The Physiology and Mechanisms of Growth (N&G 2024)

Introduction

A selection of articles published in the period from July 1, 2022, to June 30, 2023, addressing physiology and mechanisms of growth is presented in this chapter. We acknowledge that the selection is subjective, and some essential articles may have not been included, due to shortage of space.

The following themes were addressed in this year’s chapter: Management of growth disorders during puberty is complex. Puberty is the final period where gains in linear growth can be made. However, it should be emphasized that other physiological processes during puberty are also important and should not be disregarded when planning growth-promoting interventions. Physical and/or psychological stress can affect growth and could, if chronic, result in suboptimal final height. Interventions regulating stress in growing children and adolescents should be either prevented, recognized, or managed early. More insights into mechanisms involved in growth failure related to attention deficit medications and inflammation were published. It was determined that proper nutrition could alter the outcome regarding growth during acute or chronic inflammation. Several manuscripts are presented on the management of comorbidities of skeletal dysplasia, with an emphasis on nutritional management. Interesting data on the mechanisms of growth in premature infants are discussed. Nutrition and gut microbiota were further acknowledged as essential players in these subjects. Finally, more data on the role of protein-fortified nutrition in linear growth are presented.

Management of growth disorders in puberty: GH, GnRHa, and aromatase inhibitors: a clinical review

Comments: The magnitude of the growth spurt during puberty is the result of the race between
the stimulatory effect of the sex hormones on the growth hormone–insulin-like growth factor 1 axis and directly on the epiphyseal growth plate and its senescence effect on the growth plate which occurs simultaneously. In the present excellent review manuscript, the authors discuss ways to extend the growth of the long bones during puberty of children with short stature. The authors discuss the physiology of the growth during puberty and review the possible ways to influence the process with gonadotropin-releasing hormone analogues and aromatase inhibitors. This review is one of the most important manuscripts that addresses the topic in the literature and helps to bring the reader to the edge of the knowledge available today on the topic.

Methylphenidate promotes premature growth plate closure: in vitro evidence

Comments: Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by difficulties in maintaining attention, hyperactivity, excessive movement, and impulsiveness. It is the most diagnosed neuropsychiatric disorder, with a prevalence of 5–10% in children and young people. Multidisciplinary treatment that includes parental training, behavior therapy, and pharmacotherapy is the accepted mode of treatment. Methylphenidate (MPH) is among the most frequently used medication. It increases the availability of dopamine and norepinephrine in the synaptic space by inhibiting their presynaptic transporters in central adrenergic neurons, thus
leading to stimulation of their receptors [1].

Patients with ADHD have relatively reduced final height and weight [2, 3]. Anorexigenic effect of the medication, with reduced caloric intake, is the suspected mechanism. However, in this study, the authors, for the first time, describe a possible direct effect of MPH on the bone plate, influencing endochondral ossification and senescence. To this effect, it was determined that in the in vitro model, MPH did not influence the viability, proliferation, and differentiation of the prechondrogenic cells in the growth plate. However, it reduced the expression of cartilage extracellular matrix–related genes and increased the expression of genes involved in growth plate calcification.

These data suggest that MPH directly influences the mechanisms of growth in the growth plate, possibly leading to premature closure of the growth plate. This would contribute to the growth retardation that has been described to be induced by this drug. These data need to be further verified in the humans; however, they could potentially have an important influence for many patients with ADHD treated with MPH.

Stress and growth in children and adolescents

Comments: Stress is defined as a state of threatened or perceived threatened homeostasis in the
system (e.g., human organism). Impulses leading to stress in humans can be either physical or psychological and are called stressors. They can be isolated or multiple, internal or external. The human organism reacts to stress by activating adaptive hormonal and neural responses. They are protective for human health; however, if they are too extensive or persist longer, they may be maladaptive [4]. From the point of view of linear growth, stress can lead to suboptimal height velocity and reduced final height. It can impact linear growth in all phases of growth (prenatal/
fetal, infancy, childhood, or adolescence) by acting through different physiological mechanisms, either by directly modulating the growth hormone axis or indirectly through other factors. The adaptive response to stressors culminates in behavioral, physiological, and biochemical responses, which together support survival and conservation of energy [4].

The acute and time-limited response to stress does not result in long-lasting consequences for growth. Actually, growth and other processes, such as reproduction, can however be halted, the potential for both is not lost. Chronic activation of the stress system and especially hypercortisolism however do have a negative impact on growth, thyroid function, reproduction, puberty, and metabolism.

