scholarly journals Systemic and Local Regulation of the Growth Plate

2003 ◽  
Vol 24 (6) ◽  
pp. 782-801 ◽  
Author(s):  
B. C. J. van der Eerden ◽  
M. Karperien ◽  
J. M. Wit
Keyword(s):  
Growth Factors ◽  
Growth Plate ◽  
Final Height ◽  
Age At Onset ◽  
Longitudinal Growth ◽  
Growth Spurt ◽  
Growth Disorders ◽  
Growth Plate Chondrocytes ◽  
Chondrocyte Proliferation ◽  
Proliferation And Differentiation

Abstract 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.

scholarly journals Nuclear Factor-κB p65 Facilitates Longitudinal Bone Growth by Inducing Growth Plate Chondrocyte Proliferation and Differentiation and by Preventing Apoptosis

2007 ◽  
Vol 282 (46) ◽  
pp. 33698-33706 ◽  
Author(s):  
Shufang Wu ◽  
Janna K. Flint ◽  
Geoffrey Rezvani ◽  
Francesco De Luca
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Chondrocyte Apoptosis ◽  
Pyrrolidine Dithiocarbamate ◽  
Growth Plate Chondrocytes ◽  
Chondrocyte Proliferation ◽  
Longitudinal Bone Growth ◽  
Metatarsal Bones ◽  
Proliferation And Differentiation ◽  
Cultured Chondrocytes

NF-κB is a group of transcription factors involved in cell proliferation, differentiation, and apoptosis. Mice deficient in the NF-κB subunits p50 and p52 have retarded growth, suggesting that NF-κB is involved in bone growth. Yet, it is not clear whether the reduced bone growth of these mice depends on the lack of NF-κB activity in growth plate chondrocytes. Using cultured rat metatarsal bones and isolated growth plate chondrocytes, we studied the effects of two NF-κB inhibitors (pyrrolidine dithiocarbamate (PDTC) or BAY11-7082 (BAY)), p65 short interference RNA (siRNA), and of the overexpression of p65 on chondrocyte proliferation, differentiation, and apoptosis. To further define the underlying mechanisms, we studied the functional interaction between NF-κB p65 and BMP-2 in chondrocytes. PDTC and BAY suppressed metatarsal linear growth. Such growth inhibition resulted from decreased chondrocyte proliferation and differentiation and from increased chondrocyte apoptosis. In cultured chondrocytes, the inhibition of NF-κB p65 activation (by PDTC and BAY) and expression (by p65 siRNA) led to the same findings observed in cultured metatarsal bones. In contrast, overexpression of p65 in cultured chondrocytes induced chondrocyte proliferation and differentiation and prevented apoptosis. Although PDTC, BAY, and p65 siRNA reduced the expression of BMP-2 in cultured growth plate chondrocytes, the overexpression of p65 increased it. The addition of Noggin, a BMP-2 antagonist, neutralized the stimulatory effects of p65 on chondrocyte proliferation and differentiation, as well as its anti-apoptotic effect. In conclusion, our findings indicate that NF-κB p65 expressed in growth plate chondrocytes facilitates growth plate chondrogenesis and longitudinal bone growth by inducing BMP-2 expression and activity.

scholarly journals G-Protein-Coupled Estrogen Receptor-1 Positively Regulates the Growth Plate Chondrocyte Proliferation in Female Pubertal Mice

2021 ◽  
Vol 9 ◽  
Author(s):  
Ya-Shuan Chou ◽  
Shu-Chun Chuang ◽  
Chung-Hwan Chen ◽  
Mei-Ling Ho ◽  
Je-Ken Chang
Keyword(s):  
Estrogen Receptor ◽  
G Protein ◽  
Growth Plate ◽  
Longitudinal Growth ◽  
Long Bone ◽  
Early Puberty ◽  
Growth Plate Chondrocytes ◽  
Chondrocyte Proliferation ◽  
G Protein Coupled ◽  
Estrogen Receptor 1

