The Physiology and Mechanism of Growth

Introduction

In the present chapter, an international group of endocrinologists tried to select some of the most important articles dealing with the physiology of growth published in the period from July 1, 2020 to June 30, 2021. We specially looked for articles that shed more light on the already known mechanisms related to linear growth and those dealing with the interaction between nutrition and growth. We have tried our best to select some of the best manuscripts published in the specific period on this topic. We are aware of the possibility that we might have missed some other very important manuscripts, but hope that reading the chapter, the summary of the abstracts, and the comments of the authors will encourage the reader to explore the literature for more relevant publications.

Familial short stature – a novel phenotype of growth plate collagenopathies

Comments: Collagens have an important role in growth plate structure and function where they participate in the regulation of cell growth, differentiation, and migration. Mutations in various collagen genes are associated with well-defined syndromic bone dysplasia. Although there can be significant clinical heterogeneity in bone dysplasia caused by mutations in the collagen genes, pronounced short stature with obvious skeletal deformities are typically present. Mutations in genes encoding various collagen molecules were however also determined in non-syndromic short stature in a relatively high percentage [1]. In these patients, short stature was the main clinical feature, with additional only mild clinical signs. In the present study, the role of growth hormone treatment in so-called oligosymptomatic familial short stature was studied and determined as effective, by significantly and safely increasing growth velocity. Further epidemiological studies to determine prevalence of oligosymptomatic collagenopathies in other populations are needed. Although results from longer follow-up studies are needed, since growth use of up to only 3 years is provided, the data presented in this manuscript suggest the use of growth hormone as efficient and safe in children with growth plate collagenopathies. These data further suggest the importance of genetic analysis in ISS children for everyday clinical practice. By determining the genetic cause of ISS one can better discuss possible treatment approaches in ISS children.

Assessment of longitudinal bone growth in osteogenesis imperfecta using metacarpophalangeal pattern profiles

Comments: Decreased growth velocity and decreased final height are important and frequent comorbidities of osteogenesis imperfecta (OI). Short stature in OI is linked to postfracture deformities in weight-bearing limbs and the vertebra. Patients with the most severe types of OI are the most affected. Shorter stature can, however, also be present in less severe types of OI, even if the disease is treated efficiently in regard to decreased frequency and severity of fractures [2]. Defects in the mechanisms of longitudinal growth could therefore be the direct cause of shorter stature in OI. Possible direct effects of OI on longitudinal growth was studied in metacarpal and phalangeal bones of OI type I, III, and IV patients, since these bones are rarely affected by fractures and deformities in these individuals. Hand bone length was most affected in OI type III and the least in OI type I. Interestingly, hand bone length associated positively with height. These data therefore further identify collagens as important players in directly influencing longitudinal growth, most probably by their role in the growth plate. This is not important only from the point of view of better understanding of the physiology of growth, but also for the development of novel therapeutic practices in OI in regard to short stature. It has recently been reported that the use of growth hormone was effective and safe in short children with collagenopathies [1].

PTHrP targets salt-inducible kinases, HDAC4 and HDAC5, to repress chondrocyte hypertrophy in the growth plate

Comments: Unravelling the mechanisms involved in the process of endochondral ossification and senescence is the key to in-depth understanding of longitudinal growth. By elucidating these processes novel diagnostic methods and more targeted therapeutic intervention in idiopathic short stature can be engineered. Recently, it was determined that parathyroid hormone-related protein (PTHrP), better known for causing hypercalcemia in cancer patients, inhibits chondrocyte hypertrophy. This is a crucial step in the process of endochondral bone formation, in which the differentiation program is switched from chondrocyte differentiation to bone formation. PTHrP achieves this by affecting the expression of histone deacetylase 4 (HDAC4) and HDAC5 [3]. In humans, haploinsufficiency of PTHRP or HDAC4 causes the skeletal dysplasia and brachydactyly type E, therefore strengthening the role of this signaling pathway in bone formation in and suggesting a functional linkage between PTHrP and HDAC4. In this study, using multiple genetic mouse models, mechanisms by which PTHrP inhibits chondrocyte hypertrophy were further determined. It was established that PTHrP inhibits the key transcription factors (Mef2 and Runx2) that promote chondrocyte hypertrophy. HDAC4 and 5 play a role in mediating these actions.

Secondary ossification center induces and protects growth plate structure

Comments: When studying growth failure most attention is focused on the growth plate. In its early development, however, the growth plate constitutes a single anatomic entity with a structure that is later responsible for an altogether different purpose, namely the articular cartilage. These two structures are separated by the so-called secondary ossification center (SOC). In this manuscript the role the SOC might have on the development and function of the growth plate was studied by different approaches. It was determined that the SOC developed during evolution in correlation to the mechanical load species had to endure. Both mathematical modelling and functional
experiments showed that SOC has a role in reducing the mechanical load on the growth plate, especially in relation to the sensitivity of the hypertrophic chondrocytes in the growth plate to mechanical stress. These data are, therefore, of importance also from the point of view of physiology and mechanisms of growth. The role of mechanical stress, or lack of it, on longitudinal growth was studied in children practicing
sports and in physically inactive children, for example with severe neuromuscular disabilities [4]. Defects in SOC structure or function could have a role in reduced or uneven longitudinal growth in children practicing heavy or repetitive weight-bearing sports (e.g., repeated jumping). The type of relationship between the SOC and growth plate function and structure in children with lack of mechanical loading could also be studied.

