scholarly journals Targeting adipocytic discoidin domain receptor 2 impedes fat gain while increasing bone mass

2021 ◽  
Author(s):  
Xiaoyu Yang ◽  
Jing Li ◽  
Liting Zhao ◽  
Yazhuo Chen ◽  
Zhijun Cui ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fatty Acid ◽  
Bone Mass ◽  
Specific Inhibitor ◽  
Mass Gain ◽  
Conditional Knockout ◽  
Discoidin Domain Receptor ◽  
Discoidin Domain Receptor 2 ◽  
Potential Strategy ◽  
First Time

AbstractObesity is closely associated with low-bone-mass disorder. Discoidin domain receptor 2 (DDR2) plays essential roles in skeletal metabolism, and is probably involved in fat metabolism. To test the potential role of DDR2 in fat and fat-bone crosstalk, Ddr2 conditional knockout mice (Ddr2Adipo) were generated in which Ddr2 gene is exclusively deleted in adipocytes by Adipoq Cre. We found that Ddr2Adipo mice are protected from fat gain on high-fat diet, with significantly decreased adipocyte size. Ddr2Adipo mice exhibit significantly increased bone mass and mechanical properties, with enhanced osteoblastogenesis and osteoclastogenesis. Marrow adipocyte is diminished in the bone marrow of Ddr2Adipo mice, due to activation of lipolysis. Fatty acid in the bone marrow was reduced in Ddr2Adipo mice. RNA-Seq analysis identified adenylate cyclase 5 (Adcy5) as downstream molecule of Ddr2. Mechanically, adipocytic Ddr2 modulates Adcy5-cAMP-PKA signaling, and Ddr2 deficiency stimulates lipolysis and supplies fatty acid for oxidation in osteoblasts, leading to the enhanced osteoblast differentiation and bone mass. Treatment of Adcy5 specific inhibitor abolishes the increased bone mass gain in Ddr2Adipo mice. These observations establish, for the first time, that Ddr2 plays an essential role in the crosstalk between fat and bone. Targeting adipocytic Ddr2 may be a potential strategy for treating obesity and pathological bone loss simultaneously.

Association of blood n-3 fatty acid with bone mass and bone marrow TRAP-5b in the elderly with and without hip fracture

2019 ◽  
Vol 30 (5) ◽  
pp. 1071-1078 ◽  
Author(s):  
B.-J. Kim ◽  
H. J. Yoo ◽  
S. J. Park ◽  
M. K. Kwak ◽  
S. H. Lee ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fatty Acid ◽  
Hip Fracture ◽  
Bone Mass ◽  
The Elderly ◽  
Trap 5B

DLX3 promotes bone marrow mesenchymal stem cell proliferation through H19/miR-675 axis

2017 ◽  
Vol 131 (22) ◽  
pp. 2721-2735 ◽  
Author(s):  
Na Zhao ◽  
Li Zeng ◽  
Yang Liu ◽  
Dong Han ◽  
Haochen Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Transgenic Mice ◽  
Bone Mass ◽  
Noncoding Rna ◽  
Marrow Mesenchymal Stem Cells ◽  
Negative Role ◽  
Proliferation Ability ◽  
Negative Factors ◽  
First Time

The underlying molecular mechanism of the increased bone mass phenotype in Tricho-dento-osseous (TDO) syndrome remains largely unknown. Our previous study has shown that the TDO point mutation c.533A>G, Q178R in DLX3 could increase bone density in a TDO patient and transgenic mice partially through delaying senescence in bone marrow mesenchymal stem cells (BMSCs). In the present study, we provided a new complementary explanation for TDO syndrome: the DLX3 (Q178R) mutation increased BMSCs proliferation through H19/miR-675 axis. We found that BMSCs derived from the TDO patient (TDO-BMSCs) had stronger proliferation ability than controls by clonogenic and CCK-8 assays. Next, experiments of overexpression and knockdown of wild-type DLX3 via lentiviruses in normal BMSCs confirmed the results by showing its negative role in cell proliferation. Through validated high-throughput data, we found that the DLX3 mutation reduced the expression of H19 and its coexpression product miR-675 in BMSCs. Function and rescue assays suggested that DLX3, long noncoding RNA H19, and miR-675 are negative factors in modulation of BMSCs proliferation as well as NOMO1 expression. The original higher proliferation rate and the expression of NOMO1 in TDO-BMSCs were suppressed after H19 restoration. Collectively, it indicates that DLX3 regulates BMSCs proliferation through H19/miR-675 axis. Moreover, the increased expression of NOMO1 and decreased H19/miR-675 expression in DLX3 (Q178R) transgenic mice, accompanying with accrual bone mass and density detected by micro-CT, further confirmed our hypothesis. In summary, we, for the first time, demonstrate that DLX3 mutation interferes with bone formation partially through H19/miR-675/NOMO1 axis in TDO syndrome.