Mechanisms involved in how stress influences linear growth are discussed in this interesting review. In addition, targeted interventions to reduce stress during infancy, childhood, and adolescence, with the goal of maintaining long-term health and normal growth and pubertal development, are suggested.

Altogether, for those interested in growth and development of children, this is a must-read review article.

A whey-based diet can ameliorate the effects of LPS-induced growth attenuation in
young rats

Comments: Children with chronic inflammatory diseases are at an increased risk for decreased
growth velocity, and if inflammation persists over the long term, for decreased final height. It is imperative that inflammatory disease is diagnosed early in childhood and is well managed, possibly without measures that influence growth (e.g., glucocorticoids). Mechanisms linked to impaired growth in inflammatory diseases are linked to direct actions of cytokines on the growth plate, decreased energy intake, and longterm use of medications as are glucocorticoids. It has recently been shown that inflammatory cytokines (e.g., tumor necrosis factor) and therapy (e.g., dexamethasone) separately suppress chondrogenesis and bone growth [5]. Nutrition influences linear growth through different mechanisms linked to sufficient caloric intake and/or beneficial nutrition composition (protein source and ratio) [6]. In the present study, the effect of whey-based nutrition in comparison to soy-based diet on linear growth in the lipopolysaccharide animal model was studied. Humerus length and epiphyseal growth plate height were used as a proxy for determination of linear growth. Whey, but not soy, protected the growing animals from the effects of the inflammation. Those rats that were fed isoenergetic whey-based diet had longer humerus and higher epiphyseal growth plate. Therefore, nutrition with whey protein appeared to protect the experimental animals from the LPS-induced growth attenuation.

Although these findings need to be further validated and studies need to be performed in humans, they are exciting and again show the importance of proper composition of nutrition in children with chronic diseases.

TNF overexpression and dexamethasone treatment impair chondrogenesis and bone growth in an additive manner

Comments: In this manuscript, the authors describe a set of studies they have done in order to
better understand the mechanism of stunted growth during chronic inflammation and to explore the role of glucocorticoids in such cases. In the experiments, they have used a model of transgenic mouse where human tumor necrosis factor (TNF) is overexpressed (huTNFTg). In that animal model, a chronic polyarthritis is developed early in life. The authors have studied the effect of the TNF-induced chronic inflammation on linear growth and the morphology of the growth plate with and without dexamethasone treatment. The authors discovered that the TNF overexpression reduced the length of the bones and the growth plate height, increased apoptosis, suppressed Indian hedgehog, decreased hypertrophy, and disorganized chondrocytes columns.

Dexamethasone treatment reduced the inflammatory score; however, it further impaired bone growth, accelerated chondrocyte apoptosis, and reduced the number of chondrocyte columns in huTNFTg mice. It is an important basic research study that tries to explain the mechanism of a very
well-known clinical observation of the effect of chronic inflammation on linear growth of children. We are also all aware of the effect of glucocorticoid on linear growth despite the positive effect it has on inflammation. The present manuscript emphasizes the need to develop a better tool to cope with chronic inflammations in children than the use of glucocorticoids.

Osteolectin increases bone elongation and body length by promoting growth plate
chondrocyte proliferation

Comments: Osteolectin is a recently identified osteogenic growth factor. By binding to integrin α11 and activation of the Wnt signaling pathway, it promotes osteogenic differentiation in the bone marrow stromal cells. It is not required for the formation of the skeleton during fetal development, but for the maintenance of adult bone mass [7]. Osteolectin was not previously known to play any role in the regulation of bone elongation or height.

In this study, the authors however show that osteolectin promotes chondrocyte proliferation and bone elongation, by activating integrin α11 and Wnt pathway. In addition, it was shown that recombinant osteolectin promotes bone elongation in experimental animals by activating the Wnt pathway in the chondrocytes of the growth plate. The importance of osteolectin in bone elongation and height is corroborated by data in humans. A single nucleotide variant associated with reduced height in humans was determined [8]. In addition, the role of this variant was tested in human bone marrow stromal cells. In these cells, osteolectin production was diminished and osteogenic differentiation decreased. Osteolectin seems to be another important mediator of endochondral ossification and a possible target for measures addressing growth also in humans.

