Growth Hormone Induces Bone Morphogenetic Proteins and Bone-Related Proteins in the Developing Rat Periodontium

Li, Huika; Bartold, P. Mark; Young, William G.; Xiao, Yin; Waters, Michael J.

doi:10.1359/jbmr.2001.16.6.1068

Cited by 46 publications

(34 citation statements)

References 42 publications

(54 reference statements)

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“…Interestingly, three genes associated with the BMP pathway, an important regulator of bone formation (25), were downregulated by a single injection of GH. This is in contrast to a previous report in which several injections of GH stimulated BMP-2 and -4 in rats, as well as IGF-I (24). Although the different observations may be due to the different duration of GH treatment in the two experiments, the significance and mechanisms involved in the decreased expression in BMPs in the present study needs further evaluation.…”

Section: Microarray Analysiscontrasting

confidence: 99%

Whole genome microarray analysis of growth hormone-induced gene expression in bone: T-box3, a novel transcription factor, regulates osteoblast proliferation

Govoni¹,

Lee²,

Chadwick³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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Growth hormone (GH) is important in the development and maintenance of bone; however, the IGF-dependent and -independent molecular pathways involved remain to be established. We used microarray analysis to evaluate GH signaling pathways in 4-wk-old GH-deficient mice following a single injection of GH (4 mg/kg body wt) or PBS (n = 6/group) at 6 or 24 h after treatment. Six thousand one hundred sixty genes were differentially expressed at P ≤ 0.05, and 17% of these genes were identified at both time points. Several of the genes differentially expressed were expressed sequence tags, and the remaining genes fell into 49 Gene Ontology categories. For subsequent studies, we focused on T-box (Tbx)3, a novel transcription factor, which increased more than twofold at both time points. Real-time RT-PCR analysis determined that pretreatment with IGF-binding protein-4 did not block GH-induced Tbx3 expression in vitro. Pretreatment with TNF-α blocked GH-induced Tbx3 expression. Tbx3 expression increased during osteoblast differentiation and following BMP-7 and Wnt3a treatment (P ≤ 0.05). Blocking Tbx3 expression by small interfering RNA decreased cell number and [ 3 H]Thymidine incorporation (P < 0.01). In conclusion, 1) GH caused acute changes in several novel genes, suggesting that many GH-induced signaling pathways and target genes remain to be discovered; 2) because Tbx3 expression is regulated in osteoblasts and blockage of Tbx3 expression decreased cell number and DNA synthesis, we propose that Tbx3 is an important determinant of osteoblast cell number. Keywordsinsulin-like growth factor I; lit/lit mouse; signaling pathways Growth hormone (GH) is important in the development and maintenance of bone. This has been demonstrated in several experiments utilizing human and animal models that are GH deficient and/or treated with GH. In GH-deficient adults, decreased bone mineral density (BMD) can be corrected with exogenous GH treatment (20,38). In addition, GH treatment increases bone formation markers as well as serum concentrations of 19,38). We (27) and others (42) have demonstrated that mice deficient in GH production or action Copyright © 2006 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript exhibit significant deficits in body weight, femur length, and volumetric BMD. It is well known that GH may act directly on specific tissues or by binding to its receptors and stimulating the release of IGF-I. When GH binds to its receptors, JAK is phosphorylated and several pathways, including STAT, MAPK, are activated (16,31). Through these pathways, GH regulates the transcription of specific genes, such as IGF-I. Recent evidence has demonstrated that GH may also act independently of IGF-I in bone. In a previous study (27), we reported that the rate of gain in femur length and periosteal circumference during the postpubertal growth period are impaired to a greater extent in GH-deficient lit/lit mice compared with IGF-I knockout mice. Furthermore, previous published work has suggested an involv...

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Section: Microarray Analysiscontrasting

confidence: 99%

Whole genome microarray analysis of growth hormone-induced gene expression in bone: T-box3, a novel transcription factor, regulates osteoblast proliferation

Govoni¹,

Lee²,

Chadwick³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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“…A number of previous studies documented that PDL cells expressed a series of osteoblastic or cementoblastic-related Odontology genes such as Runt-related transcription factor-2 (Runx2), Col I [28], osteopontin (OPN) [29], ALP [30], OCN [31], periostin [32] and genes related to bone metabolism regulation such as receptor activator of NF-kappa B ligand (RANKL) and osteoprotegerin (OPG) [33]. The variety of the gene expression profile is most likely due to the heterogeneity of PDL tissue cells.…”

Section: Gene Expressions During Differentiation Inductionmentioning

confidence: 99%

Isolation, characterization and investigation of differentiation potential of human periodontal ligament cells and dental follicle progenitor cells and their response to BMP-7 in vitro

