**4. CNP's role in cartilage homeostasis**

cytokines directly affect appetite centers, they also disrupt growth hormone signal transduction and proteolyze IGFBP-3 and inhibit the IGF-1 expression in the growth plate [43].

C-type natriuretic peptide NP is anabolic in the growth plate, articular cartilage, and in bone tissue: We and others have shown that CNP is anabolic in the growth plate and that CNP/ natriuretic peptide receptor-B (NPR-B)/cyclic guanosine monophosphate (cGMP) signaling regulates linear bone growth/endochondral bone formation through the cGMP-dependent protein kinase II (cGK-2). CNP induces chondrocyte proliferation, differentiation, and extra-

We have recently shown that transgenic mice that overexpress CNP under the control of the type-II collagen promoter had increased endochondral bone growth with thick and matrix-rich articular joint cartilage. Most importantly, we have also shown that in an animal model of inflammatory arthritis, CNP overexpression in chondrocytes protects the articular cartilage integrity and prevents subchondral bone defects [27]. Our transgenic mice that overexpressed CNP on cartilage developed dense trabeculation under the subchondral bone supporting in vitro experiments showing increased matrix secretion by osteoblastic cells [44]. In addition, there is data about CNP enhancing ECM secretion in cultured articular chondrocytes seeded on a type-II collagen-coated scaffold [45]. CNP has a unique dual anabolic effect on chondrocytes and osteoblasts for matrix synthesis. Together, these findings suggest that CNP is an ideal growth factor to be used in TE for osteochondral defects since it may promote both cartilage and bone regeneration. CNP improves vasculogenesis and graft survival: Vascular endothelial cells also express and secrete CNP, and CNP has a major role in embryonic vasculogenesis and graft vasculogenesis

Angiogenesis is essential for bone formation during embryonic life and after fracture, indicat-

Natriuretic peptides are one of the main classes of cGMP inducers which are known as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). Natriuretic peptides are secreted proteins that control cell behavior through activation of two major transmembrane receptors, natriuretic peptide receptor 1 and 2 (NPR1 and NPR2) [48–50]. Receptors NPR1 and NPR2 have guanylyl cyclase activity and synthesize cGMP in response to ligand binding. ANP and BNP signal mainly through NPR1/GC-A, while CNP predominantly activates NPR2/GC-B. All three ligands also bind to a third receptor, NPR3, which is known as the clearance receptor that does not have an intracellular signaling part from the molecule and limits ligand availability once attached and limits natriuretic peptide signaling.

Once CNP gene and its signaling were disrupted in mice, those mice suffered from postnatal dwarfism [51]. While CNP knock-out mice developed normal membranous ossification,

**3. Other growth factors that affect longitudinal growth: C-type** 

**natriuretic peptide**

52 Newest Updates in Rheumatology

[46, 47].

cellular matrix (ECM) production.

ing a further role in bone fracture healing for CNP.

**3.1. CNP signaling pathway**

Transgenic mice that overexpress CNP (CNPcol2a1TG) in cartilage develop skeletal overgrowth and increased bone density: in order to further study the effects of CNP in skeletal growth and bone architecture in vivo, we generated transgenic mice by cloning human CNP cDNA (450 bp) into a construct that contained mouse collagen type II (Col2a1) promoter (GenBank #m65161) to specifically overexpress CNP in chondrocytes. Growth plates of CNPcol2a1TG mice showed increased numbers of proliferative chondrocytes measured by BrdU uptake (p < 0.05) and increased numbers of enlarged hypertrophic chondrocytes

**Figure 2.** 20 weeks old male CNPcol2a1TG mice with kyphosis and excess growth of longitudinal and vertebral bones.

with increased proteoglycan deposition as evidenced by strong Safranin-O staining [27]. CNPcol2a1TG mice developed increased endochondral bone growth (30%) and developed kyphosis due to vertebral overgrowth by 18 weeks (**Figure 2**). In the skeletal histomorphology of CNPcol2a1TG mice, the most intriguing finding was the increased trabecular bone formation in proximity to the growth plate cartilage, subchondral (juxta-articular) bones, and in vertebrae.

**6. CNP's role in vascular homeostasis**

**and dwarfism**

in adults.

One of the most important roles of CNP is in the venous system. CNP via its NPR2 a d NPR3 receptor signaling in the vascular wall regulates vasodilatation particularly on the venous wall. Enhanced osteoblastic and osteoclastic activities. In addition, serum levels of osteocalcin and tartrate-resistant acid phosphatase-5b, were elevated in the Tg mice. The same study showed that open and Vascular endothelial cells express and secrete CNP. CNP is suppressed by the VEGF secretion and is known to act as a vasodilator [64]. Also, CNP has been suggested to have a major role in angiogenesis [47, 65]. Once the growth plate is closed after puberty, the chondrogenic CNP will no longer available. Then CNP needed for trabecular bone remodeling will then have to be secreted partially by osteoblasts as a paracrine/autocrine factor and/ or by vascular endothelium. Steady serum levels of NT-proCNP may also be regulating the cartilage and bone homeostasis and the main source of NT-proCNP might only be the vascular endothelium. Due to the vascular wall expression of CNP and its vasodilator effect, CNP's

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

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

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role in hypertension, vasculitis and myocardial infarction has been studied.

**7. Lack of CNP signaling in growth plate causes short stature** 

articular area resembling osteopenia of inflammatory arthritis.

**8. CNP in skeletal overgrowth**

Heterozygous carriers of a mutation in NPR-B, the receptor for CNP, have idiopathic short stature suggesting a quantitative effect of the CNP pathway on skeletal growth [66]. Serum levels of CNP's N-terminal pro-peptide (NT-proCNP), the inactive form of CNP, were found to be highest at birth, gradually decreased by puberty, and plateau after 18 years of age [67]. The levels of NT-proCNP correlate with levels of alkaline phosphatase (bone formation markers) in humans [67, 68]. More importantly, serum NT-proCNP levels are maintained at a level

Individuals with acromesomelic dysplasia-type Maroteaux (AMDM), a type of human dwarfism, develop periarticular osteopenia, loss of trabecular bone structure. AMDM is caused by loss of function mutations in the CNP's receptor, natriuretic peptide-B (Npr2 gene). AMDM patients have disproportional growth retardation and abnormal development of bone tissue and appear to have (juxta-articular) metaphyseal flaring and osteopenia but do not have any other health problems [58, 69]. The trabecular bone loss is more significant in the juxta-

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