Hepatic steatosis assessment as a new strategy for the metabolic and nutritional
management of Duchenne muscular dystrophy

Metabolic assessment in children with neuromuscular disorders shows risk of liver
enlargement, steatosis and fibrosis

Comments: Pediatric neuromuscular conditions encompass a spectrum of rare hereditary disor-
ders characterized by anomalous muscle structure and function, resulting in varying degrees of muscular weakness. Among these infrequent neuromuscular disorders, the most prevalent are Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). Predictably, as these conditions progress throughout childhood, throughout adolescence, and into adulthood, suboptimal nutritional status becomes commonplace. However, as the care of these young individuals advances, leading to improved survival rates, particularly with the implementation of disease-modifying therapies such as oral glucocorticoid treatment for DMD, a new set of nutritional challenges emerges. Within the context of DMD and SMA, emerging evidence highlights a notable concern: substantial weight gain leading to obesity, accompanied by components of the metabolic syndrome. Although limited literature exists on metabolic outcomes among young people with DMD, even scarcer data pertain to those with other rare neuromuscular conditions. Understanding these outcomes is essential for informing the development of condition-specific nutritional care standards for young individuals with neuromuscular disorders.

A study conducted by Tang et al. employed a cross-sectional design to explore metabolic syndrome occurrences in young individuals with DMD. The study encompassed anthropometric assessments, biochemical analyses, and hepatic steatosis imaging using ultrasound, with a specific focus on the Nakagami parametric index (NPI) as an indicator of hepatic steatosis severity (NPI >0.73 indicating moderate to severe steatosis). In a cohort of 42 DMD patients, 79% of whom were receiving glucocorticoid therapy, no differences in fasting glucose levels were observed across the ambulatory, early nonambulatory, and late ambulatory phases. Notably, the early nonambulatory phase exhibited the highest absolute body mass index in kg/m2. In the overall cohort, 38% exhibited a body mass index above the 85th percentile, and 41% displayed evidence of moderate to severe hepatic steatosis. Conversely, abnormal triglyceride levels were detected in only 14% of cases, whereas abnormal high-density lipoprotein levels, biochemical indications of insulin resistance based on the homeostatic model assessment for insulin resistance index, and abnormal fasting glucose were observed in 5, 5, and 0% of cases, respectively. No significant differences in metabolic parameters were discerned between those undergoing glucocorticoid treatment and those who were not, except for higher NPI values in ambulatory glucocor ticoid-treated patients compared to nonambulatory patients without glucocorticoid therapy. More recently, Naume et al. reported the outcomes of their cross-sectional study, which evaluated hepatic steatosis and fibrosis in a cohort of children encompassing 44 distinct neuromuscular conditions, including DMD (23 cases), SMA (11 cases), and various other conditions (merosin-deficient congenital muscular dystrophy, Charcot-Marie-Tooth neuropathy, Bethlem myopathy, giant axonal neuropathy, and GRIN2A mutation neuropathy). This investigation employed ultrasound for hepatic abnormality assessment and vibration-controlled transient elastography (FibroScan) to evaluate fibrosis. Among the entire cohort, hepatic involvement was noted in 31%, with DMD and SMA cases exhibiting hepatic involvement rates of 41 and 50%, respectively. Notably, no hepatic involvement was observed in the remaining neuromuscular conditions. Hepatic steatosis was identified in 5% of the overall cohort, with DMD and SMA cases accounting for 5 and 13%, respectively.

Both of these studies provide preliminary evidence of hepatic level metabolic irregularities in young individuals with neuromuscular conditions, particularly DMD and SMA. The authors propose the routine assessment of hepatic metabolic abnormalities as a component of the standard nutritional monitoring and management protocol. However, it is the opinion of the reviewer that further research is required before this recommendation can be integrated into clinical care standards. This necessitates large-scale studies, longitudinal investigations utilizing standardized outcome metrics, and an exploration of the clinical significance of these findings, including the impact of disease-modifying therapies and nutritional interventions. Nevertheless, these recent studies collectively contribute evidence supporting the presence of metabolic anomalies in the context of these conditions.

Assessment of body fat mass, anthropometric measurement and cardiometabolic
risk in children and adolescents with achondroplasia and hypochondroplasia

A scoping review of nutrition issues and management strategies in individuals with
skeletal dysplasia

