scholarly journals Role of osteogenic Dickkopf-1 in bone remodeling and bone healing in mice with type I diabetes mellitus

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nick Hildebrandt ◽  
Juliane Colditz ◽  
Caio Dutra ◽  
Paula Goes ◽  
Juliane Salbach-Hirsch ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Bone Defect ◽  
Serum Levels ◽  
Diabetic Control ◽  
Male Mice ◽  
Defect Healing ◽  
Bone Defect Healing ◽  
Dickkopf 1

AbstractType 1 diabetes mellitus (T1DM) is associated with low bone mass and a higher risk for fractures. Dickkopf-1 (Dkk1), which inhibits Wnt signaling, osteoblast function, and bone formation, has been found to be increased in the serum of patients with T1DM. Here, we investigated the functional role of Dkk1 in T1DM-induced bone loss in mice. T1DM was induced in 10-week-old male mice with Dkk1-deficiency in late osteoblasts/osteocytes (Dkk1f/f;Dmp1-Cre, cKO) and littermate control mice by 5 subsequent injections of streptozotocin (40 mg/kg). Age-matched, non-diabetic control groups received citrate buffer instead. At week 12, calvarial defects were created in subgroups of each cohort. After a total of 16 weeks, weight, fat, the femoral bone phenotype and the area of the bone defect were analyzed using µCT and dynamic histomorphometry. During the experiment, diabetic WT and cKO mice did not gain body weight compared to control mice. Further they lost their perigonadal and subcutaneous fat pads. Diabetic mice had highly elevated serum glucose levels and impaired glucose tolerance, regardless of their Dkk1 levels. T1DM led to a 36% decrease in trabecular bone volume in Cre− negative control animals, whereas Dkk1 cKO mice only lost 16%. Of note, Dkk1 cKO mice were completely protected from T1DM-induced cortical bone loss. T1DM suppressed the bone formation rate, the number of osteoblasts at trabecular bone, serum levels of P1NP and bone defect healing in both, Dkk1-deficient and sufficient, mice. This may be explained by increased serum sclerostin levels in both genotypes and the strict dependence on bone formation for bone defect healing. In contrast, the number of osteoclasts and TRACP 5b serum levels only increased in diabetic control mice, but not in Dkk1 cKO mice. In summary, Dkk1 derived from osteogenic cells does not influence the development of T1DM but plays a crucial role in T1DM-induced bone loss in male mice by regulating osteoclast numbers.

scholarly journals Cellular hypoxia promotes osteogenic differentiation of mesenchymal stem cells and bone defect healing via STAT3 signaling

2019 ◽  
Vol 24 (1) ◽  
Author(s):  
Xin Yu ◽  
Qilong Wan ◽  
Xiaoling Ye ◽  
Yuet Cheng ◽  
Janak L. Pathak ◽  
...  
Keyword(s):  
Osteogenic Differentiation ◽  
Bone Defect ◽  
Precursor Cells ◽  
Defect Healing ◽  
Stat3 Signaling ◽  
Bone Defect Healing ◽  
Cellular Hypoxia

Abstract Background Hypoxia in the vicinity of bone defects triggers the osteogenic differentiation of precursor cells and promotes healing. The activation of STAT3 signaling in mesenchymal stem cells (MSCs) has similarly been reported to mediate bone regeneration. However, the interaction between hypoxia and STAT3 signaling in the osteogenic differentiation of precursor cells during bone defect healing is still unknown. Methods In this study, we assessed the impact of different durations of CoCl2-induced cellular hypoxia on the osteogenic differentiation of MSCs. Role of STAT3 signaling on hypoxia induced osteogenic differentiation was analyzed both in vitro and in vivo. The interaction between cellular hypoxia and STAT3 signaling in vivo was investigated in a mouse femoral bone defect model. Results The peak osteogenic differentiation and expression of vascular endothelial growth factor (VEGF) occurred after 3 days of hypoxia. Inhibiting STAT3 reversed this effect. Hypoxia enhanced the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and STAT3 phosphorylation in MSCs. Histology and μ-CT results showed that CoCl2 treatment enhanced bone defect healing. Inhibiting STAT3 reduced this effect. Immunohistochemistry results showed that CoCl2 treatment enhanced Hif-1α, ALP and pSTAT3 expression in cells present in the bone defect area and that inhibiting STAT3 reduced this effect. Conclusions The in vitro study revealed that the duration of hypoxia is crucial for osteogenic differentiation of precursor cells. The results from both the in vitro and in vivo studies show the role of STAT3 signaling in hypoxia-induced osteogenic differentiation of precursor cells and bone defect healing.

