scholarly journals Gut microbiota induce IGF-1 and promote bone formation and growth

2016 ◽  
Vol 113 (47) ◽  
pp. E7554-E7563 ◽  
Author(s):  
Jing Yan ◽  
Jeremy W. Herzog ◽  
Kelly Tsang ◽  
Caitlin A. Brennan ◽  
Maureen A. Bower ◽  
...  
Keyword(s):  
Bone Formation ◽  
Gut Microbiota ◽  
Bone Mass ◽  
Bone Growth ◽  
Serum Levels ◽  
Short Chain Fatty Acids ◽  
Skeletal Growth ◽  
Microbial Colonization ◽  
Adult Mice ◽  
Specific Pathogen

Appreciation of the role of the gut microbiome in regulating vertebrate metabolism has exploded recently. However, the effects of gut microbiota on skeletal growth and homeostasis have only recently begun to be explored. Here, we report that colonization of sexually mature germ-free (GF) mice with conventional specific pathogen-free (SPF) gut microbiota increases both bone formation and resorption, with the net effect of colonization varying with the duration of colonization. Although colonization of adult mice acutely reduces bone mass, in long-term colonized mice, an increase in bone formation and growth plate activity predominates, resulting in equalization of bone mass and increased longitudinal and radial bone growth. Serum levels of insulin-like growth factor 1 (IGF-1), a hormone with known actions on skeletal growth, are substantially increased in response to microbial colonization, with significant increases in liver and adipose tissue IGF-1 production. Antibiotic treatment of conventional mice, in contrast, decreases serum IGF-1 and inhibits bone formation. Supplementation of antibiotic-treated mice with short-chain fatty acids (SCFAs), products of microbial metabolism, restores IGF-1 and bone mass to levels seen in nonantibiotic-treated mice. Thus, SCFA production may be one mechanism by which microbiota increase serum IGF-1. Our study demonstrates that gut microbiota provide a net anabolic stimulus to the skeleton, which is likely mediated by IGF-1. Manipulation of the microbiome or its metabolites may afford opportunities to optimize bone health and growth.

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 Reconstitution of the host holobiont in germ-free rats acutely increases bone growth and affects marrow cellular content

2020 ◽  
Author(s):  
PJ Czernik ◽  
RM Golonka ◽  
S Chakraborty ◽  
BS Yeoh ◽  
A Abokor ◽  
...  
Keyword(s):  
Bone Growth ◽  
Serum Levels ◽  
Short Chain Fatty Acids ◽  
Male Rats ◽  
Bone Lengthening ◽  
Mineral Density ◽  
Growth Plate Chondrocytes ◽  
Germ Free ◽  
Hepatic Expression ◽  
Short Term Exposure

AbstractIn recent years there has been growing evidence regarding the effect of microbiota on the skeletal growth and homeostasis. Here we present, for the first time, accelerated longitudinal and radial bone growth in young (7-week-old) germ-free male rats after short-term exposure to a newly established gut microbiota. Changes in bone mass and structure were analyzed after 10 days following the onset of colonization through cohousing with conventional rats and revealed unprecedented acceleration of bone accrual in cortical and trabecular compartments, increased bone tissue mineral density, improved proliferation and hypertrophy of growth plate chondrocytes, bone lengthening, and preferential deposition of periosteal bone in tibia diaphysis. In addition, the number of small-in-size adipocytes increased, while the number of megakaryocytes decreased, in the bone marrow of conventionalized germ-free rats. The observed changes in bone status were paralleled with a positive shift in microbiota composition towards short chain fatty acids (SCFA)-producing microbes, which reflected a dramatic increase in cecal concentration of SCFA, specifically butyrate. Further, reconstitution of the host holobiont increased hepatic expression of IGF-1 and its circulating levels, implicating an involvement of the somatotropic axis. Increased serum levels of 25-hydroxy vitamin D and alkaline phosphatase pointed toward an active process of bone formation. The acute stimulatory effect on bone growth occurred independently of body mass increase and resembled reversal of dysbiosis in adolescence, which is marked by rapid skeletal expansion. These findings may help in developing microbiota-based therapeutics to combat bone related disorders resulting from hormonal defects and/or malnutrition in children and adolescence.

scholarly journals Quantifying the impact of gut microbiota on inflammation and hypertensive organ damage

