scholarly journals Circulating C-Type Natriuretic Peptide (CNP) Rescues Chondrodysplastic CNP Knockout Mice from Their Impaired Skeletal Growth and Early Death

Endocrinology ◽  
2010 ◽  
Vol 151 (9) ◽  
pp. 4381-4388 ◽  
Author(s):  
Toshihito Fujii ◽  
Yasato Komatsu ◽  
Akihiro Yasoda ◽  
Eri Kondo ◽  
Tetsuro Yoshioka ◽  
...  
Keyword(s):  
Body Weight ◽  
Natriuretic Peptide ◽  
Knockout Mice ◽  
Bone Growth ◽  
Therapeutic Potential ◽  
Body Weight Gain ◽  
Early Death ◽  
Systemic Administration ◽  
Skeletal Growth ◽  
Endochondral Bone

C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth through a subtype of membranous guanylyl cyclase receptor, GC-B. Although its two cognate natriuretic peptides, ANP and BNP, are cardiac hormones produced from heart, CNP is thought to act as an autocrine/paracrine regulator. To elucidate whether systemic administration of CNP would be a novel medical treatment for chondrodysplasias, for which no drug therapy has yet been developed, we investigated the effect of circulating CNP by using the CNP transgenic mice with an increased circulating CNP under the control of human serum amyloid P component promoter (SAP-Nppc-Tg mice). SAP-Nppc-Tg mice developed prominent overgrowth of bones formed through endochondral ossification. In organ culture experiments, the growth of tibial explants of SAP-Nppc-Tg mice was not changed from that of their wild-type littermates, exhibiting that the stimulatory effect on endochondral bone growth observed in SAP-Nppc-Tg mice is humoral. Then we crossed chondrodysplastic CNP-depleted mice with SAP-Nppc-Tg mice. Impaired endochondral bone growth in CNP knockout mice were considerably and significantly recovered by increased circulating CNP, followed by the improvement in not only their longitudinal growth but also their body weight. In addition, the mortality of CNP knockout mice was greatly decreased by circulating CNP. Systemic administration of CNP might have therapeutic potential against not only impaired skeletal growth but also other aspects of impaired growth including impaired body weight gain in patients suffering from chondrodysplasias and might resultantly protect them from their early death.

scholarly journals Systemic Administration of C-Type Natriuretic Peptide as a Novel Therapeutic Strategy for Skeletal Dysplasias

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3138-3144 ◽  
Author(s):  
Akihiro Yasoda ◽  
Hidetomo Kitamura ◽  
Toshihito Fujii ◽  
Eri Kondo ◽  
Naoaki Murao ◽  
...  
Keyword(s):  
Drug Therapy ◽  
Natriuretic Peptide ◽  
Therapeutic Strategy ◽  
Bone Growth ◽  
Genetic Disorders ◽  
Systemic Administration ◽  
Endochondral Bone ◽  
Skeletal Dysplasias ◽  
Peptide Family ◽  
Severe Impairment

Skeletal dysplasias are a group of genetic disorders characterized by severe impairment of bone growth. Various forms of them add to produce a significant morbidity and mortality, yet no efficient drug therapy has been developed to date. We previously demonstrated that C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, is a potent stimulator of endochondral bone growth. Furthermore, we exhibited that targeted overexpression of a CNP transgene in the growth plate rescued the impaired bone growth observed in a mouse model of achondroplasia (Ach), the most frequent form of human skeletal dysplasias, leading us to propose that CNP may prove to be an effective treatment for this disorder. In the present study, to elucidate whether or not the systemic administration of CNP is a novel drug therapy for skeletal dysplasias, we have investigated the effects of plasma CNP on impaired bone growth in Ach mice that specifically overexpress CNP in the liver under the control of human serum amyloid P component promoter or in those treated with a continuous CNP infusion system. Our results demonstrated that increased plasma CNP from the liver or by iv administration of synthetic CNP-22 rescued the impaired bone growth phenotype of Ach mice without significant adverse effects. These results indicate that treatment with systemic CNP is a potential therapeutic strategy for skeletal dysplasias, including Ach, in humans.

scholarly journals Susceptibility to diet induced obesity at thermoneutral conditions is independent of UCP1

2021 ◽  
Author(s):  
Sebastian Dieckmann ◽  
Akim Strohmeyer ◽  
Monja Willershaeuser ◽  
Stefanie Maurer ◽  
Wolfgang Wurst ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Energy Expenditure ◽  
Knockout Mice ◽  
Body Weight Gain ◽  
Uncoupling Protein ◽  
Exon 2 ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Knockout Model