Estrogen enhances long bone longitudinal growth during early puberty. Growth plate chondrocytes are the main cells that contribute to long bone elongation. The role of G-protein-coupled estrogen receptor-1 (GPER-1) in regulating growth plate chondrocyte function remains unclear. In the present study, we generated chondrocyte-specific GPER-1 knockout (CKO) mice to investigate the effect of GPER-1 in growth plate chondrocytes. In control mice, GPER-1 was highly expressed in the growth plates of 4- and 8-week-old mice, with a gradual decline through 12 to 16 weeks. In CKO mice, the GPER-1 expression in growth plate chondrocytes was significantly lower than that in the control mice (80% decrease). The CKO mice also showed a decrease in body length (crown–rump length), body weight, and the length of tibias and femurs at 8 weeks. More importantly, the cell number and thickness of the proliferative zone of the growth plate, as well as the thickness of primary spongiosa and length of metaphysis plus diaphysis in tibias of CKO mice, were significantly decreased compared with those of the control mice. Furthermore, there was also a considerable reduction in the number of proliferating cell nuclear antigens and Ki67-stained proliferating chondrocytes in the tibia growth plate in the CKO mice. The chondrocyte proliferation mediated by GPER-1 was further demonstrated via treatment with a GPER-1 antagonist in cultured epiphyseal cartilage. This study demonstrates that GPER-1 positively regulates chondrocyte proliferation at the growth plate during early puberty and contributes to the longitudinal growth of long bones.

scholarly journals Formin 1 and Filamin B physically interact to coordinate chondrocyte proliferation and differentiation in the growth plate

2014 ◽  
Vol 23 (17) ◽  
pp. 4663-4673 ◽  
Author(s):  
J. Hu ◽  
J. Lu ◽  
G. Lian ◽  
R. J. Ferland ◽  
M. Dettenhofer ◽  
...  
Keyword(s):  
Growth Plate ◽  
Chondrocyte Proliferation ◽  
Proliferation And Differentiation ◽  
Filamin B

Growth-promoting agents for nongrowth hormone-deficient short children

2011 ◽  
pp. 1083-1095
Author(s):  
Pierre Chatelain
Keyword(s):  
Growth Plate ◽  
Growth Phase ◽  
Growth Velocity ◽  
Adult Height ◽  
Final Height ◽  
Normal Range ◽  
Growth Plate Chondrocytes ◽  
Accelerate Growth ◽  
Short Children ◽  
Growth Promoting

Growth-promoting agents refer to compounds, existing naturally or otherwise, which, when given to a short child as a medication, will accelerate growth velocity (GV), bringing the child’s height closer to or within normal range. The first objective, normalizing height during the growth phase, may not normalize adult height, which is the second objective. The ideal growth-promoting agent should normalize both. The mechanism behind these two objectives is not fully understood. It seems that when the growth plate cartilage chondrocytes multiply, they also differentiate then stop multiplying. The balance between multiplication and differentiation of growth plate chondrocytes is key to normalizing final height.

scholarly journals Chemotherapeutic agents used in the treatment of childhood malignancies have direct effects on growth plate chondrocyte proliferation

1998 ◽  
Vol 157 (2) ◽  
pp. 225-235 ◽  
Author(s):  
H Robson ◽  
E Anderson ◽  
OB Eden ◽  
O Isaksson ◽  
S Shalet
Keyword(s):  
Suspension Culture ◽  
Growth Plate ◽  
Bone Growth ◽  
Chemotherapeutic Agents ◽  
Long Bone ◽  
Direct Effects ◽  
Growth Plate Chondrocytes ◽  
Chondrocyte Proliferation ◽  
Childhood Malignancies ◽  
The Impact

Short stature is one of the most well recorded long term sequelae for adult survivors of childhood malignancies. It has become increasingly apparent that cytotoxic chemotherapy, as well as craniospinal irradiation, has a major impact on growth, but there are virtually no studies which explore the mechanisms by which these cytotoxic drugs affect growth. We have used an in vitro system to investigate the direct effects of a range of chemotherapeutic agents on the proliferative responses of rat tibial growth plate chondrocytes, both in suspension and monolayer culture. The glucocorticoids and purine anti-metabolites reduced chondrocyte proliferation both in monolayer and suspension cultures and this resulted from an increase in cell doubling times with a concomittant reduction in the numbers of S phase cells. DNA damaging agents (e.g. actinomycin-D) were also able to reduce chondrocyte proliferation, both in monolayer and suspension culture. This, however, was the result of a cell cycle arrest and subsequent cell death. In our studies, methotrexate had no significant effect on the proliferative responses of the chondrocytes either in monolayer or suspension culture. These results indicate direct effects of a range of chemotherapeutic agents on the proliferative responses of growth plate chondrocytes. Both cytostatic and cytotoxic effects were observed although the impact of either the potential loss of cells from the proliferative pool during chondrocyte differentiation, or the reduction in the rate of chondrocyte turnover on long bone growth remains to be elucidated.

scholarly journals Defined Carboxy-Terminal Fragments of Insulin-Like Growth Factor (IGF) Binding Protein-2 Exert Similar Mitogenic Activity on Cultured Rat Growth Plate Chondrocytes as IGF-I

