-blind, placebo-controlled trial in which children with ACH were treated with navepegritide or placebo for 52 weeks. Based on the reported experience with an available daily CNP analogue, symptomatic hypotension and injection site reactions (ISRs) were defined as adverse events of special interest in the ApproaCH trial. Methods: Participants (N=84, aged 2-11 years) were stratified by age and sex and randomized 2:1 to receive navepegritide (100 μg/kg/week) or placebo. The primary endpoint was annualized growth velocity (AGV) at week 52. Safety and tolerability were assessed via treatment-emergent adverse events (TEAEs), laboratory values, vital signs, physical and skeletal examination, electrocardiogram, Tanner staging, bone age, and bone-related safety events. Results: Navepegritide demonstrated AGV superiority over placebo with an LS mean AGV of 5.89 cm/year vs. 4.41 cm/year in the placebo group (LS mean difference 1.49 cm/year, p<0.0001). Navepegritide was well tolerated, with ∼99% of reported AEs being mild (Grade 1) or moderate (Grade 2). No AEs led to trial withdrawal or treatment discontinuation. Incidence of treatment-related AEs was similar between groups (21.1% with navepegritide vs 25.9% with placebo). There was a low incidence of ISRs in both groups (19.3% or 0.41 events per person year of exposure to navepegritide vs 14.8% or 0.15 with placebo). All ISRs were mild (Grade 1). AEs of asymptomatic hypotension were documented in two participants in each the navepegritide group (3.5%) and the placebo group (7.4%); none were considered treatment-related. Conclusion: In the pivotal ApproaCH trial, navepegritide significantly improved linear growth in children with ACH while maintaining a safety profile comparable to placebo. The treatment was well-tolerated and most TEAEs were mild or moderate. Weekly administration of navepegritide was associated with a low incidence of ISRs and no evidence of treatment-related hypotensive effects. These results suggest that the design of once-weekly navepegritide as a prodrug with a low CNP Cmax contributes to a favorable safety and tolerability profile, and may address limitations of existing ACH therapies and support improved treatment adherence.Presentation: Monday, July 14, 2025

Abstract Disclosure: D. Kosugi: None. N. Minamino: None. D. Taura: None. M. Makoto: None. M. Ohta: None. K. Nakao: None. Background and aim: Mammalian natriuretic peptide (NP) family is composed of A-type (Atrial), B-type (Brain) and C-type NP; ANP, BNP, and CNP. CNP is widely distributed in the central and peripheral tissues. CNP induces endochondral ossification, vasorelaxation, antifibrosis, and so forth as a local regulator, and its analog, vosoritide, is used for the therapy for achondroplasia. However, the clinical significance of CNP has not yet been established, mainly due to lack of methods sensitive enough for measuring plasma CNP without extraction. Although plasma CNP levels in normal subjects are presumed to be at 0.1-0.5 pM, many researchers have reported far higher CNP levels. In the present study, we have undertaken development of sandwich chemiluminescent ELISA (CLEIA) for CNP-53, the major circulating molecular form of CNP in plasma. Methods: Monoclonal antibodies targeting the ring portion and N-terminal region of CNP-53 were generated by immunizing rats or mice with respective peptide-KLH conjugates, followed by cloning and selection. Antibody #26-7 recognizing the N-terminal region was biotinylated, fixed on the avidin plate, and used for capture antibody. Antibody #47-22 recognizing the ring portion was used for the detection antibody after labeling with alkaline phosphatase, where CDP-star/Emerald II was used as a substrate. Immunoreactive(ir) CNP-53 concentrations in plasma from healthy humans and Wistar Kyoto rats were measured. Results: The detection and quantitation limit of the developed CLEIA was 0.015pM and 0.041pM, respectively, and CNP-53 was measurable up to 250pM. This CLEIA showed equivalent recognition of mammalian CNP-53, including human and rat CNP-53, without cross-reactivity to CNP-22, ANP, BNP, or other related bioactive peptides, except for equal recognition of proCNP and CNP-53. In this CLEIA, plasma samples were measured after four-fold dilution and standard curves were generated with peptide-free-plasma. Plasma levels of irCNP-53 in healthy human subjects were 0.18±0.06 pM, and those in Wistar Kyoto rats were 0.24±0.02 pM. Further studies on plasma irCNP-53 from disease model rats and patients are ongoing in our laboratory. Conclusion: The newly developed CLEIA for CNP-53 demonstrated superior sensitivity and quantitation capabilities, allowing for direct and highly accurate measurement of plasma irCNP-53 concentrations. This method provides a more reliable and reproducible approach than previously reported assays. Utilizing this CLEIA, more detailed physiological and pathophysiological changes of plasma CNP will be elucidated in near future. Presentation: Sunday, July 13, 2025

