scholarly journals STAT1 mediates the increased apoptosis and reduced chondrocyte proliferation in mice overexpressing FGF2

Development ◽  
2001 ◽  
Vol 128 (11) ◽  
pp. 2119-2129 ◽  
Author(s):  
Malika Sahni ◽  
Regina Raz ◽  
J. Douglas Coffin ◽  
David Levy ◽  
Claudio Basilico
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Fgf Signaling ◽  
Intramembranous Ossification ◽  
Epiphyseal Growth Plate ◽  
Growth Plate Chondrocytes ◽  
Chondrocyte Proliferation ◽  
Transgenic Mouse Line ◽  
Proliferative Zone ◽  
Significant Correction

Unregulated FGF receptor signaling results in bone malformations that affect both endochondral and intramembranous ossification, and is the basis for several genetic forms of human dwarfism. FGF signaling inhibits chondrocyte proliferation and we have previously shown that the transcription factor STAT1 mediates the growth inhibitory effect of FGF in vitro. We provide genetic evidence that STAT1 is a modulator of the negative regulation of bone growth by FGF in vivo. We crossed Stat1−/− mice with a transgenic mouse line overexpressing human FGF2 (TgFGF). TgFGF mice exhibit phenotypes characterized by chondrodysplasia and macrocephaly, which affect endochondral and intramembranous ossification. We found that the chondrodysplasic phenotype of these mice results both from reduced proliferation and increased apoptosis of growth plate chondrocytes. Loss of STAT1 function in TgFGF mice led to a significant correction of the chondrodysplasic phenotype, but did not affect the skull malformations. The reduced proliferation of TgFGF growth plate chondrocytes, as well as their excessive apoptosis, were restored to near-normal levels in the absence of STAT1 function. Unregulated FGF signaling in TgFGF mice also induced apoptosis in calvarial osteoblasts that was not, however, corrected by the absence of STAT1. Detailed analysis of Stat1−/− growth plates uncovered a transient phenotype, characterized by an expansion of the proliferative zone and by acceleration of longitudinal bone growth, that attenuated as the animals grew older. These results document an essential role for STAT1 in FGF-mediated regulation of cell growth that is specific to the epiphyseal growth plate.

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 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 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.

Spaceflight and age affect tibial epiphyseal growth plate histomorphometry

1992 ◽  
Vol 73 (2) ◽  
pp. S19-S25 ◽  
Author(s):  
D. Montufar-Solis ◽  
P. J. Duke ◽  
G. Durnova
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Ultrastructural Level ◽  
Cell Number ◽  
Epiphyseal Growth Plate ◽  
Growth Plates ◽  
Proliferative Zone ◽  
Old Rats ◽  
Modifying Effect ◽  
Matrix Organization

Growth plate histomorphometry of rats flown aboard the Soviet biosatellite COSMOS 2044, a 14-day spaceflight, was compared with that of control groups. In growth plates of flight animals, there was a significant increase in cell number per column and height of the proliferative zone and a reduction in height and cell number in the hypertrophy/calcification zone. No significant differences were found in matrix organization at the ultrastructural level of flight animals, indicating that although spaceflight continues to affect bone growth of 15-wk-old rats, extracellular matrix is not altered in the same manner as seen previously in younger animals. All groups showed growth plate characteristics attributed to aging: lack of calcification zone, reduced hypertrophy zone, and unraveling of collagen fibrils. Tail-suspended controls did not differ from other controls in any of the parameters measured. Our results suggest that growth plates of older rats are less responsive to unloading by spaceflight or suspension than those of younger rats and provide new evidence about the modifying effect of spaceflight on the growth plate.

scholarly journals GPR30 Estrogen Receptor Expression in the Growth Plate Declines as Puberty Progresses

2007 ◽  
Vol 92 (12) ◽  
pp. 4873-4877 ◽  
Author(s):  
Andrei S. Chagin ◽  
Lars Sävendahl
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Receptor Expression ◽  
Skeletal Maturation ◽  
Tall Stature ◽  
Leg Length ◽  
Epiphyseal Growth Plate ◽  
Growth Plates ◽  
Longitudinal Bone Growth ◽  
Proliferative Zone