Açil

Yang

Gülses³

et al. 2015

Odontology

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The aim of this study was to assess the factors, mechanisms and the differences between periodontal ligament (PDL) cells and denta l follicle (DF) progenitor cells towards the osteoblastic/cementoblastic differentiation and to investigate the effects of BMP-7 on developmental (DF) and mature tissue-derived (PDL) cells, respectively. Primary cell culture of PDL cells and DF progenitor cells was performed. Osteogenic differentiation was evaluated using von Kossa, Alizarin Red S and immuno-histo-chemistry staining of osteocalcin. Gene expression pattern was evaluated via real-time PCR. A series of CD surface marks were tested using flow cytometry and fluorescence-activated cell-sorting analysis was performed. Real-time RT-PCR demonstrated similar gene expression pattern of PDL cells and DF progenitor cells: the expression of OPN and OCN significantly was elevated when incubated with osteogenic components, Runx2 was unaffected, and Osteorix was hardly expressed whether in basic medium or induction medium. In addition, BMP-7 induced osteoblast/cementoblast differentiation of PDLSCs and DF progenitor cells in a dose- and time-dependent manner, as reflected by enhanced Runx2 and (OCN) mRNA transcript expression. BMP-7 triggers PDL cells and DF progenitor cells to differentiate towards an osteoblast/cementoblast phenotype.

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“…This differentiation process is marked by an increase in type II collagen, cathepsin D and acid phosphatase. GH also promotes upregulation of enzymes, matrix proteins, and differentiation markers involved in mineralisation of tooth and bone matrices directly and augments the role of IGF-1 in promoting bone and tooth formation (Li et al, 2001). Further, GH is proposed to have necessary role in differentiation of preadipocytes to functional mature adipocytes (Shang & Waters, 2003).…”

Section: Proliferation and Differentiationmentioning

confidence: 99%

The growth hormone receptor mediated oncogenesis

Chhabra¹

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Growth hormone (GH) is a major regulator of postnatal growth, cellular proliferation and differentiation, as well as of metabolism. All actions of GH are mediated via its cognate Growth Hormone Receptor (GHR). It is now clear that the role of GH extends well beyond the conventional notions of longitudinal growth and childhood development. A substantial body of evidence supports a role for the GH/IGF-1 axis in cancer incidence and progression in animals and humans and because of widespread clinical application of GH, there has been considerable interest in the mechanism of activation of its receptor. It was originally thought that GH initiated its actions by sequentially binding two GHR monomers, resulting in receptor dimerisation and initiation of intracellular signalling cascades, including Jak/STAT and MAPK pathways. However, recent evidence by our group and others has indicated that the GHR is constitutively dimerised, and that dimerisation alone is not sufficient for GHR activation.To this end the main objective of this thesis was to evaluate the role of GH-mediated signalling via its GHR in mediating oncogenesis. We have taken a multi-disciplinary approach by first determining how the GHR is activated via its transmembrane domain (TMD) and the nature of its interaction with Src family of tyrosine kinase (Lyn). We have determined the basis of the contrasting actions of autocrine GH from independent publications and sought to evaluate the effect of various constitutively active GHR constructs in cancer promotion in vitro and in vivo by establishing a tissue-specific delivery system (TVA system) for introducing multiple genes in a spatial and temporally controlled manner. We have provided the molecular basis of increased cancer susceptibility of the first reported GHR variant from two independent epidemiological studies. Finally, we have evaluated cancer resistance and anti-aging pathways in various GHR knockin and knockout mice models.In order to determine the role of GHR transmembrane domain (TMD) and upper juxtamembrane domain (JMD) in signalling, cysteine-scanning mutagenesis was employed with truncated and full length receptors in a thiol-free background. Using these GHR constructs and sequentially substituting residues along the GHR JMD and TMD with cysteine we observed a ligandindependent spontaneous dimerisation pattern of upper JMD and TMD residues with evidence for a 'tilt and twist' movement for this region of GHR during activation. By using Cu-o-phenanthroline we were able to show that GHR activation could occur following disulfide bond formation at the upper TMD boundary resulting in constitutive activation. Finally we were able to conclude that GHR activation requires the JMD residues to come in close proximity which results in separation of iii the lower TMD residues and activation. Another outcome of this study was the generation of the first full-length constitutively active receptor.GHR has been shown to activate numerous pathways and one such pathway involves Src Family Kinase (SFK),...

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Growth Hormone Induces Bone Morphogenetic Proteins and Bone-Related Proteins in the Developing Rat Periodontium

Abstract: The hypothesis that growth hormone (GH) up-regulates the expression of enzymes, matrix proteins, and differentiation markers involved in mineralization of tooth and bone matrices was tested by the treatment of Lewis dwarf rats with GH over 5 days.

Cited by 46 publications

References 42 publications

Whole genome microarray analysis of growth hormone-induced gene expression in bone: T-box3, a novel transcription factor, regulates osteoblast proliferation

Whole genome microarray analysis of growth hormone-induced gene expression in bone: T-box3, a novel transcription factor, regulates osteoblast proliferation

Isolation, characterization and investigation of differentiation potential of human periodontal ligament cells and dental follicle progenitor cells and their response to BMP-7 in vitro

The growth hormone receptor mediated oncogenesis

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