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 Comparison of the Effect of Velvet Antler from Different Sections on Longitudinal Bone Growth of Adolescent Rats

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Hye Kyung Kim ◽  
Myung-Gyou Kim ◽  
Kang-Hyun Leem
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
In Vitro Study ◽  
Vitro Study ◽  
Longitudinal Bone Growth ◽  
Growing Rats ◽  
Velvet Antler ◽  
Adolescent Rats

The aim of this study was to compare the effectiveness of velvet antler (VA) from different sections for promoting longitudinal bone growth in growing rats. VA was divided into upper (VAU), middle (VAM), and basal sections (VAB). An in vivo study was performed to examine the effect on longitudinal bone growth in adolescent rats. In addition, in vitro osteogenic activities were examined using osteoblastic MG-63 cells. VA promoted longitudinal bone growth and height of the growth plate in adolescent rats. Bone morphogenetic protein-2 (BMP-2) in growth plate of VA group was highly expressed compared with control. The anabolic effect of VA on bone was further supported by in vitro study. VA enhanced the proliferation, differentiation, and mineralization of MG-63 cells. The mRNA expressions of osteogenic genes such as collagen, alkaline phosphatase, and osteocalcin were increased by VA treatment. These effects of in vivo and in vitro study were decreased from upper to basal sections of VA. In conclusion, VA treatment promotes longitudinal bone growth in growing rats through enhanced BMP-2 expression, osteogenic activities, and bone matrix gene expressions. In addition, present study provides evidence for the regional differences in the effectiveness of velvet antler for longitudinal bone growth.

scholarly journals Indirubin-3′-oxime stimulates chondrocyte maturation and longitudinal bone growth via activation of the Wnt/β-catenin pathway

2019 ◽  
Vol 51 (9) ◽  
pp. 1-10
Author(s):  
Sehee Choi ◽  
Pu-Hyeon Cha ◽  
Hyun-Yi Kim ◽  
Kang-Yell Choi
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Ex Vivo ◽  
Hormone Treatment ◽  
Current Approach ◽  
Plate Height ◽  
Growth Plate Chondrocytes ◽  
Longitudinal Bone Growth ◽  
Chondrocyte Maturation

Abstract Researchers have shown increased interest in determining what stimulates height. Currently, many children undergo precocious puberty, resulting in short stature due to premature closure of the growth plate. However, the current approach for height enhancement is limited to growth hormone treatment, which often results in side effects and clinical failure and is costly. Although recent studies have indicated the importance of paracrine signals in the growth plate for longitudinal bone growth, height-stimulating agents targeting the signaling pathways involved in growth plate maturation remain unavailable in the clinic. The Wnt/β-catenin pathway plays a major role in the maturation of growth plate chondrocytes. In this study, by using an ex vivo tibial culture system, we identified indirubin-3′-oxime (I3O) as a compound capable of enhancing longitudinal bone growth. I3O promoted chondrocyte proliferation and differentiation via activation of the Wnt/β-catenin pathway in vitro. Intraperitoneal injection of I3O in adolescent mice increased growth plate height along with incremental chondrocyte maturation. I3O promoted tibial growth without significant adverse effects on bone thickness and articular cartilage. Therefore, I3O could be a potential therapeutic agent for increasing height in children with growth retardation.

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 Effect of Allium fistulosum Extracts on the Stimulation of Longitudinal Bone Growth in Animal Modeling Diet-Induced Calcium and Vitamin D Deficiencies

2021 ◽  
Vol 11 (17) ◽  
pp. 7786
Author(s):  
Jin Ah Ryuk ◽  
Hye Jin Kim ◽  
Joo Tae Hwang ◽  
Byoung Seob Ko
Keyword(s):  
Vitamin D ◽  
Growth Plate ◽  
Bone Mineral ◽  
Bone Growth ◽  
Allium Fistulosum ◽  
Mineral Density ◽  
Mg63 Cells ◽  
Alkaline Phosphate

Allium fistulosum is a perennial plant species grown worldwide belonging to the family Liliaceae. In Korean medicine, it is referred to as Chongbaek (CB), and it is prescribed for symptoms associated with the common cold due to its antipyretic properties. This study examined the effects of aqueous (CBW) and 30% ethanol (CBE) extracts on bone growth using a calcium- and vitamin D-deficient animal model. In an in vitro experiment, the alkaline phosphate activities of the extracts were examined using MC3T3-E1 and MG63 cells, and both the aqueous and ethanolic extracts had significant alkaline phosphate activities. In vivo, a serum analysis indicated that the CB extracts promoted bone growth based on the osteogenic markers ALP, calcium, osteocalcin, and collagen type 1 and increased the bone mineral content (BMC), bone mineral density (BMD), and growth plate length. Overall, our results indicate that both CBW and CBE of A. fistulosum can be utilized to facilitate bone growth and increase BMD in children and adolescents by lengthening the growth plate without adverse side effects, such as metabolic disorders or the release of obesity-inducing hormones.

scholarly journals Loss of Autophagy In Tibial Growth Plate Chondrocytes Causes Increased Chondrocyte Apoptosis In Young Rats With Chronic Renal Insufficiency

2021 ◽  
Author(s):  
Xiao-jian Wang ◽  
Xiao Lu ◽  
Song-jia Guo ◽  
Wei Tian ◽  
Jian-bo Wu
Keyword(s):  
Renal Insufficiency ◽  
Growth Plate ◽  
Chronic Renal Insufficiency ◽  
Chondrocyte Apoptosis ◽  
Growth Plate Chondrocytes ◽  
Apoptosis Rate ◽  
Young Rats ◽  
Tibial Growth Plate

