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

2021 ◽  
Author(s):  
Piotr J Czernik ◽  
Rachel M. Golonka ◽  
Saroj Chakraborty ◽  
Beng San Yeoh ◽  
Ahmed A Abokor ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Mass ◽  
Bone Growth ◽  
Elevated Serum ◽  
Male Rats ◽  
Bone Lengthening ◽  
Mineral Density ◽  
Germ Free ◽  
Hepatic Expression ◽  
Gut Colonization

Integration of microbiota in a host begins at birth and progresses during adolescence, forming a multidirectional system of physiologic interactions. Here, we present an instantaneous effect of natural, bacterial gut colonization on the acceleration of longitudinal and radial bone growth in germ-free born, 7-week-old male rats. 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 the 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 indicating that not only bone mass but also bone marrow environment is under control of gut microbiota signaling. The changes in bone status paralleled with a positive shift in microbiota composition toward short chain fatty acids (SCFA)-producing microbes and a considerable increase in cecal SCFA concentrations, specifically butyrate. Further, reconstitution of the host holobiont increased hepatic expression of IGF-1 and its circulating levels. Elevated 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. Overall, the presented model of conventionalized germ-free rats could be used to study microbiota-based therapeutics for combatting dysbiosis-related bone disorders.

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 MicroRNA-29a represses osteoclast formation and protects against osteoporosis by regulating PCAF-mediated RANKL and CXCL12

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Wei-Shiung Lian ◽  
Jih-Yang Ko ◽  
Yu-Shan Chen ◽  
Huei-Jing Ke ◽  
Chin-Kuei Hsieh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Mass ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Estrogen Deficiency ◽  
Biomechanical Property ◽  
Mineral Density ◽  
Cxcl12 Expression ◽  
Osteogenic Cells

Abstract Osteoporosis deteriorates bone mass and biomechanical strength, becoming a life-threatening cause to the elderly. MicroRNA is known to regulate tissue remodeling; however, its role in the development of osteoporosis remains elusive. In this study, we uncovered that silencing miR-29a expression decreased mineralized matrix production in osteogenic cells, whereas osteoclast differentiation and pit formation were upregulated in bone marrow macrophages as co-incubated with the osteogenic cells in transwell plates. In vivo, decreased miR-29a expression occurred in ovariectomy-mediated osteoporotic skeletons. Mice overexpressing miR-29a in osteoblasts driven by osteocalcin promoter (miR-29aTg/OCN) displayed higher bone mineral density, trabecular volume and mineral acquisition than wild-type mice. The estrogen deficiency-induced loss of bone mass, trabecular morphometry, mechanical properties, mineral accretion and osteogenesis of bone marrow mesenchymal cells were compromised in miR-29aTg/OCN mice. miR-29a overexpression also attenuated the estrogen loss-mediated excessive osteoclast surface histopathology, osteoclast formation of bone marrow macrophages, receptor activator nuclear factor-κ ligand (RANKL) and C–X–C motif chemokine ligand 12 (CXCL12) expression. Treatment with miR-29a precursor improved the ovariectomy-mediated skeletal deterioration and biomechanical property loss. Mechanistically, miR-29a inhibited RANKL secretion in osteoblasts through binding to 3′-UTR of RANKL. It also suppressed the histone acetyltransferase PCAF-mediated acetylation of lysine 27 in histone 3 (H3K27ac) and decreased the H3K27ac enrichment in CXCL12 promoters. Taken together, miR-29a signaling in osteogenic cells protects bone tissue from osteoporosis through repressing osteoclast regulators RANKL and CXCL12 to reduce osteoclastogenic differentiation. Arrays of analyses shed new light on the miR-29a regulation of crosstalk between osteogenic and osteoclastogenic cells. We also highlight that increasing miR-29a function in osteoblasts is beneficial for bone anabolism to fend off estrogen deficiency-induced excessive osteoclastic resorption and osteoporosis.

scholarly journals MECHANISMS IN ENDOCRINOLOGY: Bone marrow adiposity and bone, a bad romance?

