**1. Introduction**

Longitudinal growth is a continuous process under the influence of multiple complex factors starting from prenatal life until end of puberty. Major factors that control longitudinal growth can be summarized as genetic background, nutrition, and endocrine growth factors. Major

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

endocrine factors that control longitudinal growth are growth hormone (GH) and insulin-like growth factor (IGF), thyroid stimulating hormone (TSH), parathyroid hormone (PTH), insulin, and sex steroids. There are also multiple growth factors in the growth plates and other organs that are involved in processing the growth factors in the regulation of longitudinal bone growth. Some of these growth factors are found and secreted by the growing cartilage and bone tissue and under the influence of the endocrine hormones. These are insulin-like growth factor 1 (IGF-1), insulin-like growth factor-binding protein 3 (IGFBP-3), fibroblast growth factors (FGF), Indian hedgehog (Ihh), parathyroid hormone-like receptor protein (Pthrp), and C-type natriuretic peptide (CNP).

#### **1.1. How do growth hormones and factors affect longitudinal skeletal growth?**

Skeletal growth and development follows two different pathways: chondrogenesis and osteogenesis (both endochondral and membranous bone growth). Longitudinal growth is mainly controlled by endochondral ossification which is orchestrated by a complex network of endocrine and paracrine growth hormones and factors that control growth plate cartilage and bone tissue.

While membranous bone such as those in our skull forms as a result of direct mechanism of mesenchymal cell differentiation into osteoblasts, endochondral osteogenesis follows an initial mesenchymal stem cell differentiation into chondrocytes, and the chondrogenesis process is later replaced by bone tissue [1–4]. During endochondral growth, mesenchymal cells (See **Figure 1**) first condense in the growth plate and then with interactions between cells via local transcription factors such as Sox9 and other extracellular molecules such as collagen II differentiate gradually into chondrocytes. Chondrocytes proliferate and organize in columns making stacks which are perpendicular to gravity. They gradually stop proliferating and become pre-hypertrophic with increased matrix synthesis (**Figure 1**) [5, 6]. Eventually, these cells stop proliferating and start terminally differentiating into hypertrophic chondrocytes. Finally, the hypertrophic zone of the growth plate becomes mineralized. Then the vascular system merges into this hypertrophic chondrocyte region and with more signaling the mineralized tissue is possibly resorbed by osteoclasts that originate from hematopoietic stem cells. Eventually, mineralized tissue is replaced by bone tissue which is made by osteoblasts that differentiate from mesenchymal cells. Thus, endochondral bone growth combines together chondrogenesis, extracellular matrix formation, mineralization, and osteogenesis process. These processes are synchronized by a series of systemic growth hormones such as growth hormone (GH), thyroid-stimulating hormone (TSH), glucocorticoids and local growth factors such as parathyroid hormone-related peptide (Pthrp) and members of the transforming growth factor β (TGF- β), fibroblast growth factors (FGF), Indian hedgehog (Ihh), and Wnt's [7, 8] (**Figure 1**). Intracellular pathways that are activated by the orchestra of factors are yet to be determined. Sox9 and Runx2, transcription factors, have been shown to regulate chondrogenesis and hypertrophic differentiation [9, 10].

then, they act directly on peripheral target tissues, such as liver [13, 14], heart [15], kidney and

**Figure 1.** Longitudinal growth is regulated by multiple systemic (in bubble) and local growth factors expressed differentially in the proliferating, hypertrophic chondrocyte zones of the growth plate (black text on the left of the figure). CNP seems to be expressed and plays a role in the growth plate cartilage, in the osteoblasts and in the endothelial

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GH action regulates growth plates using both direct and indirect mechanisms. While GH directly stimulates chondrocyte proliferation on the growth plate [17], it indirectly stimulates the production of IGF-1 that promotes chondrocyte hypertrophy, which in turn exerts its

Various danger signals or stimuli, such as TNF-α, LPS, or low-oxygen tension, increase the expression of IGF-1, vascular endothelial growth factor (VEGF), and FGF-2 with mechanisms

growth plates [14, 16].

cells of vessel walls.

effects directly on the growth plate.

