Bortezomib Is Cytotoxic to the Human Growth Plate and Permanently Impairs Bone Growth in Young Mice

For most bones, elongation is driven primarily by chondrogenesis at the growth plates. This process results from chondrocyte proliferation, hypertrophy, and extracellular matrix secretion, and it is carefully orchestrated by complex networks of local paracrine factors and modulated by endocrine factors. We review here recent advances in the understanding of growth plate physiology. These advances include new approaches to study expression patterns of large numbers of genes in the growth plate, using microdissection followed by microarray. This approach has been combined with genome-wide association studies to provide insights into the regulation of the human growth plate. We also review recent studies elucidating the roles of bone morphogenetic proteins, fibroblast growth factors, C-type natriuretic peptide, and suppressor of cytokine signaling in the local regulation of growth plate chondrogenesis and longitudinal bone growth.

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Radial shockwave treatment promotes chondrogenesis in human growth plate and longitudinal bone growth in rabbits

Bone ◽

10.1016/j.bone.2021.116186 ◽

2022 ◽

Vol 154 ◽

pp. 116186

Author(s):

Sowmya Ramesh ◽

Farasat Zaman ◽

Lars Sävendahl ◽

Vrisha Madhuri

Keyword(s):

Growth Plate ◽

Bone Growth ◽

Human Growth ◽

Longitudinal Bone Growth

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Expression of aromatase in the human growth plate

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0270249 ◽

2001 ◽

Vol 27 (2) ◽

pp. 249-253 ◽

Cited By ~ 44

Author(s):

OK Oz ◽

R Millsaps ◽

R Welch ◽

J Birch ◽

JE Zerwekh

Keyword(s):

Growth Plate ◽

Bone Growth ◽

Human Growth ◽

Adolescent Male ◽

Long Bone ◽

Rt Pcr ◽

Chain Reaction ◽

Growth Plates ◽

Estrogen Production ◽

Polymerase Chain

Aromatase catalyzes the synthesis of estrogen from its androgen precursors. Estrogen is known to be important in regulating long bone growth and epiphyseal plate closure. To assess whether there may be growth plate-specific production of estrogen, we performed reverse transcriptase polymerase chain reaction (RT-PCR) to determine whether aromatase transcripts are present in the human growth plate. Immunohistochemistry was also employed to identify the specific sites of expression. Growth plates were obtained from an adolescent male and female undergoing ephysectomy to counter premature growth plate closure in the opposite leg. Aromatase transcripts were detected in RNA preparations from both growth plates. The aromatase protein was mainly expressed in the zone of maturation and the hypertrophic zone, with greatest expression in the latter. Since estrogen receptors are known to be expressed in chondrocytes, this data is consistent with a role for local estrogen production in the autocrine/paracrine control of long bone growth and growth plate maturation.

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Genome-wide screening in human growth plates during puberty in one patient suggests a role for RUNX2 in epiphyseal maturation

Journal of Endocrinology ◽

10.1530/joe-10-0219 ◽

2011 ◽

Vol 209 (2) ◽

pp. 245-254 ◽

Cited By ~ 3

Author(s):

Joyce Emons ◽

Bas E Dutilh ◽

Eva Decker ◽

Heide Pirzer ◽

Carsten Sticht ◽

...

Keyword(s):

Transcription Factors ◽

Growth Plate ◽

Bone Growth ◽

Target Genes ◽

Morphological Changes ◽

Human Growth ◽

Tanner Stage ◽

Plate Height ◽

Promoter Regions ◽

Evolutionarily Conserved

In late puberty, estrogen decelerates bone growth by stimulating growth plate maturation. In this study, we analyzed the mechanism of estrogen action using two pubertal growth plate specimens of one girl at Tanner stage B2 and Tanner stage B3. Histological analysis showed that progression of puberty coincided with characteristic morphological changes: a decrease in total growth plate height (P=0.002), height of the individual zones (P<0.001), and an increase in intercolumnar space (P<0.001). Microarray analysis of the specimens identified 394 genes (72% upregulated and 28% downregulated) that changed with the progression of puberty. Overall changes in gene expression were small (average 1.38-fold upregulated and 1.36-fold downregulated genes). The 394 genes mapped to 13 significantly changing pathways (P<0.05) associated with growth plate maturation (e.g. extracellular matrix, cell cycle, and cell death). We next scanned the upstream promoter regions of the 394 genes for the presence of evolutionarily conserved binding sites for transcription factors implicated in growth plate maturation such as estrogen receptor (ER), androgen receptor, ELK1, STAT5B, cyclic AMP response element (CREB), and RUNX2. High-quality motif sites for RUNX2 (87 genes), ELK1 (43 genes), and STAT5B (31 genes), but not ER, were evolutionarily conserved, indicating their functional relevance across primates. Moreover, we show that some of these sites are direct target genes of these transcription factors as shown by ChIP assays.