scholarly journals Elucidating the Role of the Endocytic Protein Ap2a2 in Haematopoiesis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1568-1568
Author(s):  
Stephen Ting ◽  
Sara Rhost ◽  
Nicole Lee ◽  
Sarah Ghotb ◽  
Ruth Meex ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fatty Acid ◽  
Cell Division ◽  
Adaptor Protein ◽  
Conditional Knockout ◽  
Metabolic Effects ◽  
Lacz Reporter ◽  
Self Renewal ◽  
Endocytic Protein

Abstract The rare subpopulation of quiescent HSCs exists in limited numbers but upon in vivo requirement have the highest proliferative potency. Self-renewal via asymmetrical cell division (ACD) is vital for maintenance of HSC numbers and perturbation of this process can lead to an impaired hematopoietic system, with subsequent blood diseases such as acute leukemia and/or bone marrow failure. How and which HSCs are programmed for ACD remain central and unanswered questions. We have demonstrated that the endocytic protein, Ap2a2 distinguishes an asymmetrical from a symmetrical cell division during HSC mitoses, and when overexpressed enhances mouse HSC activity.Ap2a2 is a component of the Adaptor protein 2 complex that functions in clathrin-dependent endocytosis of receptors and nutrient cargo. The tetracycline-induceable H2B-GFP mouse (Foudi A. et al, Nature Biotech 2009) has revealed functional heterogeneity within the CD150+48- Lin-Sca+Kit+(LSK) HSC population, such that the GFPhigh subpopulation within the CD150+48- LSK is the true Long-Term repopulating HSCs (GFPhigh LT-HSCs). Using this mouse, we have shown that Ap2a2 is not only more highly expressed in the GFPhigh LT-HSCs but that Ap2a2 overexpression increases the fraction of this specific subpopulation from 20% to 60% at plus 20 weeks post-transplantation. To identify novel genes and pathways driving LT-HSC function and self-renewal, we are currently performing comparative gene expression analyses from the subpopulation of Ap2a2-transduced against control, vector-transduced GFPhighCD150+48-LSK LT-HSCs. To further investigate Ap2a2 in haematopoiesis, we have constructed an Ap2a2 conditional knockout mouse (Ap2a2 cKO) line, which has a LacZ reporter expressed from the endogenous Ap2a2 promoter. Our initial expression analyses with tissue LacZ staining shows relative increased staining in subpopulations of bone marrow cells and using a β-galactosidase (β-gal) flow cytometry method co-stained with CD150+48-LSK, have identified β-galhigh and β-gallow subpopulations. This suggests Ap2a2 expression may be an independent marker of LT-HSCs, which we are functionally assessing via comparative LSK -β-galhigh versus -β-gallow versus -β-galnegative transplantation assays. The specific function of Ap2a2 in developmental (Vav-Cre) and adult (Mx-Cre) haematopoiesis is being investigated by respective tissue specific-Cre matings with the Ap2a2fl/flmice. Mechanistically, a recent publication (Ito K. et al, Nature Med 2012) identified the importance of PPAR-δ/β-fatty acid oxidation regulation for both maintenance and ACD ofHSCs. Ap2a2 is a target of PPAR-α (Buroker N. et al Protein J 2012). Our hypothesis states that the role of Ap2a2 in LT-HSCs involves the lipid metabolic pathway, which would uniquely link endocytosis to metabolism. To this end, using our Ap2a2-LacZ reporter mouse, we have shown intense and specific LacZ expression in adipocytes of the bone marrow and other lipid containing organs. In addition, perturbation of Ap2a2 results in altered lipid droplet formation and impaired triacylgylceride storage. We are currently investigating the oxidative phosphorylation, anaerobic glycolysis and fatty acid metabolic effects in the context of altered Ap2a2 expression. Disclosures No relevant conflicts of interest to declare.