C-type natriuretic peptide (CNP), encoded by the NPPC (Natriuretic Peptide Precursor C), has been recognized as the principal endogenous factor sustaining oocyte meiotic arrest in mammalian follicles. Yet its influence on porcine ovarian granulosa cell fate and the regulatory mechanism of NPPC expression within these cells remain poorly understood. Here, utilizing an in vitro culture model of primary porcine ovarian granulosa cells and immature oocytes, we examined the impact of CNP on granulosa cell apoptosis and oocyte meiotic resumption, and elucidated the molecular circuitry governing NPPC expression. We found that follicular atresia in pigs was accompanied by a marked decline in the CNP receptor NPR2 (natriuretic peptide receptor 2). Correspondingly, exogenous CNP suppressed apoptosis in cultured porcine granulosa cells. Estradiol can significantly promote the expression level of NPPC in porcine ovarian granulosa cells and, by enhancing NPR2 levels, it can synergize with CNP to inhibit oocyte meiotic resumption in vitro. Conversely, EGF signaling can significantly downregulate NPPC mRNA expression in porcine granulosa cells, an effect likely mediated by ERK-activated tristetraprolin (TTP). Collectively, these findings broaden our understanding of CNP in follicular development and delineate the endocrine network that controls NPPC transcription in the porcine ovary.

Achondroplasia (ACH) is the most common skeletal dysplasia and the leading genetic cause of dwarfism. It is characterized by disproportionate short stature and lifelong medical complications, with an estimated incidence of 1 in 25,000–30,000 live births. The condition results from a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, causing receptor overactivation and impaired bone growth at the growth plates. This review provides an overview of achondroplasia, including its pathophysiology, clinical features, diagnostic methods, and novel therapeutic options, with emphasis on vosoritide. Historically, management has focused on symptomatic treatment and surgical interventions to address complications such as foramen magnum stenosis, hydrocephalus, and postural deformities. Vosoritide (Voxzogo) marks a breakthrough as the first disease-modifying therapy targeting the underlying pathophysiology. It is a C-type natriuretic peptide (CNP) analog that inhibits the overactive MAPK pathway, thereby promoting chondrocyte proliferation and differentiation in growth plates and enabling endochondral bone growth. Phase 3 clinical trials demonstrated that vosoritide significantly increases annual growth velocity (by approximately 1.57 cm) and improves body proportions, with a favorable safety profile. Reported adverse effects were generally mild, including transient hypotension and injection site reactions. Despite these advances, vosoritide therapy does not eliminate the need for coordinated multidisciplinary care and psychological support. Patients require ongoing monitoring and management of associated complications, including neurological, orthopedic, respiratory, and developmental issues. In summary, achondroplasia remains the most frequent genetic form of dwarfism, traditionally managed through supportive care and surgery. The introduction of vosoritide represents a paradigm shift, offering the first targeted therapy that directly modifies disease progression and opens new perspectives for improving patients’ quality of life.

Endothelium-derived C-type natriuretic peptide offsets the pathogenesis of pulmonary hypertension.