Comments: Skeletal dysplasia encompasses a range of hereditary conditions that impede proper
skeletal growth, development, and structural integrity, leading to abnormal long bone growth, stature, and skeletal fragility. This diverse group comprises nearly 800 distinct diagnoses. While the primary issues manifest as increased fracture risk, notably in association with short stature, particularly disproportionate short stature, bone pain, and other skeletal complications, secondary nutritional concerns, particularly obesity, are common and can further exacerbate some skeletal complications. Among this heterogeneous and rare spectrum of disorders, the most prevalent entities are osteogenesis imperfecta (OI), achondroplasia, and hypochondroplasia. OI, colloquially known as brittle bone disease, constitutes a collection of genetic disorders heightening susceptibility to bone fractures. This spectrum of conditions extends beyond skeletal manifestations, affecting various bodily systems with varying severity. The genetic foundation of OI lies in mutations within genes like COL1A1 and COL1A2, accounting for approximately 90% of cases. These genes direct the synthesis of critical proteins for type I collagen assembly, vital to the structural integrity of bone, skin, and connective tissues. Achondroplasia, an autosomal dominant genetic disorder, is hall marked by dwarfism, characterized by shortened limbs in conjunction with a relatively normal length torso. The average adult stature in individuals with achondroplasia approximates 131 cm (4 ft 4 in) for males and 123 cm (4 ft) for females. This condition is attributed to mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, which disrupts the corresponding fibroblast growth factor receptor 3 protein’s role in collagen synthesis and other critical structural components. These mutations hinder
the interaction between the protein and growth factors, thereby hampering proper bone formation and culminating in a stature discrepancy due to incomplete cartilage-to-bone development.

Nakano et al. conducted a cross-sectional study involving 32 participants with achondroplasia and 10 with hypochondroplasia, aged 1.9–18.7 years. Nearly half of the subjects exhibited at least one cardiometabolic abnormality, with elevated systolic blood pressure being predominant. Notably, around 70% of patients received recombinant human growth hormone, which might influence metabolic profiles. Nevertheless, metabolic syndrome or type 2 diabetes mellitus did not develop in any participants.

Significant associations were noted between body mass index and standard deviation scores and hip:height ratio, correlated with body fat percentage measured by dual-energy X-ray absorptiometry. However, no statistically significant connections emerged between anthropometric measurements, body fat mass, and various cardiometabolic risk factors. Distinctive contrasts in these parameters were absent between groups with normal versus abnormal cardiometabolic profiles. Notably, body mass index Z-scores remained comparable between females with achondroplasia and hyochondroplasia, while in males, hypochondroplasia was associated with lower BMI Z-scores, albeit not statistically significant. The findings underscore the necessity of vigilant monitoring not only for weight gain and hip/height alterations but also encompassing a comprehensive evaluation of individual cardiometabolic risk factors.

These considerations are pivotal in the healthcare management of pediatric patients
afflicted with achondroplasia and hypochondroplasia, aiming to preempt potential cardiometabolic events. Furthermore, future research should explore suitable nutritional outcome measures, particularly those associated with or predictive of clinically significant metabolic outcomes in these young individuals. Billich et al. conducted a scoping review on nutritional outcomes and intervention in young people with skeletal dysplasia. A comprehensive search was conducted across multiple databases, including Ovid MEDLINE, Ovid EMBASE, Ebsco CINAHL, Scopus, and the Cochrane Central Register of Controlled Trials and Database of Systematic Reviews. Supplementary searches encompassed perusal of reference lists and citations within the included studies. The inclusion criteria involved studies featuring participants with skeletal dysplasia, focusing on elucidating aspects such as anthropometry, body composition, nutrition-related biochemistry, clinical manifestations, dietary intake, quantified energy or nutrition requisites, and nutritional interventions. A detailed exploration of the literature yielded a total of 8,509 references, subsequently leading to the inclusion of 138 studies in the analysis. The compiled dataset comprised 130 observational studies, 3 intervention studies, 2 systematic reviews, and 3 clinical guidelines. Spanning across a spectrum of 17 distinct diagnoses, the studies predominantly revolved around OI (n = 50) and achondroplasia or hypochondroplasia (n = 47). Prevailing subjects of investigation included nutrition-linked clinical concerns, biochemical aspects, obesity, and metabolic intricacies. Remarkably, a limited number of studies (n = 5) broached the assessment of energy requirements. Specifically, none of the studies in achondroplasia and/or hypochondroplasia or OI have conducted research into total energy expenditure, which is key to developing evidence-based guidelines for nutritional intake. This comprehensive scoping review into the area of nutrition in people with skeletal dysplasia underscored the documented presence of nutrition-related comorbidities. Nevertheless, the dearth of substantial evidence for guiding effective management strategies remains conspicuous.

Notably, a discernible gap exists in the literature concerning the nutritional facets of less common skeletal dysplasia conditions. Thus, the imperative to propel advances in our understanding of skeletal dysplasia nutrition cannot be overstated, as it stands to optimize broader health outcomes within this population. A key area of research of priority is on the nutritional outcome measure to be used to delineate increased fat mass in children and adolescents with significant short stature given potential limitations of BMI. In particular, research into energy expenditure, especially total energy expenditure, is much needed to develop nutritional guidelines that are catered to this
population.