2021 ◽  
Author(s):  
Elllen G Avery ◽  
Hendrik Bartolomaeus ◽  
Ariana Rauch ◽  
Chia-Yu Chen ◽  
Gabriele N'diaye ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Th17 Cells ◽  
Suppressor Cells ◽  
Short Chain Fatty Acids ◽  
Organ Damage ◽  
Microbial Colonization ◽  
Cardiac Damage ◽  
The Impact ◽  
Colonization Status

Aims: Hypertension (HTN) can lead to heart and kidney damage. The gut microbiota has been linked to HTN, although it is difficult to estimate its significance due to the variety of other features known to influence HTN. Methods and Results: In the present study, we used germ-free (GF) and colonized (COL) littermate mice to quantify the impact of microbial colonization on organ damage in HTN. Four-week-old male GF C57BL/6J littermates were randomized to remain GF or receive microbial colonization. HTN was induced by subcutaneous infusion with angiotensin (Ang) II (1.44mg/kg/d) and 1% NaCl in the drinking water; sham-treated mice served as control. Renal damage was exacerbated in GF mice, whereas cardiac damage was more comparable between COL and GF, suggesting that the kidney is more sensitive to microbial influence. Multivariate analysis revealed a larger effect of HTN in GF mice. Serum metabolomics demonstrated that the colonization status influences circulating metabolites relevant to HTN. Importantly, GF mice were deficient in anti-inflammatory fecal short-chain fatty acids (SCFA). Flow cytometry showed that the microbiome has an impact on the induction of anti-hypertensive myeloid-derived suppressor cells and pro-inflammatory Th17 cells in HTN. In vitro inducibility of Th17 cells was significantly higher for cells isolated from GF than conventionally raised mice. Conclusion: Microbial colonization status of mice had potent effects on their phenotypic response to a hypertensive stimulus, and the kidney is a highly microbiota-susceptible target organ in HTN. The magnitude of the pathogenic response in GF mice underscores the role of the microbiome in mediating inflammation in HTN.

scholarly journals Microbial Colonization in Adulthood Shapes the Intestinal Macrophage Compartment

2019 ◽  
Vol 13 (9) ◽  
pp. 1173-1185 ◽  
Author(s):  
Franziska Schmidt ◽  
Katja Dahlke ◽  
Arvind Batra ◽  
Jacqueline Keye ◽  
Hao Wu ◽  
...  
Keyword(s):  
Intestinal Wall ◽  
Functional Restoration ◽  
Microbial Colonization ◽  
Germ Free ◽  
Adult Mice ◽  
Immune Mediated ◽  
Complete Restoration ◽  
Specific Pathogen ◽  
Intestinal Macrophage ◽  
The Impact

Abstract Background and Aims Contact with distinct microbiota early in life has been shown to educate the mucosal immune system, hence providing protection against immune-mediated diseases. However, the impact of early versus late colonization with regard to the development of the intestinal macrophage compartment has not been studied so far. Methods Germ-free mice were colonized with specific-pathogen-free [SPF] microbiota at the age of 5 weeks. The ileal and colonic macrophage compartment were analysed by immunohistochemistry, flow cytometry, and RNA sequencing 1 and 5 weeks after colonization and in age-matched SPF mice, which had had contact with microbiota since birth. To evaluate the functional differences, dextran sulfate sodium [DSS]-induced colitis was induced, and barrier function analyses were undertaken. Results Germ-free mice were characterized by an atrophied intestinal wall and a profoundly reduced number of ileal macrophages. Strikingly, morphological restoration of the intestine occurred within the first week after colonization. In contrast, ileal macrophages required 5 weeks for complete restoration, whereas colonic macrophages were numerically unaffected. However, following DSS exposure, the presence of microbiota was a prerequisite for colonic macrophage infiltration. One week after colonization, mild colonic inflammation was observed, paralleled by a reduced inflammatory response after DSS treatment, in comparison with SPF mice. This attenuated inflammation was paralleled by a lack of TNFα production of LPS-stimulated colonic macrophages from SPF and colonized mice, suggesting desensitization of colonized mice by the colonization itself. Conclusions This study provides the first data indicating that after colonization of adult mice, the numeric, phenotypic, and functional restoration of the macrophage compartment requires the presence of intestinal microbiota and is time dependent.