Objective Activation of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) upon cold stimulation leads to substantial increase in energy expenditure to defend body temperature. Increases in energy expenditure after a high caloric food intake, termed diet-induced thermogenesis, are also attributed to BAT. These properties render BAT a potential target to combat diet-induced obesity. However, studies investigating the role of UCP1 to protect against diet-induced obesity are controversial and rely on the phenotyping of a single constitutive UCP1-knockout model. To address this issue, we generated a novel UCP1-knockout model by Cre-mediated deletion of Exon 2 in the UCP1 gene. We studied the effect of constitutive UCP1 knockout on metabolism and the development of diet-induced obesity. Methods UCP1 knockout and wildtype mice were housed at 30°C and fed a control diet for 4-weeks followed by 8-weeks of high-fat diet. Body weight and food intake were monitored continuously over the course of the study and indirect calorimetry was used to determine energy expenditure during both feeding periods. Results Based on Western blot analysis, thermal imaging and noradrenaline test, we confirmed the lack of functional UCP1 in knockout mice. However, body weight gain, food intake and energy expenditure were not affected by deletion of UCP1 gene function during both feeding periods. Conclusion Conclusively, we show that UCP1 does not protect against diet-induced obesity at thermoneutrality. Further we introduce a novel UCP1-KO mouse enabling the generation of conditional UCP1-knockout mice to scrutinize the contribution of UCP1 to energy metabolism in different cell types or life stages.

scholarly journals C-type natriuretic peptide regulates endochondral bone growth through p38 MAP kinase-dependent and – independent pathways

2007 ◽  
Vol 7 (1) ◽  
pp. 18 ◽  
Author(s):  
Hanga Agoston ◽  
Sameena Khan ◽  
Claudine G James ◽  
J Ryan Gillespie ◽  
Rosa Serra ◽  
...  
Keyword(s):  
Map Kinase ◽  
Natriuretic Peptide ◽  
Bone Growth ◽  
P38 Map Kinase ◽  
Endochondral Bone

scholarly journals Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats

2008 ◽  
Vol 295 (1) ◽  
pp. E78-E84 ◽  
Author(s):  
Sabine Strassburg ◽  
Stefan D. Anker ◽  
Tamara R. Castaneda ◽  
Lukas Burget ◽  
Diego Perez-Tilve ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Food Intake ◽  
Energy Expenditure ◽  
Therapeutic Potential ◽  
Body Weight Gain ◽  
Metabolic Effects ◽  
Positive Energy ◽  
High Dose ◽  
Growth Hormone Secretagogue

Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), is the only circulating agent to powerfully promote a positive energy balance. Such action is mediated predominantly by central nervous system pathways controlling food intake, energy expenditure, and nutrient partitioning. The ghrelin pathway may therefore offer therapeutic potential for the treatment of catabolic states. However, the potency of the endogenous hormone ghrelin is limited due to a short half-life and the fragility of its bioactivity ensuring acylation at serine 3. Therefore, we tested the metabolic effects of two recently generated GHS-R agonists, BIM-28125 and BIM-28131, compared with ghrelin. All agents were administered continuously for 1 mo in doses of 50 and 500 nmol·kg−1·day−1 using implanted subcutaneous minipumps in rats. High-dose treatment with single agonists or ghrelin increased body weight gain by promoting fat mass, whereas BIM-28131 was the only one also increasing lean mass significantly. Food intake increased during treatment with BIM-28131 or ghrelin, whereas no effects on energy expenditure were detected. With the lower dose, only BIM-28131 had a significant effect on body weight. This also held true when the compound was administered by subcutaneous injection three times/day. No symptoms or signs of undesired effects were observed in any of the studies or treated groups. These results characterize BIM-28131 as a promising GHS-R agonist with an attractive action profile for the treatment of catabolic disease states such as cachexia.

scholarly journals Haploinsufficiency of osterix in chondrocytes impairs skeletal growth in mice

2013 ◽  
Vol 45 (19) ◽  
pp. 917-923 ◽  
Author(s):  
Shaohong Cheng ◽  
Weirong Xing ◽  
Xin Zhou ◽  
Subburaman Mohan
Keyword(s):  
Bone Growth ◽  
Skeletal Growth ◽  
Endochondral Bone Formation ◽  
Volumetric Bone Mineral Density ◽  
Mineral Density ◽  
Endochondral Bone ◽  
Alizarin Red ◽  
Adult Mice ◽  
Elevated Expression ◽  
Skeletal Phenotype

