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1.
Cell Death Dis ; 6: e1723, 2015 Apr 16.
Article in English | MEDLINE | ID: mdl-25880090

ABSTRACT

Immune surveillance through Foxp3+ regulatory T cells plays a crucial role in bone homeostasis. Scurfy, the mouse model of autoimmune IPEX syndrome, bears a loss-of-function mutation in Foxp3 that leads to multi-organ inflammation. Herein, we report that scurfy mice exhibit severe bone loss mediated by accelerated osteoclastogenesis. Mechanistically, Foxp3 deficiency results in the upregulation of NF-κB in T helper cells through the loss of repressive Foxp3/NEMO interaction, thereby unleashing NF-κB-mediated over-production of pro-osteoclastogenic cytokines. Flow cytometry analysis shows marked increase in lin-Sca-1+c-kit+ hematopoietic stem cells (LSK HSCs) and granulocyte/macrophage progenitors (GMPs) in bone marrow of scurfy mice with corresponding exacerbated osteoclastogenic potential, implying that osteoclast progenitors are affected at a very primitive stage in this disorder. Scurfy LSK HSCs exhibit greater sensitivity to M-CSF and contain abundant PU.1+ Sf LSK HSCs compared with WT. Accordingly, genetic or pharmacological inhibition of M-CSF or mTOR signaling, but not IL-17 signaling, attenuates osteoclastogenesis and osteopenia in scurfy. Thus, our study suggests that Foxp3 deficiency leads to osteopenia owing to dysregulated NF-κB activity and subsequent cytokine-mediated hyper-proliferation of myeloid precursors, and positions the NF-κB pathway as a potential target for therapeutic intervention for this disorder.


Subject(s)
Bone Diseases, Metabolic/pathology , Forkhead Transcription Factors/metabolism , Myeloid Cells/pathology , NF-kappa B/metabolism , Animals , Bone Diseases, Metabolic/genetics , Bone Diseases, Metabolic/metabolism , Cell Differentiation/physiology , Cell Lineage , Female , Forkhead Transcription Factors/genetics , Male , Mice , Myeloid Cells/metabolism , Signal Transduction
2.
Osteoporos Int ; 24(4): 1455-70, 2013 Apr.
Article in English | MEDLINE | ID: mdl-22932734

ABSTRACT

UNLABELLED: Effects of cladrin treatment and withdrawal in osteopenic rats were studied. Cladrin improved trabecular microarchitecture, increased lumbar vertebral compressive strength, augmented coupled remodeling, and increased bone osteogenic genes. A significant skeletal gain was maintained 4 weeks after cladrin withdrawal. Findings suggest that cladrin has significant positive skeletal effects. INTRODUCTION: We showed that a standardized extract of Butea monosperma preserved trabecular bone mass in ovariectomized (OVx) rats. Cladrin, the most abundant bioactive compound of the extract, promoted peak bone mass achievement in growing rats by stimulating osteoblast function. Here, we studied the effects of cladrin treatment and withdrawal on the osteopenic bones. METHODS: Adult female Sprague-Dawley rats were OVx and left untreated for 12 weeks to allow for significant estrogen deficiency-induced bone loss, at which point cladrin (1 and 10 mg/kg/day) was administered orally for another 12 weeks. Half of the rats were killed at the end of the treatments and the other half at 4 weeks after treatment withdrawal. Sham-operated rats and OVx rats treated with PTH or 17ß-estradiol (E2) served as various controls. Efficacy was evaluated by bone microarchitecture using microcomputed tomographic analysis and fluorescent labeling of bone. qPCR and western blotting measured mRNA and protein levels in bone and uterus. Specific ELISA was used for measuring levels of serum PINP and urinary CTx. RESULTS: In osteopenic rats, cladrin treatment dose dependently improved trabecular microarchitecture, increased lumbar vertebral compression strength, bone formation rate (BFR), cortical thickness (Cs.Th), serum PINP levels, and expression of osteogenic genes in bones; and reduced expression of bone osteoclastogenic genes and urinary CTx levels. Cladrin had no uterine estrogenicity. Cladrin at 10 mg/kg maintained acquired skeletal gains 4 weeks after withdrawal. CONCLUSION: Cladrin had positive skeletal effects in osteopenic rats that were maintained after treatment withdrawal.


