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      The growth plate: a physiologic overview

      review-article
      1
      EFORT Open Reviews
      British Editorial Society of Bone and Joint Surgery
      bone growth, chondrodysplasia, growth plate, physis

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          Abstract

          • The growth plate is the cartilaginous portion of long bones where the longitudinal growth of the bone takes place. Its structure comprises chondrocytes suspended in a collagen matrix that go through several stages of maturation until they finally die, and are replaced by osteoblasts, osteoclasts, and lamellar bone.

          • The process of endochondral ossification is coordinated by chondrocytes and a variety of humoral factors including growth hormone, parathyroid hormone, oestrogen, growth factors, cytokines, and various signalling pathways.

          • Chondrocytes progress from a resting state to enter the phases of proliferation and hypertrophy. Under the influence of oestrogen, the proliferation of chondrocytes decreases as the resting chondrocytes are consumed. During the terminal phase of differentiation, cartilage is replaced by blood vessels and organized bone tissue, and once chondrocytes have died, the longitudinal growth of the bone ceases and the growth plate closes.

          • The highly complex regulatory signals involved in this process are genetically determined, and genetic perturbations in any of the associated genes can result in abnormalities of bone growth. Hundreds of chondrodysplasias have been described, pointing to the complexity of the humoral control systems involved in endochondral ossification.

          • While our knowledge of the mechanisms behind the various bone growth control systems is improving, a deeper understanding of the underlying processes could aid clinicians to better understand bone health and bone growth abnormalities. This review describes the current clinical research into the physiology of the growth plate.

          Cite this article: EFORT Open Rev 2020;5:498-507. DOI: 10.1302/2058-5241.5.190088

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          Most cited references48

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          The skeleton: a multi-functional complex organ: the growth plate chondrocyte and endochondral ossification.

          Endochondral ossification is the process that results in both the replacement of the embryonic cartilaginous skeleton during organogenesis and the growth of long bones until adult height is achieved. Chondrocytes play a central role in this process, contributing to longitudinal growth through a combination of proliferation, extracellular matrix (ECM) secretion and hypertrophy. Terminally differentiated hypertrophic chondrocytes then die, allowing the invasion of a mixture of cells that collectively replace the cartilage tissue with bone tissue. The behaviour of growth plate chondrocytes is tightly regulated at all stages of endochondral ossification by a complex network of interactions between circulating hormones (including GH and thyroid hormone), locally produced growth factors (including Indian hedgehog, WNTs, bone morphogenetic proteins and fibroblast growth factors) and the components of the ECM secreted by the chondrocytes (including collagens, proteoglycans, thrombospondins and matrilins). In turn, chondrocytes secrete factors that regulate the behaviour of the invading bone cells, including vascular endothelial growth factor and receptor activator of NFκB ligand. This review discusses how the growth plate chondrocyte contributes to endochondral ossification, with some emphasis on recent advances.
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            SOX9 enhances aggrecan gene promoter/enhancer activity and is up-regulated by retinoic acid in a cartilage-derived cell line, TC6.

            SOX9 is a transcription factor that plays a key role in chondrogenesis. Aggrecan is one of the major structural components in cartilage; however, the molecular mechanism of aggrecan gene regulation has not yet been fully elucidated. TC6 is a clonal chondrocytic cell line derived from articular cartilage. The purpose of this study was to examine whether SOX9 modulates aggrecan gene expression and to further identify molecules that regulate Sox9 expression in TC6 cells. SOX9 overexpression in TC6 cells enhanced by approximately 3-fold the transcriptional activity of the AgCAT-8 construct containing 8-kilobase (kb) promoter/first exon/first intron fragments of the aggrecan gene. SOX9 enhancement of aggrecan promoter activity was lost when we deleted a 4.5-kb fragment from the 3'-end of the 8-kb fragment corresponding to the region including the first intron. In TC6 cells, SOX9 enhanced the transcriptional activity of a reporter construct containing the Sry/Sox consensus sequence >10-fold. SOX9 enhancement of aggrecan gene promoter activity and SOX9 transactivation through the Sry/Sox consensus sequence were not observed in osteoblastic osteosarcoma cells (ROS17/2.8), indicating the dependence on the cellular background. Northern blot analysis indicated that TC6 cells constitutively express Sox9 mRNA at relatively low levels. To examine regulation of Sox9 gene expression, we investigated the effects of calciotropic hormones and cytokines. Among these, retinoic acid (RA) specifically enhanced Sox9 mRNA expression in TC6 cells. The basal levels of Sox9 expression and its enhancement by RA were observed similarly at both permissive (33 degrees C) and nonpermissive (39 degrees C) temperatures. Furthermore, RA treatment enhanced the transcriptional activity of a reporter construct containing the Sry/Sox consensus sequence in TC6 cells. Moreover, RA treatment also enhanced the transcriptional activity of another reporter construct containing the enhancer region of the type II procollagen gene in TC6 cells. These observations indicate that SOX9 enhances aggrecan promoter activity and that its expression is up-regulated by RA in TC6 cells.
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              Systemic and local regulation of the growth plate.

              The growth plate is the final target organ for longitudinal growth and results from chondrocyte proliferation and differentiation. During the first year of life, longitudinal growth rates are high, followed by a decade of modest longitudinal growth. The age at onset of puberty and the growth rate during the pubertal growth spurt (which occurs under the influence of estrogens and GH) contribute to sex difference in final height between boys and girls. At the end of puberty, growth plates fuse, thereby ceasing longitudinal growth. It has been recognized that receptors for many hormones such as estrogen, GH, and glucocorticoids are present in or on growth plate chondrocytes, suggesting that these hormones may influence processes in the growth plate directly. Moreover, many growth factors, i.e., IGF-I, Indian hedgehog, PTHrP, fibroblast growth factors, bone morphogenetic proteins, and vascular endothelial growth factor, are now considered as crucial regulators of chondrocyte proliferation and differentiation. In this review, we present an update on the present perception of growth plate function and the regulation of chondrocyte proliferation and differentiation by systemic and local regulators of which most are now related to human growth disorders.
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                Author and article information

                Journal
                EFORT Open Rev
                EFORT Open Rev
                EFORT Open Reviews
                British Editorial Society of Bone and Joint Surgery
                2058-5241
                August 2020
                10 September 2020
                : 5
                : 8
                : 498-507
                Affiliations
                [1 ]Department of Orthopaedics and Traumatology, İzzet Baysal State Hospital, Bolu, Turkey
                Author notes
                [*]Yücel Ağırdil, Department of Orthopaedics and Traumatology, İzzet Baysal State Hospital, Bolu, Turkey. Email: yucelagirdil@ 123456gmail.com
                Article
                10.1302_2058-5241.5.190088
                10.1302/2058-5241.5.190088
                7484711
                32953135
                a6348cd7-cb83-44ab-b009-e24455990d98
                © 2020 The author(s)

                This article is distributed under the terms of the Creative Commons Attribution-Non Commercial 4.0 International (CC BY-NC 4.0) licence ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed.

                History
                Categories
                Paediatrics
                9
                Bone Growth
                Chondrodysplasia
                Growth Plate
                Physis

                bone growth,chondrodysplasia,growth plate,physis
                bone growth, chondrodysplasia, growth plate, physis

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