The effects of systemic insulin, insulin-like growth factor-I and growth hormone on bone growth and turnover in spontaneously diabetic BB rats

1992 ◽  
Vol 134 (3) ◽  
pp. 485-492 ◽  
Author(s):  
J. Verhaeghe ◽  
A. M. H. Suiker ◽  
W. J. Visser ◽  
E. Van Herck ◽  
R. Van Bree ◽  
...  
Keyword(s):  
Weight Gain ◽  
Growth Factor ◽  
Bone Formation ◽  
Bone Growth ◽  
Diabetic Rats ◽  
Skeletal Growth ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Bb Rats ◽  
Igf I

ABSTRACT Spontaneously diabetic BB rats have a markedly depressed longitudinal bone growth and bone formation/turnover. In this study, male diabetic BB rats were infused intraperitoneally or subcutaneously for 2 weeks with hormones that are believed to stimulate skeletal growth and/or trabecular bone formation: insulin (3 or 4 U/day), human GH (hGH; 400 mU/day), recombinant human insulin-like growth factor-I (rhIGF-I; 300 or 600 μg/day) and testosterone (80 μg/100 g body weight per day). Saline-treated diabetic BB rats had decreased plasma concentrations of IGF-I and osteocalcin (OC) (OC, 3·7 ±0·3 vs 13·1 ± 0·8 (s.e.m.) nmol/l in controls); bone histomorphometry showed decreased epiphyseal width, osteoblast surface (0·04±0·04 vs 1·5±0·3%) and osteoid surface, and mineral apposition rate (MAR) (1·8±0·5 vs 7·9±0·6 μm/day). Testosterone and hGH infusions had no effect on weight loss or on decreased skeletal growth and bone formation of diabetic rats, nor did they increase plasma IGF-I concentrations. Insulin infusions into diabetic rats resulted in hyperinsulinaemia and accelerated weight gain. The epiphyseal width, osteoblast/osteoid surfaces and OC levels of insulin-treated rats were normalized or stimulated well above control values (osteoblast surface, 4·3 ±0·8%; plasma OC, 16·1 ± 1·4 nmol/l); the MAR (4·0 ± 0·9 μm/day) was only partly corrected after the 2-week infusion. Infusions of rhIGF-I into diabetic rats doubled but did not restore plasma IGF-I levels to normal; weight gain, however, was similar to that in control rats. IGF-I treatment had no effect on epiphyseal width, osteoblast/osteoid surfaces and OC concentrations, but improved the decreased MAR (4·6±1·2 μm/day). These results indicate (1) that the decreased epiphyseal width and osteoblast recruitment of diabetic BB rats are directly related to their insulin deficiency, and (2) that IGF-I, administered systemically, corrects, in part, the decreased MAR in diabetes, suggesting a role in osteoblast function and/or mineralization. Journal of Endocrinology (1992) 134, 485–492

scholarly journals Leptin stimulates bone formation in ob/ob mice at doses having minimal impact on energy metabolism

2017 ◽  
Vol 232 (3) ◽  
pp. 461-474 ◽  
Author(s):  
Kenneth A Philbrick ◽  
Carmen P Wong ◽  
Adam J Branscum ◽  
Russell T Turner ◽  
Urszula T Iwaniec
Keyword(s):  
Energy Metabolism ◽  
Bone Formation ◽  
Bone Growth ◽  
Serum Levels ◽  
Protein Product ◽  
Serum Leptin ◽  
Minimal Impact ◽  
Expression Of Genes ◽  
Stat Signaling ◽  
The Impact

Leptin, the protein product of the ob gene, is essential for normal bone growth, maturation and turnover. Peripheral actions of leptin occur at lower serum levels of the hormone than central actions because entry of leptin into the central nervous system (CNS) is limited due to its saturable transport across the blood–brain barrier (BBB). We performed a study in mice to model the impact of leptin production associated with different levels of adiposity on bone formation and compared the response with well-established centrally mediated actions of the hormone on energy metabolism. Leptin was infused (0, 4, 12, 40, 140 or 400 ng/h) for 12 days into 6-week-old female ob/ob mice (n = 8/group) using sc-implanted osmotic pumps. Treatment resulted in a dose-associated increase in serum leptin. Bone formation parameters were increased at EC50 infusion rates of 7–17 ng/h, whereas higher levels (EC50, 40–80 ng/h) were required to similarly influence indices of energy metabolism. We then analyzed gene expression in tibia and hypothalamus at dose rates of 0, 12 and 140 ng/h; the latter dose resulted in serum leptin levels similar to WT mice. Infusion with 12 ng/h leptin increased the expression of genes associated with Jak/Stat signaling and bone formation in tibia with minimal effect on Jak/Stat signaling and neurotransmitters in hypothalamus. The results suggest that leptin acts peripherally to couple bone acquisition to energy availability and that limited transport across the BBB insures that the growth-promoting actions of peripheral leptin are not curtailed by the hormone’s CNS-mediated anorexigenic actions.