Osterix ( Osx) is essential for both intramembranous or endochondral bone formation. Osteoblast-specific ablation of Osx using Col1α1-Cre resulted in osteopenia, because of impaired osteoblast differentiation in adult mice. Since Osx is also known to be expressed in chondrocytes, we evaluated the role of Osx expressed in chondrocytes by examining the skeletal phenotype of mice with conditional disruption of Osx in Col2α1-expressing chondrocytes. Surprisingly, Cre-positive mice that were homozygous for Osx floxed alleles died after birth. Alcian blue and alizarin red staining revealed that the lengths of skeleton, femur, and vertebrae were reduced by 21, 26, and 14% ( P < 0.01), respectively, in the knockout (KO) compared with wild-type mice. To determine if haploid insufficiency of Osx in chondrocytes influenced postnatal skeletal growth, we compared skeletal phenotype of floxed heterozygous mice that were Cre-positive or Cre-negative. Body length was reduced by 8% ( P < 0.001), and areal BMD of total body, femur, and tibia was reduced by 5, 7, and 8% ( P < 0.05), respectively, in mice with conditional disruption of one allele of Osx in chondrocytes. Micro-CT showed reduced cortical volumetric bone mineral density and trabecular bone volume to total volume in the femurs of Osxflox/+; col2α1-Cre mice. Histological analysis revealed that the impairment of longitudinal growth was associated with disrupted growth plates in the Osxflox/+; col2α1-Cre mice. Primary chondrocytes isolated from KO embryos showed reduced expression of chondral ossification markers but elevated expression of chondrogenesis markers. Our findings indicate that Osx expressed in chondrocytes regulates bone growth in part by regulating chondrocyte hypertrophy.

scholarly journals Plasma C-Type Natriuretic Peptide: Emerging Applications in Disorders of Skeletal Growth

2018 ◽  
Vol 90 (6) ◽  
pp. 345-357 ◽  
Author(s):  
Eric Espiner ◽  
Tim Prickett ◽  
Robert Olney
Keyword(s):  
Clinical Practice ◽  
Natriuretic Peptide ◽  
Bone Growth ◽  
Plasma Concentrations ◽  
Skeletal Growth ◽  
Height Velocity ◽  
Long Bone ◽  
Blood Levels ◽  
Growth Disorders ◽  
Reference Ranges

Although studies in experimental animals show that blood levels of C-type natriuretic peptide (CNP) and its bioinactive aminoterminal propeptide (NTproCNP) are potential biomarkers of long bone growth, a lack of suitable assays and appropriate reference ranges has limited the application of CNP measurements in clinical practice. Plasma concentrations of the processed product of proCNP, NTproCNP – and to a lesser extent CNP itself – correlate with concurrent height velocity throughout all phases of normal skeletal growth, as well as during interventions known to affect skeletal growth in children. Since a change in levels precedes a measurable change in height velocity during interventions, measuring NTproCNP may have predictive value in clinical practice. Findings from a variety of genetic disorders affecting CNP signaling suggest that plasma concentrations of both peptides may be helpful in diagnosis, provided factors such as concurrent height velocity, feedback regulation of CNP, and differential changes in peptide clearance are considered when interpreting values. An improved understanding of factors affecting plasma levels, and the availability of commercial kits enabling accurate measurement using small volumes of plasma, can be expected to facilitate potential applications in growth disorders including genetic causes ­affecting the CNP signaling pathway.

scholarly journals Chondrocytes Play a Major Role in the Stimulation of Bone Growth by Thyroid Hormone

Endocrinology ◽  
2014 ◽  
Vol 155 (8) ◽  
pp. 3123-3135 ◽  
Author(s):  
Clémence Desjardin ◽  
Cyril Charles ◽  
Catherine Benoist-Lasselin ◽  
Julie Riviere ◽  
Mailys Gilles ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Bone Growth ◽  
Cell Types ◽  
Postnatal Growth ◽  
Dominant Negative ◽  
Skeletal Growth ◽  
Endochondral Bone Formation ◽  
Endochondral Bone ◽  
Phenotype Analysis ◽  
Visible Effect

Thyroid hormone (T3) is required for postnatal skeletal growth. It exerts its effect by binding to nuclear receptors, TRs including TRα1 and TRβ1, which are present in most cell types. These cell types include chondrocytes and osteoblasts, the interactions of which are known to regulate endochondral bone formation. In order to analyze the respective functions of T3 stimulation in chondrocytes and osteoblasts during postnatal growth, we use Cre/loxP recombination to express a dominant-negative TRα1L400R mutant receptor in a cell-specific manner. Phenotype analysis revealed that inhibiting T3 response in chondrocytes is sufficient to reproduce the defects observed in hypothyroid mice, not only for cartilage maturation, but also for ossification and mineralization. TRα1L400R in chondrocytes also results in skull deformation. In the meantime, TRα1L400R expression in mature osteoblasts has no visible effect. Transcriptome analysis identifies a number of changes in gene expression induced by TRα1L400R in cartilage. These changes suggest that T3 normally cross talks with several other signaling pathways to promote chondrocytes proliferation, differentiation, and skeletal growth.

