**2. Growth delay in chronic inflammatory diseases**

In chronic inflammatory childhood diseases such as inflammatory bowel diseases, mainly Crohn's disease, juvenile idiopathic arthritis, systemic lupus erythematosus, or other diseases in which there are excess number of circulating cytokines, it is suggested that growth hormone signaling pathways are disrupted [25–27].

Out of all factors that affect growth during chronic inflammatory diseases, growth hormone GH/IGF axis has been studied the most. Multiple steps of the growth hormone and its effector IGF-1 axis may be interrupted; these are poor signal transduction of growth hormone in the liver and in the growth plate and diminished IGFBP concentrations, which directly affect the growth plate and suppress the sensitivity of IGF-1.

After the growth hormone is secreted by the pituitary gland, it stimulates the hepatic tissue to generate IGF-1 which increases the growth plate chondrocyte proliferation.

Pro-inflammatory cytokines play a critical role in the disruption of the IGF-1/GH axis. Many studies have shown that pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β interact with the IGF-1/GH system. Transgenic mice for IL-6 develop low serum level IGF-1 and develop severe growth delay [25]. There is also evidence that suggests a role for suppressors of the cytokine signaling (SOCS) family proteins in IL-6 dysregulation [26]. The KxB/N transgenic mouse model for arthritis has also been described to have growth delay during our studies [27]. KxB/N mouse has increased serum levels of IL-1β and TNF-α and they develop systemic inflammatory arthritis [28]. Thus, high levels of any pro-inflammatory cytokine are sufficient to arrest the growth process in developing organisms with open growth plates.

dependent on NF-κB activation and result in bone resorption, osteopenia [11]. Excess of TNF-α during systemic arthritis has been found to be responsible for periarticular osteopenia most probably due to the same mechanism. GH action has both direct and indirect effects on the growth plate. GH acts indirectly, stimulating the production of IGF-1 that promotes chondrocyte hypertrophy, which in turn exerts its effects on the growth plate. The direct effect of GH on the growth plate stimulates chondrocyte proliferation [18]. Most recently, nitric oxide (NO) and C-type natriuretic peptide (CNP) have been identified as new regulators of endochondral bone growth, as they both stimulate chondrogenesis and both act through a

While it is important to study anabolic effects of growth factors and hormones that promote chondrogenic differentiation in the growth plate, it is also very important to recognize the effects of factors that play roles in remodeling such as factors that control osteoclastic differentiation or activity. Osteoclasts are major cells that degrade bones for remodeling. The balance between bone degradation and bone building is critical for physiological bone homeostasis. Factors such as NF-κB and cytokines that are controlled by this factor may cause an imbalance during systemic inflammatory diseases such as JIA [20, 21]. NF-κB activation is a relevant component for osteoclast development, differentiation, and survival, cooperating with other pro-inflammatory cytokines [22]. Loss of NF-κB signaling prevents osteoclastogenesis [23].

In chronic inflammatory childhood diseases such as inflammatory bowel diseases, mainly Crohn's disease, juvenile idiopathic arthritis, systemic lupus erythematosus, or other diseases in which there are excess number of circulating cytokines, it is suggested that growth hor-

Out of all factors that affect growth during chronic inflammatory diseases, growth hormone GH/IGF axis has been studied the most. Multiple steps of the growth hormone and its effector IGF-1 axis may be interrupted; these are poor signal transduction of growth hormone in the liver and in the growth plate and diminished IGFBP concentrations, which directly affect the

After the growth hormone is secreted by the pituitary gland, it stimulates the hepatic tissue to

Pro-inflammatory cytokines play a critical role in the disruption of the IGF-1/GH axis. Many studies have shown that pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β interact with the IGF-1/GH system. Transgenic mice for IL-6 develop low serum level IGF-1 and develop severe growth delay [25]. There is also evidence that suggests a role for suppressors of the cytokine signaling (SOCS) family proteins in IL-6 dysregulation [26]. The KxB/N transgenic mouse model for arthritis has also been described to have growth delay during our studies [27]. KxB/N mouse has increased serum levels of IL-1β and TNF-α and they develop systemic inflammatory

generate IGF-1 which increases the growth plate chondrocyte proliferation.

common mediator, cyclic guanosine monophosphate (cGMP) [19].