2018 ◽  
Vol 179 (4) ◽  
pp. R165-R182 ◽  
Author(s):  
Tareck Rharass ◽  
Stéphanie Lucas
Keyword(s):  
Bone Marrow ◽  
Bone Growth ◽  
Bone Marrow Cells ◽  
Adult Life ◽  
Osteoclast Formation ◽  
Childhood And Adolescence ◽  
Primary Osteoporosis ◽  
Mineral Density ◽  
Paracrine Factors ◽  
Haematopoietic Tissue

Bone marrow adipocytes (BMA-) constitute an original and heterogeneous fat depot whose development appears interlinked with bone status throughout life. The gradual replacement of the haematopoietic tissue by BMA arises in a well-ordered way during childhood and adolescence concomitantly to bone growth and continues at a slower rate throughout the adult life. Importantly, BM adiposity quantity is found well associated with bone mineral density (BMD) loss at different skeletal sites in primary osteoporosis such as in ageing or menopause but also in secondary osteoporosis consecutive to anorexia nervosa. Since BMA and osteoblasts originate from a common mesenchymal stem cell, adipogenesis is considered as a competitive process that disrupts osteoblastogenesis. Besides, most factors secreted by bone and bone marrow cells (ligands and antagonists of the WNT/β-catenin pathway, BMP and others) reciprocally regulate the two processes. Hormones such as oestrogens, glucocorticoids, parathyroid and growth hormones that control bone remodelling also modulate the differentiation and the activity of BMA. Actually, BMA could also contribute to bone loss through the release of paracrine factors altering osteoblast and/or osteoclast formation and function. Based on clinical and fundamental studies, this review aims at presenting and discussing these current arguments that support but also challenge the involvement of BMA in the bone mass integrity.

scholarly journals Early-Onset Type 2 Diabetes Impairs Skeletal Acquisition in the Male TALLYHO/JngJ Mouse

Endocrinology ◽  
2014 ◽  
Vol 155 (10) ◽  
pp. 3806-3816 ◽  
Author(s):  
M. J. Devlin ◽  
M. Van Vliet ◽  
K. Motyl ◽  
L. Karim ◽  
D. J. Brooks ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bone Marrow ◽  
Bone Mass ◽  
Early Onset ◽  
Volume Fraction ◽  
Mineral Density ◽  
Bone Volume Fraction ◽  
Skeletal Acquisition

Abstract Type 2 diabetes (T2D) incidence in adolescents is rising and may interfere with peak bone mass acquisition. We tested the effects of early-onset T2D on bone mass, microarchitecture, and strength in the TALLYHO/JngJ mouse, which develops T2D by 8 weeks of age. We assessed metabolism and skeletal acquisition in male TALLYHO/JngJ and SWR/J controls (n = 8–10/group) from 4 weeks to 8 and 17 weeks of age. Tallyho mice were obese; had an approximately 2-fold higher leptin and percentage body fat; and had lower bone mineral density vs SWR at all time points (P < .03 for all). Tallyho had severe deficits in distal femur trabecular bone volume fraction (−54%), trabecular number (−27%), and connectivity density (−82%) (P < .01 for all). Bone formation was higher in Tallyho mice at 8 weeks but lower by 17 weeks of age vs SWR despite similar numbers of osteoblasts. Bone marrow adiposity was 7- to 50-fold higher in Tallyho vs SWR. In vitro, primary bone marrow stromal cell differentiation into osteoblast and adipocyte lineages was similar in SWR and Tallyho, suggesting skeletal deficits were not due to intrinsic defects in Tallyho bone-forming cells. These data suggest the Tallyho mouse might be a useful model to study the skeletal effects of adolescent T2D.

scholarly journals Astragalus Extract Mixture HT042 Improves Bone Growth, Mass, and Microarchitecture in Prepubertal Female Rats: A Microcomputed Tomographic Study

2017 ◽  
Vol 2017 ◽  
pp. 1-7
Author(s):  
Jungbin Song ◽  
Sung Hyun Lee ◽  
Donghun Lee ◽  
Hocheol Kim
Keyword(s):  
Bone Mass ◽  
Cortical Bone ◽  
Bone Growth ◽  
Volume Fraction ◽  
Control Diet ◽  
Female Rats ◽  
Volumetric Bone Mineral Density ◽  
Mineral Density ◽  
Longitudinal Bone Growth ◽  
Tibial Length

