Disproportional Skeletal Growth and Markedly Decreased Bone Mineral Content in Growth Hormone Receptor −/− Mice

doi:10.1006/bbrc.1999.1986

Biochemical and Biophysical Research Communications

Volume 267, Issue 2, 19 January 2000, Pages 603-608

https://doi.org/10.1006/bbrc.1999.1986 Get rights and content

Abstract

Growth hormone (GH) is important for skeletal growth as well as for a normal bone metabolism in adults. The skeletal growth and adult bone metabolism was studied in mice with an inactivated growth hormone receptor (GHR) gene. The lengths of femur, tibia, and crown–rump were, as expected, decreased in GHR−/− mice. Unexpectedly, GHR−/− mice displayed disproportional skeletal growth reflected by decreased femur/crown–rump and femur/tibia ratios. GHR−/− mice demonstrated decreased width of the growth plates in the long bones and disturbed ossification of the proximal tibial epiphysis. Furthermore, the area bone mineral density (BMD) as well as the bone mineral content (BMC)/body weight were markedly decreased in GHR−/− mice. The decrease in BMC in GHR−/− mice was not due to decreased trabecular volumetric BMD but to a decreased cross-sectional cortical bone area In conclusion, GHR−/− mice demonstrate disproportional skeletal growth and markedly decreased bone mineral content.

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Cited by (99)