Abstract Objective: Our objective was to study whether GPR30 is expressed in the epiphyseal growth plate and its potential role as a modulator of pubertal growth. Background: Estrogens play a crucial role in the regulation of skeletal maturation and longitudinal bone growth. We have previously shown that both estrogen receptors (ERs) α and β are expressed in the human epiphyseal growth plate. Recently, a membrane-bound ER referred to as GPR30 was discovered, but the role played by this receptor in the regulation of longitudinal bone growth is not yet known. Patients/Methods: Biopsies were collected from the tibial growth plates of 14 boys and seven girls that underwent epiphyseal surgery to arrest longitudinal bone growth. The patients were in different stages of puberty and suffered from inequality in leg length or extreme tall stature. Paraffin-embedded sections of the growth plates were used to detect expression of the GPR30 protein. Results: The highest level of GPR30 expression was observed in hypertrophic chondrocytes, although cells with positive immunostaining were also detected in the resting zone. In contrast, no immunoreactivity was found in the proliferative zone. During pubertal progression there was a clear decline in the level of GPR30 expression in both boys and girls. Conclusions: The novel ER GPR30 is expressed in the human growth plate, and the level of expression declines during pubertal progression. Although a relationship between GPR30 expression and age may underlie the observed pubertal decline in the GPR30 level, our observations suggest that this receptor could be involved in the modulation of longitudinal bone growth during puberty.

scholarly journals Growth plate senescence is associated with loss of DNA methylation

2005 ◽  
Vol 186 (1) ◽  
pp. 241-249 ◽  
Author(s):  
Ola Nilsson ◽  
Robert D Mitchum ◽  
Lenneke Schrier ◽  
Sandra P Ferns ◽  
Kevin M Barnes ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Growth Plate ◽  
Bone Growth ◽  
Indirect Evidence ◽  
Adult Size ◽  
Growth Plate Chondrocytes ◽  
Longitudinal Bone Growth ◽  
Proliferative Zone

The overall body size of vertebrates is primarily determined by longitudinal bone growth at the growth plate. With age, the growth plate undergoes programmed senescence, causing longitudinal bone growth to slow and eventually cease. Indirect evidence suggests that growth plate senescence occurs because stem-like cells in the growth plate resting zone have a finite proliferative capacity that is gradually exhausted. Similar limits on replication have been observed when many types of animal cells are placed in cell culture, an effect known as the Hayflick phenomenon. However, we found that the number of population doublings of rabbit resting zone chondrocytes in culture did not depend on the age of the animal from which the cells were harvested, suggesting that the mechanisms limiting replicative capacity of growth plate chondrocytes in vivo are distinct from those in vitro. We also observed that the level of DNA methylation in resting zone chondrocytes decreased with age in vivo. This loss of methylation appeared to occur specifically with the slow proliferation of resting zone chondrocytes in vivo and was not observed with the rapid proliferation of proliferative zone chondrocytes in vivo (i.e. the level of DNA methylation did not change from the resting zone to the hypertrophic zone), with proliferation of chondrocytes in vitro, or with growth of the liver in vivo. Thus, the overall level of DNA methylation decreases during growth plate senescence. This finding is consistent with the hypothesis that the mechanism limiting replication of growth plate chondrocytes in vivo involves loss of DNA methylation and, thus, loss of DNA methylation might be a fundamental biological mechanism that limits longitudinal bone growth in mammals, thereby determining the overall adult size of the organism.

scholarly journals In vivo and in vitro Chondrocyte Metabolism in Relationship to the Developemnt of Tibial Dyschondroplasia in Broiler Chickens

1993 ◽  
Author(s):  
Roland M. Leach ◽  
Mark Pines ◽  
Carol V. Gay ◽  
Shmuel Hurwitz
Keyword(s):  
In Situ Hybridization ◽  
Growth Plate ◽  
Bone Growth ◽  
Future Research ◽  
Epiphyseal Growth Plate ◽  
Growth Plate Chondrocytes ◽  
Tibial Dyschondroplasia ◽  
Sequence Of Events

Skeletal deformities are a significant financial and welfare problem for the world poultry industry. Tibial dyschondroplasia (TD) is the most prevalent skeletal abnormality found in young broilers, turkeys and ducks. Tibial dyschondroplasia results from a perturbation of the sequence of events in the epiphyseal growth plate, the tissue responsible for longitudinal bone growth. The purpose of this investigation was to test the hypothesis that TD was the result of a failure of growth plate chondrocytes to differentiate and express the chemotactic molecules required for cartilage vascularization. In this investigation in situ hybridization and immunocytochemical techniques were used to study chondrocyte gene products associated with cartilage maturation and vascularization such as osteopontin, osteonectin, type X collagen, and alkaline phosphatase. All markers were present in the growth plate tissue anter or to the TD lesion but were greatly diminished in the TD lesion. Thus, rather than not acquiring the markers for hypertrophy, it appears that the growth plate chondrocytes reach a certain stage of hypertrophy and then de-differentiate into cells which resemble chondrocytes in the prehypertrophic zone. Similar patterns were observed in all TD tissues examined whether the lesions were spontaneous or induced by dietary treatments or genetic selection. The decrease in gene expression can at least be partially explained by the fact that many of the dysplastic chondrocytes show classic signs of apoptosis. These results provide an explanation for the observation that a variety of genes show reduced expression in the TD lesion when examined by in situ hybridization. This would suggest that future research should focus on the earliest detectable stages in the development of TD and examine endocrine and autocrine factors which cause chondrocytes to de-differentiate and undergo premature apoptosis.

