**8. CNP in skeletal overgrowth**

Before CNP and it effectors can be used as a remedy for short stature and growth delay, its effects in humans need to be studied well. Evidence for complications of excess systemic CNP came after the description of two novel mutations that resulted in gain of function in humans. The C-type natriuretic peptide (CNP), encoded by NPPC gene, is located on chromosome 2q37.1. Two independent studies have described three patients with a Marfan-like phenotype presenting a de novo balanced translocation involving the same chromosomal region 2q37.1 and overexpression of NPPC [70]. One study reported on two partially overlapping interstitial 2q37 deletions. These two patients showed opposite phenotypes characterized by short stature and skeletal overgrowth, respectively. The patient with short stature presented a 2q37 deletion causing the loss of one copy of the NPPC gene with normal CNP plasma concentration. The deletion identified in the patient with a Marfan-like phenotype interrupted the DIS3L2 gene without involving the NPPC gene. In addition, a strongly elevated CNP plasma concentration was found in this patient with Marfanoid features and a tall stature [71, 72].

neuroendocrine regulation [87]. CNP is suggested to play important roles in central energy

Longitudinal Growth in Rheumatologic Conditions: Current and Emerging Treatments...

http://dx.doi.org/10.5772/intechopen.75879

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Initial reports about CNP's effect on inflammatory disease activity came from osteoarthritis disease models. Since both nitric oxide and CNP are the two main activators of cGMP in cartilage they were checked for their role in development of osteoarthritis. The production of nitric oxide (NO) regulates host defense and inflammation. Nitric oxide has vasodilation, cytotoxicity, and it has a role in cytokine-dependent tissue injury. NO effects have been blamed in the tissue injury of a variety of rheumatologic conditions including systemic lupus erythematosus, rheumatoid arthritis, and osteoarthritis. Pro-inflammatory effects of nitric oxide include vasodilation, edema, cytotoxicity, and the mediation of cytokine-dependent processes that can lead to tissue destruction. In contrast to NO effect in the cartilage, NO secretion from vascular wall is protective against neutrophil adhesion and related vascular injury. Thus, nitric oxide has been found as a clear role player in osteoarthritis pathogenesis but not in microvasculature injury [88, 89]. Although CNP is known to induce articular chondrocyte hypertrophy, it was never blamed to be involved in osteoarthritis pathogenesis, while it was considered to contribute to the disease progression. On the other hand, we were able to show in an inflammatory arthritis murine model that cartilage overexpression of CNP increased the chondrocyte number, matrix synthesis, and maintained a thicker hypertrophic cartilage in the growth plate and in the joints and thus was protective against the cartilage degenerative effects of inflammatory arthritis. The mouse model we used was for a K/BxN rheumatoid arthritis mouse model that developed severe inflammatory arthritis which was evident from first synovitis, pannus formation, and then secondary cartilage deterioration [28, 90]. Our transgenic mouse under Col2a1 promoter overexpressed CNP in the cartilage tissue mainly in the growth plate and in the joint cartilage. CNP transgenic mice developed thick growth plates with enlarged chondrocytes and wider growth plates with proliferating chondrocytes that produced a rich matrix. Furthermore, when CNP overexpressing mice was crossed with K/BxN mouse and developed systemic arthritis, we observed that cartilage matrix integrity and cartilage structure was protected against the inflammation. CNP transgenic mice did not

Another evidence for CNP's systemic anti-inflammatory effect was reported in a rat model of hemorrhagic shock and resuscitation. CNP infusion to this model lowered the myeloperoxidase activity and decreased the expression of TNF-α, IL-6, and IL-1β in the kidneys. CNP treatment suppressed oxidative stress, ameliorated the inflammatory response, and caused acute kidney injury [92]. Investigators suggested that they demonstrated CNP infusion's inhibitory effect on the generation of reactive oxygen species (ROS) and pro-inflammatory cytokines after hemorrhagic shock induction and subsequently suppressed the activation, recruitment, and adherence of neutrophils in the kidney. Neutrophil recruitment is one of the fundamental pathways in hemorrhagic shock. It is suggested that neutrophil recruitment is also delayed after CNP treatment. In an earlier study, Chen et al. showed that CNP treatment

expenditure and food intake via its effects on the central nervous system (**Figure 3**).

**10. CNP during inflammatory disease activity**

develop severe complications of arthritis (**Figure 4**) [27, 91].