Growth hormone receptor gene disruption
2023, Vitamins and Hormones
Much of our understanding of growth hormone's (GH)’s numerous activities stems from studies utilizing GH receptor (GHR) knockout mice. More recently, the role of GH action has been examined by creating mice with tissue-specific or temporal GHR disruption. To date, 37 distinct GHR knockout mouse lines have been created. Targeted tissues include fat, liver, muscle, heart, bone, brain, macrophage, intestine, hematopoietic stem cells, pancreatic β cells, and inducible multi-tissue “global” disruption at various ages. In this chapter, a summary of each mouse line is provided with background information on the generation of the mouse line as well as important physiological outcomes resulting from GHR gene disruption. Collectively, these mouse lines provide unique insights into GH action and have resulted in the development of new hypotheses about the functions ascribed to GH action in particular tissues.
Mice with an RGS-insensitive Gα<inf>i2</inf> protein show growth hormone axis dysfunction
2021, Molecular and Cellular Endocrinology
Citation Excerpt :
It is well known that GH plays a relevant role in postnatal growth. Humans and mice with GH deficiency show impaired longitudinal bone growth (Rosenfeld et al., 1994; Zhou et al., 1997; Ohlsson et al., 1998; Sjogren et al., 2000), and children of pathologically short stature are commonly treated with human GH (Labarta et al., 2009). The main source of this hormone is the somatotroph pituitary cells, where it is synthesized and then secreted in a pulsatile manner under the stimulatory effect of GH releasing hormone (GHRH) and the inhibitory action of somatostatin (SST), both delivered from hypothalamus.
Mice carrying an RGS-insensitive Gαi2 mutation display growth retardation early after birth. Although the growth hormone (GH)-axis is a key endocrine modulator of postnatal growth, its functional state in these mice has not been characterized. The present study was undertaken to address this issue. Results revealed that pituitary mRNA levels for GH, prolactin (PRL), somatostatin (SST), GH-releasing-hormone receptor (GHRH-R) and GH secretagogue receptor (GHS-R) were decreased in mutants compared to controls. These changes were reflected by a significant decrease in plasma levels of GH, IGF-1 and IGF-binding protein-3 (IGFBP-3). Mutants were also less responsive to GHRH and ghrelin (GhL) on GH stimulation of release from pituitary primary cell cultures. In contrast, they were more sensitive to the inhibitory effect of SST. These data provide the first evidence for an alteration of the functional state of the GH-axis in Gαi2G184S mice that likely contributes to their growth retardation.
Effects of GH/IGF axis on bone and cartilage
2021, Molecular and Cellular Endocrinology
Citation Excerpt :
Likewise, overexpression of a GH antagonist (Stevenson et al., 2009), which causes blunted activation of the GHR, result in a ~45% reduction in body size in mice. Overall, decreases in skeletal size in GH-deficient states is associated with significant decreases in bone size and BMD (Kasukawa et al., 2003; Sjogren et al., 2000) (Sims et al., 2000). On the other hand, transgenic lines with overexpression of GHRH (Mayo et al., 1988a; Hammer et al., 1985), human (h) GH (Steinke et al., 1999; Tseng et al., 1996; Wanke et al., 1992; Wanke et al., 1991; Wolf et al., 1991; Wolf et al., 1991a; Wolf et al., 1991b) or bovine (b) GH in mice, all show an excess of GH, increased body size, skeletal gigantism, and increased BMD (Wanke et al., 1992; Lim et al., 2015; Palmer et al., 2009; Eckstein et al., 2002, 2004; Bartke et al., 2002; Tseng and Goldstein, 1998; Sandstedt et al., 1996).
Growth hormone (GH) and its mediator, the insulin-like growth factor-1 (IGF-1) regulate somatic growth, metabolism and many aspects of aging. As such, actions of GH/IGF have been studied in many tissues and organs over decades. GH and IGF-1 are part of the hypothalamic/pituitary somatotrophic axis that consists of many other regulatory hormones, receptors, binding proteins, and proteases. In humans, GH/IGF actions peak during pubertal growth and regulate skeletal acquisition through stimulation of extracellular matrix production and increases in bone mineral density. During aging the activity of these hormones declines, a state called somatopaguss, which associates with deleterious effects on the musculoskeletal system. In this review, we will focus on GH/IGF-1 action in bone and cartilage. We will cover many studies that have utilized congenital ablation or overexpression of members of this axis, as well as cell-specific gene-targeting approaches used to unravel the nature of the GH/IGF-1 actions in the skeleton in vivo.
GHR and IGF2R genes may contribute to normal variations in craniofacial dimensions: Insights from an admixed population
2020, American Journal of Orthodontics and Dentofacial Orthopedics
Citation Excerpt :
Complete results are presented in the Supplementary Data (Supplementary Tables I-V). The roles of GH, IGFs, and their receptors have been well described and recognized for participating in the physiology of skeletal growth and development.1 The expression of some of them in the mandibular condyle,4,5,23 where cartilage-mediated growth occurs, suggests they can influence the mandibular morphology.
This study aimed to determine whether single nucleotide polymorphisms in the growth hormone receptor (GHR) and insulin-like growth factor 2 receptor (IGF2R) genes are associated with different craniofacial phenotypes.