scholarly journals The glucocorticoid receptor in osteoprogenitors regulates bone mass and marrow fat

2019 ◽  
Vol 243 (1) ◽  
pp. 27-42 ◽  
Author(s):  
Jessica L Pierce ◽  
Ke-Hong Ding ◽  
Jianrui Xu ◽  
Anuj K Sharma ◽  
Kanglun Yu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Mass ◽  
Glucocorticoid Receptor ◽  
Cortical Bone ◽  
Metabolic Stress ◽  
Conditional Knockout ◽  
Marrow Fat ◽  
Adrenergic Signaling ◽  
Glucocorticoid Signaling ◽  
Ad Libitum

Excess fat within bone marrow is associated with lower bone density. Metabolic stressors such as chronic caloric restriction (CR) can exacerbate marrow adiposity, and increased glucocorticoid signaling and adrenergic signaling are implicated in this phenotype. The current study tested the role of glucocorticoid signaling in CR-induced stress by conditionally deleting the glucocorticoid receptor (Nr3c1; hereafter abbreviated as GR) in bone marrow osteoprogenitors (Osx1-Cre) of mice subjected to CR and ad libitum diets. Conditional knockout of the GR (GR-CKO) reduced cortical and trabecular bone mass as compared to WT mice under both ad libitum feeding and CR conditions. No interaction was detected between genotype and diet, suggesting that the GR is not required for CR-induced skeletal changes. The lower bone mass in GR-CKO mice, and the further decrease in bone by CR, resulted from suppressed bone formation. Interestingly, treatment with the β-adrenergic receptor antagonist propranolol mildly but selectively improved metrics of cortical bone mass in GR-CKO mice during CR, suggesting interaction between adrenergic and glucocorticoid signaling pathways that affects cortical bone. GR-CKO mice dramatically increased marrow fat under both ad libitum and CR-fed conditions, and surprisingly propranolol treatment was unable to rescue CR-induced marrow fat in either WT or GR-CKO mice. Additionally, serum corticosterone levels were selectively elevated in GR-CKO mice with CR, suggesting the possibility of bone–hypothalamus–pituitary–adrenal crosstalk during metabolic stress. This work highlights the complexities of glucocorticoid and β-adrenergic signaling in stress-induced changes in bone mass, and the importance of GR function in suppressing marrow adipogenesis while maintaining healthy bone mass.

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.

scholarly journals Aberrant Expression of TLR2, TLR7, TLR9, Splicing Variants of TLR4 and MYD88 in Chronic Lymphocytic Leukemia Patients

2021 ◽  
Vol 10 (4) ◽  
pp. 867
Author(s):  
Katarzyna Skorka ◽  
Paulina Wlasiuk ◽  
Agnieszka Karczmarczyk ◽  
Krzysztof Giannopoulos
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Cytotoxic T Cells ◽  
Lymphocytic Leukemia ◽  
Aberrant Expression ◽  
Downstream Signaling ◽  
Splicing Variants ◽  
High Level ◽  
Time To First Treatment ◽  
First Time

Functional toll-like receptors (TLRs) could modulate anti-tumor effects by activating inflammatory cytokines and the cytotoxic T-cells response. However, excessive TLR expression could promote tumor progression, since TLR-induced inflammation might stimulate cancer cells expansion into the microenvironment. Myd88 is involved in activation NF-κB through TLRs downstream signaling, hence in the current study we provided, for the first time, a complex characterization of expression of TLR2, TLR4, TLR7, TLR9, and MYD88 as well as their splicing forms in two distinct compartments of the microenvironment of chronic lymphocytic leukemia (CLL): peripheral blood and bone marrow. We found correlations between MYD88 and TLRs expressions in both compartments, indicating their relevant cooperation in CLL. The MYD88 expression was higher in CLL patients compared to healthy volunteers (HVs) (0.1780 vs. 0.128, p < 0.0001). The TLRs expression was aberrant in CLL compared to HVs. Analysis of survival curves revealed a shorter time to first treatment in the group of patients with low level of TLR4(3) expression compared to high level of TLR4(3) expression in bone marrow (13 months vs. 48 months, p = 0.0207). We suggest that TLRs expression is differentially regulated in CLL but is similarly shared between two distinct compartments of the microenvironment.