50 Newest Updates in Rheumatology

NF-κB knockout mice showed severe osteopetrosis [24].

mone signaling pathways are disrupted [25–27].

growth plate and suppress the sensitivity of IGF-1.

**2. Growth delay in chronic inflammatory diseases**

The IGF-1 signaling pathway is altered in chondrocytes during chronic inflammatory conditions by pro-inflammatory cytokine activities (TNF-α, IL-6, and IL-1). These pro-inflammatory mediators work via disruption of intracellular MAPK/extracellular signal-regulated kinases (ERKs) and phosphoinositide 3-kinase (PI3K) [29, 30].

Besides the inhibition of the MAPK pathway, there are also debates about the potential of disrupted miRNA effect on overexpression of proteins involved in the regulation of GH/IGF-1 axis. miRNA deregulation previously has been reported during childhood chronic inflammatory diseases such as IBD and JIA [21, 31].

In juvenile idiopathic arthritis (JIA), bone growth abnormalities are seen as either or both short stature and bone deformities. The prevalence of juvenile rheumatoid arthritis is as high as 20 per 100,000 people per year. Growth delay in generalized linear growth occurs predominantly in the systemic onset juvenile arthritis population and to a lesser degree in those with poly-articular onset JIA associated with RF positivity [32]. During active disease in JIA, elevated serum levels of cytokines may modify target cell's sensitivity by down-regulating the GH receptor (GHR) gene expression, leading to short stature as an adult [33]. Therefore, the shortcoming of GH function during JIA is explained more as resistance to growth hormones than deficiency in growth hormone secretion.

Growth hormone (GH) treatment by providing excess GH in the circulation can overcome growth hormone resistance and improve growth velocity and prevent development of short stature in children affected from JIA.

Recent studies suggest that early initiation of GH treatment helps in maintaining normal growth in children with JIA [34, 35]. Thus, recombinant growth hormone treatment has been the mainstream since no other medications that induce skeletal growth are available to be used in pediatrics [36, 37]. Nevertheless, even with GH treatment, catch-up growth is variable and is more dependent on the severity of the inflammatory state, duration, and additional corticosteroid treatment [34, 37–41].

Another childhood disease studied for its growth delay complication is Crohn's disease, an inflammatory bowel disease (IBD). Almost, one-third of the children affected by Crohn's disease (CD) develop longitudinal growth delay. Unlike JIA, Crohn's disease patients do not develop bony deformities since the major inflammatory target is not the joint cartilage but the intestinal system. Additional to the pro-inflammatory cytokine excess that directly affects the growth plate during active disease in Crohn's disease, other factors such as malnutrition, mal-absorption of the nutrients, and central nervous system were also blamed for longitudinal growth delay. Especially those patients affected more with jejunum inflammation have poor nutrition and severe deficiency in energy metabolism as well as a chronic inflammation state which contributes to the growth delay [42]. In Crohn's disease it has been suggested that chronic inflammation interferes with both central and peripheral growth hormone/factor secretion causing hormonal deficiency and/or resistance. While inflammatory 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].

endochondral ossification was severely impaired and all long bones and vertebrae were significantly shorter. About 70% of null mice die in the first 100 days after birth. When crossed with transgenic mice that overexpressed CNP in cartilage, knock-out mice phenotype was

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

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

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Further organ culture experiments (femur) confirmed CNP's effect as the potent stimulator of endochondral bone growth. Other mice models were present in which Npr2 was knocked out and similar dwarf phenotype was observed, thus further confirming the importance of CNP signaling pathways. A loss-of-function mutation in the cGMP-dependent protein kinase II (cGKII gene) has also recently been identified as the cause of dwarfism in mice which is a downstream effector of CNP. When Npr3 is knocked out, an opposite phenotype of skeletal

All natriuretic peptides (ANP, BNP, and CNP) have the ability to bind NPRA, NPRB, and NPRC, while CNP has the most affinity to bind NPRB which seems to control endochondral bone growth the most. Mice deficient for ANP, BNP, or NPR1 genes were reported not to develop dwarfism or abnormal skeletal phenotypes [54, 55], suggesting that these genes play only minor supportive roles during endochondral bone formation. Overexpression of BNP in transgenic mice developed skeletal overgrowth, but this was explained as overstimulation of

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.

completely rescued.

over growth is observed [52, 53].

NPR2 by excess levels of BNP [56, 57].

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