Endocrinology ◽  
2008 ◽  
Vol 149 (10) ◽  
pp. 4901-4911 ◽  
Author(s):  
Daniela Kiepe ◽  
Anke Van Der Pas ◽  
Sonia Ciarmatori ◽  
Ludger Ständker ◽  
Burkhardt Schütt ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Biological Activity ◽  
Growth Plate ◽  
Longitudinal Growth ◽  
Growth Plate Chondrocytes ◽  
Igf I ◽  
Rat Growth ◽  
Igf Binding ◽  
Carboxy Terminal ◽  
Igf Binding Protein

The IGF/IGF binding protein (IGFBP) system is an important component in the hormonal regulation of longitudinal growth. Evidence from in vitro studies indicates that IGFBPs may have IGF-independent effects. We analyzed the biological activity of intact IGFBP-2 and defined carboxy-terminal IGFBP-2 fragments isolated from human hemofiltrate in two cell culture systems of the growth plate: rat growth plate chondrocytes in primary culture and the mesenchymal chondrogenic cell line RCJ3.1C5.18. The IGFBP-2 fragments IGFBP-2167–279, IGFBP-2167–289, and IGFBP-2104–289 exerted a strong (2- to 3-fold) mitogenic effect on growth plate chondrocytes, which was comparable with IGF-I in equimolar concentrations (7.8 nm) but was not mediated through the type 1 IGF receptor. In a dose-response experiment, the most effective concentration of IGFBP-2104–289 for the stimulation of cell proliferation was 10 nm. This biological activity of IGFBP-2 fragments was associated with cell membrane binding, demonstrated by Western blot analysis of fractionated cell lysates and immunohistochemistry. Whereas intact IGFBP-2 did not modulate chondrocyte proliferation, partially reduced (by dithiothreitol) full-length IGFBP-2 stimulated cell proliferation to a comparable extent (3.4-fold) as carboxy-terminal IGFBP-2 fragments. The mitogenic activity of these IGFBP-2 fragments and of partially reduced full-length IGFBP-2 was mediated through the use of the MAPK/ERK 1/2. These data imply a novel role of naturally occurring IGFBP-2 fragments for the endocrine and paracrine/autocrine regulation of longitudinal growth.

scholarly journals Locally produced estrogen promotes fetal rat metatarsal bone growth; an effect mediated through increased chondrocyte proliferation and decreased apoptosis

2006 ◽  
Vol 188 (2) ◽  
pp. 193-203 ◽  
Author(s):  
A S Chagin ◽  
D Chrysis ◽  
M Takigawa ◽  
E M Ritzen ◽  
L Sävendahl
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Longitudinal Growth ◽  
Epiphyseal Growth Plate ◽  
Chondrocyte Proliferation ◽  
Growth Plate Cartilage ◽  
Ici 182,780 ◽  
Metatarsal Bones ◽  
Fetal Rat ◽  
Estrogen Synthesis

The importance of estrogens for the regulation of longitudinal bone growth is unequivocal. However, any local effect of estrogens in growth plate cartilage has been debated. Recently, several enzymes essential for estrogen synthesis were shown to be expressed in rat growth plate chondrocytes. Local production of 17β-estradiol (E2) has also been demonstrated in rat costal chondrocytes. We aimed to determine the functional role of locally produced estrogen in growth plate cartilage. The human chondrocyte-like cell line HCS-2/8 was used to study estrogen effects on cell proliferation (3H-labeled thymidine uptake) and apoptosis (cell death detection ELISA kit). Chondrocyte production of E2 was measured by RIA and organ cultures of fetal rat metatarsal bones were used to study the effects of estrogen on longitudinal growth rate. We found that significant amounts of E2 were produced by HCS-2/8 chondrocytes (64.1 ± 5.3 fmol/3 days/106cells). The aromatase inhibitor letrozole (1 μM) and the pure estrogen receptor antagonist ICI 182,780 (10 μM) inhibited proliferation of HCS-2/8 chondrocytes by 20% (P<0.01) and almost 50% (P<0.001), respectively. Treatment with ICI 182,780 (10 μM) increased apoptosis by 228% (P<0.05). Co-treatment with either caspase-3 or pan-caspase inhibitors completely blocked ICI 182,780-induced apoptosis (P<0.001 vs ICI 182,780 only). Moreover, both ICI 182,780 (10 μM) and letrozole (1 μM) decreased longitudinal growth of fetal rat metatarsal bones after 7 days of culture (P<0.01). In conclusion, our data clearly show that chondrocytes endogenously produce E2 and that locally produced estrogen stimulates chondrocyte proliferation and protects from spontaneous apoptosis. In addition, longitudinal growth is promoted by estrogens locally produced within the epiphyseal growth plate.

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