Abstract Background: To observed the effect of autophagy in tibial growth plate chondrocytes on apoptosis in chronic renal insufficiency(CRI) rats.Method: Male 4-week-old Sprague Dawley(SD) rats were randomly divided into two groups (n=20/per group): (1) the normal group was intragastrically administered distilled water; and (2) the CRI group was given a 150 mg/(kg·d) adenine suspension. All rats were sacrificed after continuous gavage for 6 weeks. The tibial length and the width of the tibial growth plate were measured using micro-CT. The width of the tibial growth plate was also measured in histological sections at both 4 w and 10 w. The level of the autophagy marker Beclin-1 in chondrocytes was measured by immunofluorescence. The level of glycogenin-1, a marker of intracellular glycogen accumulation, was measured by immunohistochemistry in chondrocytes in vivo and in vitro. The apoptosis rate of chondrocytes was measured by the TUNEL method in vivo and in vitro.Results: The results showed that the length of tibia was shorter and the width of tibia growth plate was narrower in CRF young rats. Autophagy level of chondrocytes in tibial growth plate decreased, and accumulation of glycogen granules in chondrocytes increased significantly. Meanwhile, the apoptosis rate of chondrocytes in tibial growth plate increased.Conclusion: When CRF occurred in young rats, the autophagy level of chondrocytes in tibial growth plate decreased significantly.As a result, there are not enough autophagic vesicles to swallow glycogen granules in chondrocytes and degrade them into glucose for energy supply, which leads to chondrocyte apoptosis.Autophagy of chondrocytes is at least partly involved in energy metabolism of cells.

scholarly journals Loss of Foxc1 and Foxc2 function in chondroprogenitor cells disrupts endochondral ossification

2021 ◽  
Author(s):  
Asra Almubarak ◽  
Rotem Lavy ◽  
Nikola Srnic ◽  
Yawen Hu ◽  
Devi P. Maripuri ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Growth Plate ◽  
Endochondral Ossification ◽  
Expression Patterns ◽  
Embryonic Stem ◽  
Chondrocyte Differentiation ◽  
Growth Plate Chondrocytes ◽  
Chondroprogenitor Cells

AbstractEndochondral ossification forms and grows the majority of the mammalian skeleton and is tightly controlled through gene regulatory networks. The forkhead box transcription factors Foxc1 and Foxc2 have been demonstrated to regulate aspects of osteoblast function in the formation of the skeleton but their roles in chondrocytes to control endochondral ossification are less clear. We demonstrate that Foxc1 expression is directly regulated by SOX9 activity, one of the earliest transcription factors to specify the chondrocyte lineages. Moreover we demonstrate that elevelated expression of Foxc1 promotes chondrocyte differentiation in mouse embryonic stem cells and loss of Foxc1 function inhibits chondrogenesis in vitro. Using chondrocyte-targeted deletion of Foxc1 and Foxc2 in mice, we reveal a role for these factors in chondrocyte differentiation in vivo. Loss of both Foxc1 and Foxc2 caused a general skeletal dysplasia predominantly affecting the vertebral column. The long bones of the limb were smaller and mineralization was reduced and organization of the growth plate was disrupted. In particular, the stacked columnar organization of the proliferative chondrocyte layer was reduced in size and cell proliferation in growth plate chondrocytes was reduced. Differential gene expression analysis indicated disrupted expression patterns in chondrogenesis and ossification genes throughout the entire process of endochondral ossification in Col2-cre;Foxc1Δ/Δ;Foxc2Δ/Δ embryos. Our results suggest that Foxc1 and Foxc2 are required for correct chondrocyte differentiation and function. Loss of both genes results in disorganization of the growth plate, reduced chondrocyte proliferation and delays in chondrocyte hypertrophy that prevents correct ossification of the endochondral skeleton.

scholarly journals CXXC5 mediates growth plate senescence and is a target for enhancement of longitudinal bone growth

2019 ◽  
Vol 2 (2) ◽  
pp. e201800254 ◽  
Author(s):  
Sehee Choi ◽  
Hyun-Yi Kim ◽  
Pu-Hyeon Cha ◽  
Seol Hwa Seo ◽  
Chulho Lee ◽  
...  
Keyword(s):  
Growth Plate ◽  
Molecular Mechanisms ◽  
Bone Growth ◽  
Negative Regulator ◽  
Screening Assay ◽  
Longitudinal Bone Growth ◽  
Delayed Senescence ◽  
Before And After ◽  
Delayed Growth

Longitudinal bone growth ceases with growth plate senescence during puberty. However, the molecular mechanisms of this phenomenon are largely unexplored. Here, we examined Wnt-responsive genes before and after growth plate senescence and found that CXXC finger protein 5 (CXXC5), a negative regulator of the Wnt/β-catenin pathway, was gradually elevated with reduction of Wnt/β-catenin signaling during senescent changes of rodent growth plate. Cxxc5−/− mice demonstrated delayed growth plate senescence and tibial elongation. As CXXC5 functions by interacting with dishevelled (DVL), we sought to identify small molecules capable of disrupting this interaction. In vitro screening assay monitoring CXXC5–DVL interaction revealed that several indirubin analogs were effective antagonists of this interaction. A functionally improved indirubin derivative, KY19382, elongated tibial length through delayed senescence and further activation of the growth plate in adolescent mice. Collectively, our findings reveal an important role for CXXC5 as a suppressor of longitudinal bone growth involving growth plate activity.

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