Astragalus extract mixture HT042 is a standardized multiherbal mixture comprising Astragalus membranaceus, Eleutherococcus senticosus, and Phlomis umbrosa, which has proven to promote children’s height growth. The aim of this study was to investigate the effects of HT042 on longitudinal bone growth, bone mass, and bone microstructure in growing rats using a high-resolution microcomputed tomography system. Four-week-old female rats were fed an HT042-containing diet for 2 weeks. Tibial length was measured at baseline and weekly in vivo. At the end of the study, volumetric bone mineral density (vBMD) and microarchitectural parameters were estimated in the trabecular and cortical bone of the tibia. Tibial length gain was significantly increased by HT042 compared to that reported with the control diet. In the proximal tibial metaphysis, HT042-treated rats had significantly higher trabecular vBMD, bone volume fraction, and trabecular number and lower trabecular separation, trabecular pattern factor, and structure model index values than control rats did. Total cross-sectional area and bone area of the cortical bone in the tibial diaphysis also increased. These findings suggest that HT042 increases longitudinal bone growth rate, improves trabecular bone mass, and enhances the microarchitecture of trabecular and cortical bone during growth.

scholarly journals Monomethylfumarate protects against ovariectomy-related changes in body composition

2019 ◽  
Vol 243 (1) ◽  
pp. 15-26 ◽  
Author(s):  
Anna E Bollag ◽  
Tianyang Guo ◽  
Ke-Hong Ding ◽  
Vivek Choudhary ◽  
Xunsheng Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Bone Marrow ◽  
Body Weight ◽  
Bone Mass ◽  
The United States ◽  
Nuclear Factor ◽  
Mineral Density ◽  
Marrow Adiposity ◽  
Nrf2 Target Gene ◽  
Anti Oxidant

Osteoporosis, low bone mass that increases fracture susceptibility, affects approximately 75 million individuals in the United States, Europe and Japan, with the number of osteoporotic fractures expected to increase by more than three-fold over the next 50 years. Bone mass declines with age, although the mechanisms for this decrease are unclear. Aging enhances production of reactive oxygen species, which can affect bone formation and breakdown. The multiple sclerosis drug Tecfidera contains dimethylfumarate, which is rapidly metabolized to monomethylfumarate (MMF); MMF is thought to function through nuclear factor erythroid-derived-2-like-2 (NRF2), a transcription factor activated by oxidative stress which induces the expression of endogenous anti-oxidant systems. We hypothesized that MMF-elicited increases in anti-oxidants would inhibit osteopenia induced by ovariectomy, as a model of aging-related osteoporosis and high oxidative stress. We demonstrated that MMF activated NRF2 and induced anti-oxidant NRF2 target gene expression in bone marrow-derived mesenchymal stem cells. Sham-operated or ovariectomized adult female mice were fed chow with or without MMF and various parameters were monitored. Ovariectomy produced the expected effects, decreasing bone mineral density and increasing body weight, fat mass, bone marrow adiposity and serum receptor activator of nuclear factor-kappa-B ligand (RANKL) levels. MMF decreased fat but not lean mass. MMF improved trabecular bone microarchitecture after adjustment for body weight, although the unadjusted data showed few differences; MMF also tended to increase adjusted cortical bone and to reduce bone marrow adiposity and serum RANKL levels. Because these results suggest the possibility that MMF might be beneficial for bone, further investigation seems warranted.

scholarly journals Long-term effects on bone of postnatal immunization against GHRH in female and male rats

2003 ◽  
Vol 177 (1) ◽  
pp. 93-100 ◽  
Author(s):  
V Sibilia ◽  
AE Rigamonti ◽  
F Pagani ◽  
N Lattuada ◽  
F Guidobono ◽  
...  
Keyword(s):  
Bone Mineral ◽  
Bone Growth ◽  
Passive Immunization ◽  
Female Rats ◽  
Male Rats ◽  
Whole Body ◽  
Long Term Effects ◽  
Mineral Density ◽  
Male And Female Rats ◽  
Igf I

The effects of neonatal passive immunization against GHRH on bone was examined in male and female rats. Pups were treated subcutaneously with GHRH-antiserum (GHRH-Ab) from day 1 to day 10 of age. Bone mineral content (BMC) and bone mineral density (BMD) were evaluated at monthly intervals until 7 months. Markers of bone resorption (urinary lysylpyridinoline, LP), bone formation (serum osteocalcin, OC) and serum IGF-I were measured at 2, 3 and 7 months. In male rats, GHRH-Ab did not modify BMC and BMD when compared with controls. In contrast, female rats demonstrated lower whole body and femoral BMC and BMD from 2 to 7 months of age. Reduced bone growth in the females was associated with lower IGF-I levels than controls at 2 and 3 months of age, whereas in males IGF-I titers did not change during the period of the study. LP excretion was higher in GHRH-Ab-treated rats at 2 and 3 months in both sexes. In females, no difference in OC values was recorded, whereas in GHRH-Ab-treated males, there was an increase in OC levels at 2 and 3 months. These data indicate that transient GHRH deprivation induces an osteopenic effect in female rats which is not evident in male rats.