Subject(s)
Bone Density Conservation Agents/therapeutic use , Bone Diseases, Metabolic/drug therapy , Isoflavones/therapeutic use , Animals , Biomarkers/blood , Body Weight/drug effects , Bone Density Conservation Agents/administration & dosage , Bone Density Conservation Agents/pharmacology , Bone Diseases, Metabolic/physiopathology , Compressive Strength/drug effects , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Evaluation, Preclinical/methods , Female , Femur/drug effects , Femur/metabolism , Femur/physiopathology , Gene Expression Regulation/drug effects , Isoflavones/administration & dosage , Isoflavones/pharmacology , Lumbar Vertebrae/drug effects , Lumbar Vertebrae/physiopathology , Organ Size/drug effects , Osteoblasts/drug effects , Osteoblasts/metabolism , Osteoclasts/drug effects , Osteoclasts/metabolism , Osteogenesis/drug effects , Osteogenesis/genetics , Ovariectomy , RNA, Messenger/genetics , Rats , Rats, Sprague-Dawley , Tibia/drug effects , Tibia/physiopathology , Uterus/drug effects , Uterus/pathology , X-Ray Microtomography
3.
Osteoporos Int ; 22(12): 3013-27, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21225417

ABSTRACT

UNLABELLED: The effect of quercetin C-glucoside (QCG) on osteoblast function in vitro and bone formation in vivo was investigated. QCG supplementation promoted peak bone mass achievement in growing rats and new bone formation in osteopenic rats. QCG has substantial oral bioavailability. Findings suggest a significant bone anabolic effect of QCG. INTRODUCTION: Recently, we showed that extracts of Ulmus wallichiana promoted peak bone mass achievement in growing rats and preserved trabecular bone mass and cortical bone strength in ovariectomized (OVx) rats. 3,3',4',5,7-Pentahydroxyflavone-6-C-ß-D-glucopyranoside, a QCG, is the most abundant bioactive compound of U. wallichiana extract. We hypothesize that QCG exerts bone anabolic effects by stimulating osteoblast function. METHODS: Osteoblast cultures were harvested from rat calvaria and bone marrow (BM) to study differentiation and mineralization. In vivo, growing female Sprague Dawley rats and OVx rats with osteopenia were administered QCG (5.0 or 10.0 mg kg(-1) day(-1)) orally for 12 weeks. Efficacy was evaluated by examining changes in bone microarchitecture using histomorphometric and microcomputed tomographic analyses and by determination of new bone formation by fluorescent labeling of bone. Plasma and BM levels of QCG were determined by high-performance liquid chromatography. RESULTS: QCG was much more potent than quercetin (Q) in stimulating osteoblast differentiation, and the effect of QCG was not mediated by estrogen receptors. In growing rats, QCG increased BM osteoprogenitors, bone mineral density, bone formation rate, and cortical deposition. In osteopenic rats, QCG treatment increased bone formation rate and improved trabecular microarchitecture. Comparison with the sham group (ovary intact) revealed significant restoration of trabecular bone in osteopenic rats treated with QCG. QCG levels in the BM were ~50% of that of the plasma levels. CONCLUSION: QCG stimulated modeling-directed bone accrual and exerted anabolic effects on osteopenic rats by direct stimulatory effect on osteoprogenitors likely due to substantial QCG delivery at tissue level following oral administration.


Subject(s)
Bone Density/drug effects , Bone Diseases, Metabolic/drug therapy , Glucosides/isolation & purification , Osteoblasts/drug effects , Osteogenesis/drug effects , Quercetin/analogs & derivatives , Animals , Bone Marrow/chemistry , Chromatography, Liquid , Female , Femur/diagnostic imaging , Femur/drug effects , Glucosides/chemistry , Glucosides/pharmacology , Hindlimb , Ovariectomy , Quercetin/blood , Quercetin/chemistry , Quercetin/pharmacology , Rats , Rats, Sprague-Dawley , Tibia/diagnostic imaging , Tibia/drug effects , X-Ray Microtomography
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