During linear growth, endocrine hormones such as GH, IGF-1, glucocorticoids, and thyroid stimulating hormone first interact at the level of hypothalamus and pituitary [11, 12] and Longitudinal Growth in Rheumatologic Conditions: Current and Emerging Treatments... http://dx.doi.org/10.5772/intechopen.75879 49

endocrine factors that control longitudinal growth are growth hormone (GH) and insulin-like growth factor (IGF), thyroid stimulating hormone (TSH), parathyroid hormone (PTH), insulin, and sex steroids. There are also multiple growth factors in the growth plates and other organs that are involved in processing the growth factors in the regulation of longitudinal bone growth. Some of these growth factors are found and secreted by the growing cartilage and bone tissue and under the influence of the endocrine hormones. These are insulin-like growth factor 1 (IGF-1), insulin-like growth factor-binding protein 3 (IGFBP-3), fibroblast growth factors (FGF), Indian hedgehog (Ihh), parathyroid hormone-like receptor protein

**1.1. How do growth hormones and factors affect longitudinal skeletal growth?**

Skeletal growth and development follows two different pathways: chondrogenesis and osteogenesis (both endochondral and membranous bone growth). Longitudinal growth is mainly controlled by endochondral ossification which is orchestrated by a complex network of endocrine and paracrine growth hormones and factors that control growth plate cartilage and bone

While membranous bone such as those in our skull forms as a result of direct mechanism of mesenchymal cell differentiation into osteoblasts, endochondral osteogenesis follows an initial mesenchymal stem cell differentiation into chondrocytes, and the chondrogenesis process is later replaced by bone tissue [1–4]. During endochondral growth, mesenchymal cells (See **Figure 1**) first condense in the growth plate and then with interactions between cells via local transcription factors such as Sox9 and other extracellular molecules such as collagen II differentiate gradually into chondrocytes. Chondrocytes proliferate and organize in columns making stacks which are perpendicular to gravity. They gradually stop proliferating and become pre-hypertrophic with increased matrix synthesis (**Figure 1**) [5, 6]. Eventually, these cells stop proliferating and start terminally differentiating into hypertrophic chondrocytes. Finally, the hypertrophic zone of the growth plate becomes mineralized. Then the vascular system merges into this hypertrophic chondrocyte region and with more signaling the mineralized tissue is possibly resorbed by osteoclasts that originate from hematopoietic stem cells. Eventually, mineralized tissue is replaced by bone tissue which is made by osteoblasts that differentiate from mesenchymal cells. Thus, endochondral bone growth combines together chondrogenesis, extracellular matrix formation, mineralization, and osteogenesis process. These processes are synchronized by a series of systemic growth hormones such as growth hormone (GH), thyroid-stimulating hormone (TSH), glucocorticoids and local growth factors such as parathyroid hormone-related peptide (Pthrp) and members of the transforming growth factor β (TGF- β), fibroblast growth factors (FGF), Indian hedgehog (Ihh), and Wnt's [7, 8] (**Figure 1**). Intracellular pathways that are activated by the orchestra of factors are yet to be determined. Sox9 and Runx2, transcription factors, have been shown to regulate chondrogenesis and hypertrophic dif-

During linear growth, endocrine hormones such as GH, IGF-1, glucocorticoids, and thyroid stimulating hormone first interact at the level of hypothalamus and pituitary [11, 12] and

(Pthrp), and C-type natriuretic peptide (CNP).

48 Newest Updates in Rheumatology

tissue.

ferentiation [9, 10].

**Figure 1.** Longitudinal growth is regulated by multiple systemic (in bubble) and local growth factors expressed differentially in the proliferating, hypertrophic chondrocyte zones of the growth plate (black text on the left of the figure). CNP seems to be expressed and plays a role in the growth plate cartilage, in the osteoblasts and in the endothelial cells of vessel walls.

then, they act directly on peripheral target tissues, such as liver [13, 14], heart [15], kidney and growth plates [14, 16].

GH action regulates growth plates using both direct and indirect mechanisms. While GH directly stimulates chondrocyte proliferation on the growth plate [17], it indirectly stimulates the production of IGF-1 that promotes chondrocyte hypertrophy, which in turn exerts its effects directly on the growth plate.

Various danger signals or stimuli, such as TNF-α, LPS, or low-oxygen tension, increase the expression of IGF-1, vascular endothelial growth factor (VEGF), and FGF-2 with mechanisms 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 common mediator, cyclic guanosine monophosphate (cGMP) [19].

arthritis [28]. Thus, high levels of any pro-inflammatory cytokine are sufficient to arrest the

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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

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 inflamma-

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

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

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

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

growth process in developing organisms with open growth plates.

kinases (ERKs) and phosphoinositide 3-kinase (PI3K) [29, 30].

tory diseases such as IBD and JIA [21, 31].

than deficiency in growth hormone secretion.

stature in children affected from JIA.

corticosteroid treatment [34, 37–41].

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