scholarly journals Effects of bisphosphonates on different zones of the epiphyseal growth plate of rats

2021 ◽  
Vol 10 (14) ◽  
pp. e518101422159
Author(s):  
Deise Ponzoni ◽  
Elissa Kerli Fernandes ◽  
Mateus Muller da Silva ◽  
Izabel Cristina Custódio de Souza ◽  
John Kim Neubert ◽  
...  
Keyword(s):  
Growth Plate ◽  
Histological Analysis ◽  
Skeletal Development ◽  
Fold Increase ◽  
Control Group ◽  
Epiphyseal Growth Plate ◽  
Alendronate Sodium ◽  
Proliferative Zone ◽  
Clinical Disorders ◽  
Plate Cell

Bisphosphonates (BIS) are indicated for several clinical disorders (e.g., osteoporosis). However, BIS has been associated with osteonecrosis and alterations in osteoclastogenesis and skeletal development. This study aimed to evaluate the effects of BIS (zoledronic acid - ZA and alendronate sodium - AS) on zones of the growth plate of rat femur. Animals (Wistar rats, n = 19) were divided into groups: 1) AS Group: animals received alendronate sodium orally (3 mg/kg per day); 2) ZA Group: ZA was administered intraperitoneally (0.2 mg/kg per week); and 3) Control Group (CG): a vehicle was administered. Animals were euthanized 21 days after the treatment, and femurs were collected for histological analysis. The images of all zones (resting, proliferative, hypertrophic, and calcified) were processed by the Qcapture® software providing a 40 and 400-fold increase.  ZA decreased epiphyseal growth plate cell zones (ZA Group vs. CG) in most cases. Likewise, AS diminished the proliferative zone (AS Group vs. CG). Furthermore, ZA increased the calcified zone (ZA Group vs. CG). Previous works demonstrated that BIS decrease the epiphyseal disc. This reduction is probably due to the shortening of the cellular zones that undergoes calcification/ossification. The present results suggest that BIS should be carefully indicated because these drugs might accelerate epiphyseal closure.

scholarly journals Catch-Up Growth after Hypothyroidism Is Caused by Delayed Growth Plate Senescence

Endocrinology ◽  
2008 ◽  
Vol 149 (4) ◽  
pp. 1820-1828 ◽  
Author(s):  
Rose Marino ◽  
Anita Hegde ◽  
Kevin M. Barnes ◽  
Lenneke Schrier ◽  
Joyce A. Emons ◽  
...  
Keyword(s):  
Growth Rate ◽  
Growth Inhibition ◽  
Growth Plate ◽  
Bone Growth ◽  
Structural Characteristics ◽  
Linear Growth Rate ◽  
Growth Plate Chondrocytes ◽  
Growth Plates ◽  
Catch Up ◽  
Growth Inhibiting

Catch-up growth is defined as a linear growth rate greater than expected for age after a period of growth inhibition. We hypothesized that catch-up growth occurs because growth-inhibiting conditions conserve the limited proliferative capacity of growth plate chondrocytes, thus slowing the normal process of growth plate senescence. When the growth-inhibiting condition resolves, the growth plates are less senescent and therefore grow more rapidly than normal for age. To test this hypothesis, we administered propylthiouracil to newborn rats for 8 wk to induce hypothyroidism and then stopped the propylthiouracil to allow catch-up growth. In untreated controls, the growth plates underwent progressive, senescent changes in multiple functional and structural characteristics. We also identified genes that showed large changes in mRNA expression in growth plate and used these changes as molecular markers of senescence. In treated animals, after stopping propylthiouracil, these functional, structural, and molecular senescent changes were delayed, compared with controls. This delayed senescence included a delayed decline in longitudinal growth rate, resulting in catch-up growth. The findings demonstrate that growth inhibition due to hypothyroidism slows the developmental program of growth plate senescence, including the normal decline in the rate of longitudinal bone growth, thus accounting for catch-up growth.

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