A total of 596 orthodontic and 98 orthognathic patients from 4 cities in Brazil were included for analyses. Angular and linear cephalometric measurements were obtained, and phenotype characterizations were performed. Genomic DNA was collected from buccal cells and single nucleotide polymorphisms in GHR (rs2910875, rs2973015, rs1509460) and IGF2R (rs2277071, rs6909681, rs6920141) were genotyped by polymerase chain reactions using TaqMan assay. Genotype–phenotype associations were assessed in the total sample (statistical significance was set at P <8.333 × 10⁻³) and by a meta-analytic approach implemented to calculate the single effect size measurement for the different cohorts.
Rare homozygotes for the GHR rs2973015 showed increased measurements for the lower anterior facial height (ANS-Me) and mandibular sagittal lengths (Co-Gn and Go-Pg). In contrast, common homozygotes for the IGF2R rs6920141 presented reduced measurements for these dimensions (ANS-Me and Go-Pg). Furthermore, the less common homozygotes for IGF2R rs2277071 had reduced maxillary sagittal length (Ptm′-A′). The meta-analytical approach replicated the associations of rs2973015 with ANS-Me, rs2277071 with Ptm′-A′, and rs6920141 with Go-Pg.
Our results provide further evidence that GHR contributes to the determination of mandibular morphology. In addition, we report that IGF2R is a possible gene associated with variations in craniofacial dimensions. Applying meta-analytical approaches to genetic variation data originating from likely underpowered samples may provide additional insight regarding genotype and/or phenotype associations.
Growth hormone, insulin-like growth factors, and IGF binding proteins
2019, Principles of Bone Biology
Growth hormone and insulin-like growth factors are essential for longitudinal growth and maintenance of the mammalian skeleton. These recombinant proteins are used to treat short stature and other growth defects in children. Additionally, rhGH is now an established part of the treatment algorithm for pituitary insufficiency. But neither growth hormone nor IGF-I is approved for the treatment of osteoporosis. In part this is because the skeletal effects of growth hormone and IGF-I are complex, temporal, and cell specific. Their actions include stimulation of bone formation, recruitment of osteoblasts and osteoclasts, and targeted changes in the osteocyte. In addition, IGF-I is essential for the anabolic effect of parathyroid hormone on bone, and its signaling nodes interact with other major anabolic factors such as the Wnts and BMPs. IGF-I may also be important in regulating substrate metabolism, and in particular, glycolysis in osteoblasts. This review focuses on the systemic and local actions of growth hormone, insulin-like growth factors, and their binding proteins and proteases.
Growth hormone receptor-deficient pigs resemble the pathophysiology of human Laron syndrome and reveal altered activation of signaling cascades in the liver
2018, Molecular Metabolism
Laron syndrome (LS) is a rare, autosomal recessive disorder in humans caused by loss-of-function mutations of the growth hormone receptor (GHR) gene. To establish a large animal model for LS, pigs with GHR knockout (KO) mutations were generated and characterized.
CRISPR/Cas9 technology was applied to mutate exon 3 of the GHR gene in porcine zygotes. Two heterozygous founder sows with a 1-bp or 7-bp insertion in GHR exon 3 were obtained, and their heterozygous F1 offspring were intercrossed to produce GHR-KO, heterozygous GHR mutant, and wild-type pigs. Since the latter two groups were not significantly different in any parameter investigated, they were pooled as the GHR expressing control group. The characterization program included body and organ growth, body composition, endocrine and clinical-chemical parameters, as well as signaling studies in liver tissue.
GHR-KO pigs lacked GHR and had markedly reduced serum insulin-like growth factor 1 (IGF1) levels and reduced IGF-binding protein 3 (IGFBP3) activity but increased IGFBP2 levels. Serum GH concentrations were significantly elevated compared with control pigs. GHR-KO pigs had a normal birth weight. Growth retardation became significant at the age of five weeks. At the age of six months, the body weight of GHR-KO pigs was reduced by 60% compared with controls. Most organ weights of GHR-KO pigs were reduced proportionally to body weight. However, the weights of liver, kidneys, and heart were disproportionately reduced, while the relative brain weight was almost doubled. GHR-KO pigs had a markedly increased percentage of total body fat relative to body weight and displayed transient juvenile hypoglycemia along with decreased serum triglyceride and cholesterol levels. Analysis of insulin receptor related signaling in the liver of adult fasted pigs revealed increased phosphorylation of IRS1 and PI3K. In agreement with the loss of GHR, phosphorylation of STAT5 was significantly reduced. In contrast, phosphorylation of JAK2 was significantly increased, possibly due to the increased serum leptin levels and increased hepatic leptin receptor expression and activation in GHR-KO pigs. In addition, increased mTOR phosphorylation was observed in GHR-KO liver samples, and phosphorylation studies of downstream substrates suggested the activation of mainly mTOR complex 2.
GHR-KO pigs resemble the pathophysiology of LS and are an interesting model for mechanistic studies and treatment trials.

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Regular ArticleDisproportional Skeletal Growth and Markedly Decreased Bone Mineral Content in Growth Hormone Receptor −/− Mice

Abstract

Cell

J. Biol. Chem.

J. Pediatr.

Annu. Rev. Physiol.

Science

Endocr. Rev.

Proc. Natl. Acad. Sci. USA

Acta. Paediatr.

Development

Endocr. Rev.

Acta. Endocrinol. (Copenh)

Growth Regul.

EMBO J.

Endocrinology

Calcif. Tissue Int.

Regular Article
Disproportional Skeletal Growth and Markedly Decreased Bone Mineral Content in Growth Hormone Receptor −/− Mice