Axial mechanical loading to ex vivo mouse long bone regulates endochondral ossification and endosteal mineralization through activation of the BMP-Smad pathway during postnatal growth

Comments: The role of mechanical loading on bone development, specifically the regulatory mechanisms underlying endochondral ossification and endosteal mineralization, were studied in this paper. In an ex vivo organ culture model the metacarpal mice bones were exposed to mechanical loading. Mechanical loading regulated the thickness of the calcified zone in the growth plate and endosteal mineralization in the diaphysis in a load-dependent manner and resulted in load-dependent upregulation of endochondral ossification and bone mineralization-related genes, including bone morphogenetic protein 2 (BMP-2). BMP-2 administration caused similar changes in
tissue structures, whereas inhibition of the BMP-Smad pathway diminished the stimulatory effects of mechanical loading and BMP-2 administration. It was also determined that mechanical loading increased alkaline phosphatase activity and decreased carbonic anhydrase IX (Car9) mRNA expression, resulting in a significant pH increase in the culture supernatant. The authors hypothesize that mechanical loading activated the BMP-Smad pathway, which downregulated expression of Car9, the result being alkalization of the local milieu, thereby inducing bone formation and long bone mineralization. These findings advance our understanding of the regulation of
mineralization mechanisms by mechanical loading mediated through activation of the BMP-Smad pathway.

H3K36 methyltransferase NSD1 regulates chondrocyte differentiation for skeletal development and fracture repair

Comments: Chondrocyte differentiation in the growth plate is a critical process for endochondral ossification, which is responsible for long bone development. Sex-determining region Y box 9 (Sox9) is the key transcription factor of chondrogenic differentiation. The role of epigenetic modifications of this process was studied in the present manuscript. Mono- and dimethylation of histone H3 at lysine 36 (H3K36) has an important role during chondrogenic differentiation and cartilage development. Variations in the nuclear receptor binding SET domain-containing protein 1 (NSD1), a methyltransferase that catalyzes H3K36, cause Sotos syndrome. Characteristics of this syndrome are increased bone growth during infancy and childhood and normal height after puberty. It was determined that Sox9 is a functional target gene of NSD1, as it modulates H3K36 levels in the Sox9 promoter region. In addition, it was shown that NSD1 directly activates the expression of hypoxia-inducible factor 1α (HIF1α), which plays a vital role in chondrogenic differentiation through its regulation of Sox9 expression. It was therefore determined that NSD1 has a key role in chondrogenic differentiation and skeletal growth. These data further acknowledge the importance of epigenetic mechanisms in the control of longitudinal growth and modulation of NSD1 as potential treatment targets in short stature.

Early detection of abnormal growth associated with juvenile acquired hypothyroidism

Comments: In the present retrospective study, the authors tried to characterize longitudinal growth patterns up to 5 years prior to juvenile acquired hypothyroidism (JHT) diagnosis, and tested the performance of auxological screening for the condition. The authors compared growth patterns of 109 children and adolescents diagnosed with JHT with 10,900 age- and sex-matched controls. They indeed demonstrated that growth pattern and growth parameters are a powerful tool to diagnose JHT. They found that, at diagnosis, JHT patients were significantly shorter and heavier than healthy controls. The most pronounced difference was seen in linear height growth during the 1-year period preceding JHT diagnosis. Growth monitoring programs are available in countries where public medical services are developed. Nowadays, growth monitoring programs start already during fetal life, followed by regular measurements during infancy, childhood, and adolescence. Interrupted growth pattern is a very potent screening tool for many different medical and socio- psychological conditions. If a pediatrician is allowed to take a single tool to an isolated island (such as a stethoscope or otoscope, etc.) it is the growth chart that he/she should carry because of the important clinical information it can provide to a knowledgeable pediatrician. Celiac, hypothyroidism, malabsorption, eating disorders, growth hormone deficiency, and Cushing disease are just a short list of the potential situations where the growth chart can help the clinician make an early diagnosis of an important problem that a child might experience. Indeed, growth monitoring programs are not available in many places around the world. However, from the recent experience that many pediatricians have accumulated during the COVID-19 pandemic, home measurements of height can be made pretty accurately by parents at home that may serve as a screening program for detecting normal growth deviations [5].

References
1 Plachy L, Strakova V, Elblova L, Obermannova B, Kolouskova S, Snajderova M, et al. High prevalence of growth plate gene variants in children with familial short stature treated with growth hormone. J Clin Endocrinol Metab. 2019;104:4273–81.
2 Deguchi M, Tsuji S, Katsura D, Kasahara K, Kimura F, Murakami T. Current overview of osteogenesis imperfecta. Medicina. 2021;57:464.
3 Nishimori S, Lai F, Shiraishi M, Kobayashi T, Kozhemyakina E, Yao TP, et al. PTHrP targets HDAC4 and HDAC5 to repress chondrocyte hypertrophy. JCI Insight. 2019;4:e97903.
4 Mirtz TA, Chandler JP, Eyers CM. The effects of physical activity on the epiphyseal growth plates: a review of the literature on normal physiology and clinical implications. J Clin Med Res. 2011;3:1–7.
5 Tenenbaum A, Shefer-Averbuch N, Lazar L, Yakobovitch- Gavan M, Phillip M, Oron T. Growth assessment of children during the COVID-19 pandemic – can we rely on parental measurements? Acta Paediatr. 2021;110:3040–5.