Effects of extracellular ATP on hepatic fatty acid metabolism

1996 ◽  
Vol 270 (4) ◽  
pp. G701-G707 ◽  
Author(s):  
M. Guzman ◽  
G. Velasco ◽  
J. Castro
Keyword(s):  
Fatty Acid ◽  
De Novo ◽  
Specific Inhibitor ◽  
Rat Hepatocytes ◽  
Inhibitory Effect ◽  
Extracellular Atp ◽  
Acid Oxidation ◽  
A 23187 ◽  
Malonyl Coa ◽  
Cpt I

Incubation of rat hepatocytes with extracellular ATP inhibited acetyl-CoA carboxylase (ACC) activity and fatty acid synthesis de novo, with a concomitant decrease of intracellular malonyl-CoA concentration. However, both carnitine O-palmitoyltransferase I (CPT-I) activity and ketogenesis from palmitate were inhibited in parallel by extracellular ATP. The inhibitory effect of extracellular ATP on ACC and CPT-I activities was not evident in Ca2+ -depleted hepatocytes. Incubation of hepatocytes with thapsigargin, 2,5-di-(t-butyl)-1,4-benzohydroquinone (BHQ), or A-23187, compounds that increase cytosolic free Ca2+ concentration ([Ca2+]i), depressed ACC activity, whereas CPT-I activity was unaffected. The phorbol ester 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA) increased ACC activity, whereas it decreased CPT-I activity in a nonaddictive manner with respect to extracellular ATP. The inhibitory effect of extracellular ATP on ACC activity was also evident in the presence of bisindolyl-maleimide, a specific inhibitor of protein kinase C (PKC), whereas this compound abolished the extracellular ATP-mediated inhibition of CPT-I. In addition, the PMA-induced inhibition of CPT-I was not potentiated by thapsigargin, BHQ, or A-23187. Results thus show 1) that the intracellular concentration of malonyl-CoA is not the factor responsible for the inhibition of hepatic long-chain fatty acid oxidation by extracellular ATP, and 2) that the inhibition of ACC by extracellular ATP may be mediated by an elevation of [Ca2+]i, whereas CPT-I may be inhibited by extracellular ATP through a PKC-dependent mechanism.

scholarly journals Tissue-specific expression of Sprouty1 in mice protects against high-fat diet-induced fat accumulation, bone loss and metabolic dysfunction

2011 ◽  
Vol 108 (6) ◽  
pp. 1025-1033 ◽  
Author(s):  
Sumithra Urs ◽  
Terry Henderson ◽  
Phuong Le ◽  
Clifford J. Rosen ◽  
Lucy Liaw
Keyword(s):  
Adipose Tissue ◽  
Bone Loss ◽  
Bone Mass ◽  
Body Fat ◽  
High Fat Diet ◽  
Conditional Knockout ◽  
Whole Body ◽  
High Fat ◽  
Tissue Specific ◽  
Diet Induced Obesity

We recently characterised Sprouty1 (Spry1), a growth factor signalling inhibitor as a regulator of marrow progenitor cells promoting osteoblast differentiation at the expense of adipocytes. Adipose tissue-specific Spry1 expression in mice resulted in increased bone mass and reduced body fat, while conditional knockout of Spry1 had the opposite effect with decreased bone mass and increased body fat. Because Spry1 suppresses normal fat development, we tested the hypothesis that Spry1 expression prevents high-fat diet-induced obesity, bone loss and associated lipid abnormalities, and demonstrate that Spry1 has a long-term protective effect on mice fed a high-energy diet. We studied diet-induced obesity in mice with fatty acid binding promoter-driven expression or conditional knockout of Spry1 in adipocytes. Phenotyping was performed by whole-body dual-energy X-ray absorptiometry, microCT, histology and blood analysis. In conditional Spry1-null mice, a high-fat diet increased body fat by 40 %, impaired glucose regulation and led to liver steatosis. However, overexpression of Spry1 led to 35 % (P < 0·05) lower body fat, reduced bone loss and normal metabolic function compared with single transgenics. This protective phenotype was associated with decreased circulating insulin (70 %) and leptin (54 %; P < 0·005) compared with controls on a high-fat diet. Additionally, Spry1 expression decreased adipose tissue inflammation by 45 %. We show that conditional Spry1 expression in adipose tissue protects against high-fat diet-induced obesity and associated bone loss.

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