scholarly journals Gut microbiota and fecal short-chain fatty acids are not associated with bone mass in healthy Chinese children: a cross-sectional study

2020 ◽  
Author(s):  
Fengyan Chen ◽  
Qinzhi Wei ◽  
Dafeng Xu ◽  
Yuanhuan Wei ◽  
Jue Wang ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Gut Microbiota ◽  
Bone Mass ◽  
Bone Mineral ◽  
Short Chain Fatty Acids ◽  
Chinese Children ◽  
Short Chain ◽  
Fecal Samples ◽  
Healthy Chinese ◽  
Total Body

Abstract Background The link between the gut microbiota, short-chain fatty acids (SCFAs), and bone loss has already been observed in animal models and a few human studies in adults, but no such study has been conducted in children. We aimed to investigate whether the gut microbiota and fecal SCFAs are associated with bone mass in healthy Chinese children aged 6–9 years. Methods In this study, 236 healthy children including 145 boys and 91 girls were enrolled. Fecal samples from children were collected, and DNA was extracted. 16S rRNA gene sequencing was used to characterize the composition of their gut microbiota. Total and 10 subtypes of SCFAs in the fecal samples were determined by high-performance liquid chromatography. Dual X-ray absorptiometry was used to measure the bone mineral density and bone mineral content (BMC) for total body and total body less head (TBLH). Size-adjusted BMC for TBLH was calculated. Result The boys showed less gut microbial diversity than the girls, as indicated by the Chao1 index (364.02 (63.07) vs. 375.12 (43.50), P = 0.018) and abundance-based coverage estimator (362.65 (54.48) vs. 381.07 (40.19), P = 0.007). No significant sex difference was found in the relative abundance of the gut microbiota at any level. Multiple regression analysis after adjustment for covariates and multiple test correction showed that neither gut microbial richness (β: −0.15–0.16, P: 0.376–0.984) nor fecal subtypes of or total SCFAs (β: −0.06–0.17, P: 0.699–0.979) were correlated with bone mass measures in total samples. Similar results were observed in sex-specific analysis. Conclusions Our results did not support the hypothesis that the gut microbiota and fecal SCFA concentrations are associated with bone mass in children.

scholarly journals IL-23 receptor deficiency results in lower bone mass via indirect regulation of bone formation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wida Razawy ◽  
Celso H. Alves ◽  
Marijke Koedam ◽  
Patrick S. Asmawidjaja ◽  
Adriana M. C. Mus ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Mass ◽  
Cortical Bone ◽  
Bone Growth ◽  
Osteoclast Differentiation ◽  
Bone Homeostasis ◽  
Littermate Control ◽  
Cortical Bone Mass

AbstractThe IL-23 receptor (IL-23R) signaling pathway has pleiotropic effects on the differentiation of osteoclasts and osteoblasts, since it can inhibit or stimulate these processes via different pathways. However, the potential role of this pathway in the regulation of bone homeostasis remains elusive. Therefore, we studied the role of IL-23R signaling in physiological bone remodeling using IL-23R deficient mice. Using µCT, we demonstrate that 7-week-old IL-23R−/− mice have similar bone mass as age matched littermate control mice. In contrast, 12-week-old IL-23R−/− mice have significantly lower trabecular and cortical bone mass, shorter femurs and more fragile bones. At the age of 26 weeks, there were no differences in trabecular bone mass and femur length, but most of cortical bone mass parameters remain significantly lower in IL-23R−/− mice. In vitro osteoclast differentiation and resorption capacity of 7- and 12-week-old IL-23R−/− mice are similar to WT. However, serum levels of the bone formation marker, PINP, are significantly lower in 12-week-old IL-23R−/− mice, but similar to WT at 7 and 26 weeks. Interestingly, Il23r gene expression was not detected in in vitro cultured osteoblasts, suggesting an indirect effect of IL-23R. In conclusion, IL-23R deficiency results in temporal and long-term changes in bone growth via regulation of bone formation.

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