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Effects of the selective GPER1 agonist G1 on bone growth

Endocrine Connections ◽

10.1530/ec-19-0274 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1302-1309 ◽

Cited By ~ 2

Author(s):

Maryam Iravani ◽

Marie K Lagerquist ◽

Elham Karimian ◽

Andrei S Chagin ◽

Claes Ohlsson ◽

...

Keyword(s):

Growth Plate ◽

Bone Growth ◽

Ex Vivo ◽

Human Growth ◽

Growth Plate Chondrocytes ◽

Metatarsal Bones ◽

Ligand Stimulation ◽

G Protein Coupled ◽

Estrogen Receptor 1

Estrogens may affect bone growth locally or systemically via the known estrogen receptors ESR1, ESR2 and G protein-coupled estrogen receptor 1 (GPER1). Mouse and human growth plate chondrocytes have been demonstrated to express GPER1 and ablation of this receptor increased bone length in mice. Therefore, GPER1 is an attractive target for therapeutic modulation of bone growth, which has never been explored. To investigate the effects of activated GPER1 on the growth plate, we locally exposed mouse metatarsal bones to different concentrations of the selective GPER1 agonist G1 for 14 days ex vivo. The results showed that none of the concentrations of G1 had any direct effect on metatarsal bone growth when compared to control. To evaluate if GPER1 stimulation may systemically modulate bone growth, ovariectomized C57BL/6 mice were treated with G1 or β-estradiol (E2). Similarly, G1 did not influence tibia and femur growth in treated mice. As expected, E2 treatment suppressed bone growth in vivo. We conclude that ligand stimulation of GPER1 does not influence bone growth in mice.

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DEVELOPMENTAL SCENARIOS OF THE EPIPHYSIS AND GROWTH PLATE UPON MECHANICAL LOADING: A COMPUTATIONAL MODEL

Journal of Mechanics in Medicine and Biology ◽

10.1142/s0219519416500986 ◽

2016 ◽

Vol 16 (07) ◽

pp. 1650098

Author(s):

JOHANA MARIA GUEVARA ◽

MARIA LUCIA GUTIERREZ GOMEZ ◽

LUIS ALEJANDRO BARRERA LA ◽

DIEGO ALEXANDER GARZÓN-ALVARADO

Keyword(s):

Growth Plate ◽

Computational Models ◽

Bone Growth ◽

Bone Development ◽

Human Growth ◽

Relevant Information ◽

Biological Behavior ◽

Long Bone ◽

Mechanical Stimuli

Long bone growth relies on the continuous bone formation from cartilaginous tissue (endochondral ossification). This process starts in the central region (diaphysis) of the forming bone and short before birth, ossification starts in bone extremes (epiphysis). A cartilaginous region known as the growth plate is maintained until adolescence between epiphysis and diaphysis to further contribute to longitudinal growth. Even though there are several biochemical factors controlling this process, there is evidence revealing an important regulatory role of mechanical stimuli. Up to now approaches to understand mechanical effects on ossification have been limited to epiphysis. In this work, based on Carter's mathematical model for epiphyseal ossification, we explored human growth plate response to mechanical loads. We analyzed growth plate stress distribution using finite element method for a generic bone considering different stages of bone development in order to shed light on mechanical contribution to growth plate function. Results obtained revealed that mechanical environment within the growth plate change as epiphyseal ossification progresses. Furthermore, results were compared with physiological behavior, as reported in literature, to analyze the role of mechanical stimulus over development. Our results suggest that mechanical stimuli may play different regulation roles on growth plate behavior through normal long bone development. However, as this approach only took into account mechanical aspects, failed to accurately predict biological behavior in some stages. In order to derive biologically relevant information from computational models it is necessary to consider biological contribution and possible mechanical–biochemical interactions affecting human growth plate physiology. Along these lines, we propose the dilatatorial parameter k used by Carter et al. should assume different values corresponding to the developmental stage in question. Thus, reflecting biochemical contribution changes over time.

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