Immunoscintigraphy in Medullary Thyroid Cancer Using an 123I- or 111ln-Labelled Monoclonal Anti-CEA Antibody Fragment

1986 ◽  
Vol 25 (06) ◽  
pp. 227-231 ◽  
Author(s):  
Chr. Eilles ◽  
W. Spiegel ◽  
W. Becker ◽  
W. Börner ◽  
Chr. Reiners
Keyword(s):  
Bone Marrow ◽  
Thyroid Cancer ◽  
Potassium Iodide ◽  
Medullary Thyroid Cancer ◽  
Elevated Serum ◽  
Antibody Fragment ◽  
Special Importance ◽  
Medullary Thyroid ◽  
Medullary Cancer ◽  
Serum Cea

The monoclonal anti-CEA F(ab’)2 fragment MAb BW 431/31, labelled with 123I or111 In, was used for immunoscintigraphy (IS) in 9 patients with medullary cancer of the thyroid (CCC). The results of 11 studies lead to the following conclusions: 1) When using radioiodine as a label for MAb in IS, potassium iodide is absolutely necessary to block the thyroid which is of special importance in patients with thyroid cancer; 2) Preinjection of “cold” MAb reduces the relatively high unspecific uptake (especially in bone marrow) of MAb BW 431/31, which is of special importance for the antibody labelled with 111 In; 3) IS with MAb BW 413/31 in patients with CCC and elevated serum CEA is positive only in cases with large secondaries; and 4) In patients with CCC and several manifestations of secondaries, only a single (large) metastasis may be apparent.

scholarly journals Association between Visceral and Bone Marrow Adipose Tissue and Bone Quality in Sedentary and Physically Active Ovariectomized Wistar Rats

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 478
Author(s):  
Hélder Fonseca ◽  
Andrea Bezerra ◽  
Ana Coelho ◽  
José Alberto Duarte
Keyword(s):  
Physical Activity ◽  
Bone Marrow ◽  
Adipose Tissue ◽  
Bone Mass ◽  
Bone Quality ◽  
Wistar Rats ◽  
Biomechanical Properties ◽  
Physically Active ◽  
Bone Formation Rate ◽  
Marrow Adiposity

Background: Obesity is considered protective for bone mass, but this view has been progressively challenged. Menopause is characterized by low bone mass and increased adiposity. Our aim was to determine how visceral and bone marrow adiposity change following ovariectomy (OVX), how they correlate with bone quality and if they are influenced by physical activity. Methods: Five-month-old Wistar rats were OVX or sham-operated and maintained in sedentary or physically active conditions for 9 months. Visceral and bone marrow adiposity as well as bone turnover, femur bone quality and biomechanical properties were assessed. Results: OVX resulted in higher weight, visceral and bone marrow adiposity. Visceral adiposity correlated inversely with femur Ct.Th (r = −0.63, p < 0.001), BV/TV (r = −0.67, p < 0.001), Tb.N (r = −0.69, p < 0.001) and positively with Tb.Sp (r = 0.58, p < 0.001). Bone marrow adiposity also correlated with bone resorption (r = 0.47, p < 0.01), bone formation rate (r = −0.63, p < 0.01), BV/TV (r = −0.85, p < 0.001), Ct.Th (r = −0.51, p < 0.0.01), and with higher empty osteocyte lacunae (r = 0.39, p < 0.05), higher percentage of osteocytes with oxidative stress (r = 0.64, p < 0.0.01) and lower femur maximal stress (r = −0.58, p < 0.001). Physical activity correlated inversely with both visceral (r = −0.74, p < 0.01) and bone marrow adiposity (r = −0.92, p < 0.001). Conclusions: OVX increases visceral and bone marrow adiposity which are associated with inferior bone quality and biomechanical properties. Physical activity could contribute to reduce adipose tissue and thereby improve bone quality.

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