scholarly journals Dose-Response Effects of 2-Methoxyestradiol on Estrogen Target Tissues in the Ovariectomized Rat

Endocrinology ◽  
2003 ◽  
Vol 144 (3) ◽  
pp. 785-792 ◽  
Author(s):  
J. D. Sibonga ◽  
S. Lotinun ◽  
G. L. Evans ◽  
V. S. Pribluda ◽  
S. J. Green ◽  
...  
Keyword(s):  
Body Weight ◽  
Bone Loss ◽  
Cancellous Bone ◽  
Dose Response ◽  
Bone Growth ◽  
Body Weight Gain ◽  
Hormone Replacement ◽  
Adult Rats ◽  
Cell Height ◽  
Ovx Rats

In three experiments, we evaluated the pharmacological effects of 2-methoxyestradiol (2ME2) on several estrogen target tissues. Experiment 1: we gavaged recently ovariectomized (OVX) 9.5-wk-old rats with 2ME2 at doses of 0, 0.1, 1, 4, 20, and 75 mg/kg in a 21-d dose-response study. 2ME2 reduced body weight and serum cholesterol, increased uterine weight and epithelial cell height, and inhibited longitudinal and radial bone growth compared with values in the untreated OVX rat. All doses of 2ME2 maintained cancellous bone mass at the baseline level, the lowest effective dose being 20-fold less than a uterotrophic dose. Experiment 2: in an 8-wk experiment in adult OVX rats, a nonuterotrophic dose of 2ME2 (4 mg/kg·d) suppressed body weight gain, inhibited bone formation in cancellous bone and partially prevented bone loss in the tibial metaphysis. Experiment 3: in weanling rats, ICI 182,780 did not antagonize the effect of 2ME2. We conclude that 2ME2 antagonizes the skeletal changes that follow OVX at doses that have minimal or no effects in the uterus in both young and adult rats; 2ME2 does not appear to act via estrogen receptors and is active on bone at doses well below those required for tumor suppression in mice. 2ME2, through a novel pathway, may be a useful alternative to conventional hormone replacement therapy for prevention of postmenopausal bone loss.

scholarly journals Adipose tissue transplantation protects ob/ob mice from obesity, normalizes insulin sensitivity and restores fertility

2005 ◽  
Vol 186 (1) ◽  
pp. 203-211 ◽  
Author(s):  
Simon Klebanov ◽  
Clinton M Astle ◽  
Olga DeSimone ◽  
Vitaly Ablamunits ◽  
David E Harrison
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Therapeutic Potential ◽  
Body Weight Gain ◽  
Hormone Replacement ◽  
Tolerance Test ◽  
Reduced Body ◽  
Insulin Tolerance

Adipose tissue affects metabolism by secreting various adipokines. Lipodystropic mice benefit both from leptin replacement therapy and from transplantation of normal fat. Leptin-deficient Lepob/Lepob (ob/ob) mice can also be treated with leptin. Surprisingly, there have been no reports of successful treatment of obese ob/ob mice by transplantation of normal white adipose tissue (WAT). If WAT transplantation is ineffective in treating insulin resistance and diabetes in obese individuals, its applicability may be limited in humans as such abnormalities are usually associated with obesity. In the current study, we tested whether WAT transplantation might prevent, and even reverse, abnormalities characteristic of ob/ob mice. To assess the preventive potential, 6-week-old ob/ob mice were transplanted, subcutaneously, with gonadal fat pads from normal mice. Profound effects on multiple physiological phenotypes were achieved despite leptin levels below 25% of those in control mice. WAT from one donor reduced body weight gain, and WAT from 4 or 8 donors prevented obesity in ob/ob mice. Nonfasting insulin levels and insulin tolerance test were normalized. Corticosterone elevation was also prevented. Finally, WAT from 4 donors restored fertility in ob/ob females. The effects of WAT transplantation were long-lasting, with body weight gain suppressed for at least 40 weeks. To assess the therapeutic potential, obese 13-month-old ob/ob mice with a long history of leptin deficiency were used. Their body weight decreased by approximately 50% when transplanted with WAT from 8 donors. As in young recipients, transplantation greatly reduced nonfasting insulin, suggesting normalized insulin sensitivity. Thus, WAT transplantation was effective for both prevention and therapy. In the future, WAT transplantation may become a useful alternative to hormone replacement in treating not only lipodystropy, but also certain types of obesity.

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