The crosstalk between FGF21 and GH leads to weakened GH receptor signalling
and IGF1 expression and is associated with growth failure in very preterm infants

Comments: Fibroblast growth factor 21 (FGF21), a liver-secreted peptide hormone encoded by
the FGF21 gene in humans, constitutes a member of the endocrine subgroup within the fibroblast growth factor (FGF) family, accompanied by FGF19 (FGF15 in rodents) and FGF23. FGF21 functions as a potent extracellular metabolic regulator, its significance having been initially unveiled through in vitro phenotypic screening and rodent-based diet manipulation studies. Its beneficial impact extends to the orchestration of lipid, glucose, and energy metabolism. While the peptide finds synthesis across various organs and tissues, its primary production site is the liver, with secretion responsive to stress or dietary cues, encompassing caloric or protein intake. The modality of FGF21’s function hinges upon the context of its production and target sites, encompassing autocrine, paracrine, or endocrine modes. Recent investigations highlight FGF21’s pivotal role in mediating growth impairment in chronic conditions, particularly its involvement in growth plate growth hormone (GH) resistance. In infants born very preterm (<32 weeks gestation), an initial growth deceleration phase after birth is succeeded by a period of catch-up growth. However, the precise mechanistic underpinnings of this growth pattern, especially the interplay of FGF21 with the GH receptor and downstream GH signaling pathways, remain incompletely elucidated.

Mistry et al. developed an in vitro model employing GH and FGF21-responsive HEK-
293 cells, revealing that FGF21 intensified GH-induced GH receptor turnover and augmented SOCS2 expression, consequently inhibiting STAT5 phosphorylation. This observation was validated in a clinical study where circulating FGF21 surged during the growth deceleration phase in infants born very preterm, subsequently receding during the catch-up growth period. Notably, in this clinical context, circulating FGF21 levels exhibited an inverse correlation with length velocity and circulating IGF1 levels. The intricate interplay between factors such as nutrition, inflammation, infection, and FGF21 may offer avenues for interventions aimed at enhancing growth and nutritional status in the highly vulnerable population of infants born very preterm.

The gut microbiome and early-life growth in a population with high prevalence of
stunting

Comments: Globally, stunting stands as a consequential clinical challenge marked by significant impacts on critical outcomes such as infectious disease–related morbidity, diminished childhood survival rates, and impaired cognitive function. While nutritional deficiencies contribute to stunting, research into nutritional interventions has yielded only modest improvements, with rates of stunting barely surpassing a 10% reduction. This implies the involvement of other mechanisms underlying this condition. Recent focus has shifted toward investigating the influence of gut microbiota on outcomes like stunting; however, studies assessing the composition and functional maturation
of gut microbiota in relation to stunting remain scarce.

In a study employing comprehensive metagenomic sequencing, Robertson et al. meticulously elucidated the developmental trajectory of the gut microbiome in a cohort of 335 children aged 1–18 months from rural Zimbabwe. This study unfolded within the framework of the Sanitation, Hygiene, Infant Nutrition Efficacy Trial (SHINE; NCT01824940), a randomized trial scrutinizing augmented water, sanitation, and hygiene practices, alongside infant and young child feeding interventions. The study’s findings underscore that the early-life gut microbiome follows a programmed assembly pattern, resilient to alterations through the randomized interventions targeting linear growth enhancement. Intriguingly, maternal HIV infection emerges as a factor
associated with heightened diversification and early maturation of the early-life gut microbiome in their noninfected offspring, alongside a depletion of Bifidobacterium species. Employing machine learning models, specifically XGBoost, the authors establish that taxonomic microbiome attributes exhibit limited predictive capability for child growth. However, the predictive potential of functional metagenomic attributes, particularly pathways linked to B vitamin and nucleotide biosynthesis, emerge as a moderate predictor of both linear and ponderal growth, as well as growth velocity. These findings suggest that innovative strategies targeting the gut microbiome during early childhood could serve as a promising complement to ongoing initiatives addressing child undernutrition globally. Importantly, the impact of HIV exposure on infant gut microbiota remains a significant and enigmatic aspect, warranting further dedicated investigation and exploration of potential effective intervention.

The effect of a nutritional supplement on growth and body composition in short
and lean preadolescent boys following one-year of intervention

Comments: The present study again stresses the point of the importance of adequate nutrition to
linear growth even where food shortage does not exist. It is important to remember that even in privileged areas where shortrange of food is not an issue, there are children and adolescents who might benefit from more attention to their diet requirements. It is important to emphasize that prospective randomized double-blind studies in preadolescents children are scarce and of significance.

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