**12. Current clinical use of CNP**

effectively attenuates lipopolysaccharide (LPS)-induced endothelial activation by eliminating intracellular ROS production, inhibiting the NF-κB and MAPK p38 signaling pathways and activating the PI3 K/Akt/HO-1 pathway in human umbilical vein endothelial cells (HUVECs),

**Figure 4.** K/BxN+CNPcol2a1TG double transgenic mice do not develop growth retardation or severe complications of

Another study that showed CNP's effect in reducing the LPS-induced lung injury suggested that mechanism of action might involve downregulation of inflammatory cytokine expression in lung parenchyma and again downregulation of neutrophil migration in the lungs [94].

Finally, evidence for CNP and its derivate anti-inflammatory treatment potential were shown in a wounded cartilage explant model in steers. In this study, wounded explants were cultured with 0 or 10 ng/mL IL-1β and/or microcapsules loaded with or without CNP for a period of 48 h. The presence of CNP microcapsules had a concentration-dependent effect with significant inhibition of NO release in response to IL-1β at 2000 (p < 0.01), 10,000 (p < 0.01), and 50,000 microcapsules/well (p < 0.001) [45]. Others suggested that the effect of CNP on preventing the inflammatory effects of IL-1β in chondrocytes depends on local protein concentration. While low concentrations (pM) were shown to promote a proliferative response, high concentrations (μM) lead to anabolic effects such as matrix synthesis in chondrocytes [95, 96].

Acute inflammation and the inflammatory mediators seems to suppress the activity of CNP in growing organisms [97]. It is possible that in chronic inflammatory diseases, serum NT-proCNP levels are also low and contribute to the growth arrest during active disease in children.

CNP regulates fat metabolism in adipogenic tissue, and adipogenic CNP transgenic mice is resistant to obesity when fed by high fat content. Natriuretic peptides regulate intracellular cGMP and phosphorylated vasodilator-stimulated phosphoprotein (VASP). Adipogenic CNP

**11. Other conditions in which circulating CNP levels are affected**

[93] suggesting an anti-inflammatory effect for CNP.

arthritis.

58 Newest Updates in Rheumatology

Use of CNP and its analogues in achondroplasias: gain-of-function mutations in the FGFR3 gene result in achondroplasia. Achondroplasia is known as the most common form of dwarfism. In patients with achondroplasia there is impaired proliferation and differentiation of the chondrocytes in the growth plate cartilage that causes stunted longitudinal growth due to endochondral growth suppression and skull abnormalities due to membranous ossification disruption. In achondroplasia, FGFR3 mutations induce increased phosphorylation of the tyrosine kinase receptor FGFR3 and increase the mitogen-activated protein kinase (MAPK). It is known that C-type natriuretic peptide (CNP) suppresses FGFR3 downstream signaling by inhibiting the pathway of mitogen-activated protein kinase (MAPK) in vivo and in vitro. Mice overexpressing CNP rescues FGFR3 gain of mutation-related dwarfism. Exogenous administration of CNP has been challenging since it is rapidly cleared and degraded in vivo through receptor-mediated and proteolytic pathways such as proteolyticneutral endopeptidase degradation. Therefore, multiple variants of CNP molecules have been tested for their efficacy. Recently, a variant of CNP called BMN111, neutral endopeptidase-resistant CNP analog, showed significant ability to stimulate signaling downstream of the CNP receptor, natriuretic peptide receptor B. Initial trial of continuous delivery of CNP through intravenous (IV) infusion in the form of BMN111 in 2014 showed normalization of dwarfism [101].

Since subcutaneous (SC) route of administration is preferred over continuous infusion in pediatric individuals, it is expected that BMN 111, a 39 amino acid CNP pharmacological analog, would be very effective in diseases where CNP signaling pathway is impaired. BMN 111 can be applied once daily via SC administration at physiological concentrations [101].

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In the near future, CNP analogues might be used in other diseases where CNP signaling is impaired or blocked by chronic inflammation affecting cartilage and bone. Use of CNP analogues can be applicable to both adult and pediatric diseases.