scholarly journals DZNep promotes mouse bone defect healing via enhancing both osteogenesis and osteoclastogenesis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiankun Cao ◽  
Wenxin He ◽  
Kewei Rong ◽  
Shenggui Xu ◽  
Zhiqian Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Bone Defect ◽  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Cell Counting ◽  
Nuclear Factor ◽  
Defect Healing ◽  
Bone Defect Healing

Abstract Background Enhancer of zeste homolog 2 (EZH2) is a novel oncogene that can specifically trimethylate the histone H3 lysine 27 (H3K27me3) to transcriptionally inhibit the expression of downstream tumor-suppressing genes. As a small molecular inhibitor of EZH2, 3-Deazaneplanocin (DZNep) has been widely studied due to the role of tumor suppression. With the roles of epigenetic regulation of bone cells emerged in past decades, the property and molecular mechanism of DZNep on enhancing osteogenesis had been reported and attracted a great deal of attention recently. This study aims to elucidate the role of DZNep on EZH2-H3K27me3 axis and downstream factors during both osteoclasts and osteoblasts formation and the therapeutic possibility of DZNep on bone defect healing. Methods Bone marrow-derived macrophages (BMMs) cells were cultured, and their responsiveness to DZNep was evaluated by cell counting kit-8, TRAP staining assay, bone resorption assay, podosome actin belt. Bone marrow-derived mesenchymal stem cells (BMSC) were cultured and their responsiveness to DZNep was evaluated by cell counting kit-8, ALP and AR staining assay. The expression of nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), Wnt signaling pathway was determined by qPCR and western blotting. Mouse bone defect models were created, rescued by DZNep injection, and the effectiveness was evaluated by X-ray and micro-CT and histological staining. Results Consistent with the previous study that DZNep enhances osteogenesis via Wnt family member 1(Wnt1), Wnt6, and Wnt10a, our results showed that DZNep also promotes osteoblasts differentiation and mineralization through the EZH2-H3K27me3-Wnt4 axis. Furthermore, we identified that DZNep promoted the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast formation via facilitating the phosphorylation of IKKα/β, IκB, and subsequently NF-κB nuclear translocation, which credit to the EZH2-H3K27me3-Foxc1 axis. More importantly, the enhanced osteogenesis and osteoclastogenesis result in accelerated mice bone defect healing in vivo. Conclusion DZNep targeting EZH2-H3K27me3 axis facilitated the healing of mice bone defect via simultaneously enhancing osteoclastic bone resorption and promoting osteoblastic bone formation.

scholarly journals Systemically replicated organic and inorganic bony microenvironment for new bone formation generated by a 3D printing technology

RSC Advances ◽  
2016 ◽  
Vol 6 (14) ◽  
pp. 11546-11553 ◽  
Author(s):  
Wan-Gun La ◽  
Jinah Jang ◽  
Byoung Soo Kim ◽  
Min Suk Lee ◽  
Dong-Woo Cho ◽  
...  
Keyword(s):  
3D Printing ◽  
Bone Formation ◽  
Bone Defect ◽  
New Bone Formation ◽  
Printing Technology ◽  
3D Printing Technology ◽  
Defect Healing ◽  
Bone Defect Healing ◽  
3D Printed

3D-printed bioimplants for enhanced bone defect healing using decellularized and demineralized ECM coating.

scholarly journals Strontium ranelate stimulates trabecular bone formation in a rat tibial bone defect healing process

2017 ◽  
Vol 28 (12) ◽  
pp. 3475-3487 ◽  
Author(s):  
C. Lavet ◽  
G. Mabilleau ◽  
D. Chappard ◽  
R. Rizzoli ◽  
P. Ammann
Keyword(s):  
Bone Formation ◽  
Trabecular Bone ◽  
Bone Defect ◽  
Strontium Ranelate ◽  
Healing Process ◽  
Defect Healing ◽  
Tibial Bone ◽  
Bone Defect Healing

scholarly journals Increased Sclerostin Serum Levels Associated with Bone Formation and Resorption Markers in Patients with Immobilization-Induced Bone Loss

2010 ◽  
Vol 95 (5) ◽  
pp. 2248-2253 ◽  
Author(s):  
Agostino Gaudio ◽  
Pietra Pennisi ◽  
Cornelia Bratengeier ◽  
Venerando Torrisi ◽  
Brigitte Lindner ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Postmenopausal Women ◽  
Quantitative Ultrasound ◽  
Type I Collagen ◽  
Mechanical Strain ◽  
Serum Levels ◽  
Type I ◽  
Ultrasound Measurements ◽  
Dickkopf 1

Abstract Context: Sclerostin, a Wnt signaling antagonist on the osteoblasts produced by osteocytes, is regulated by mechanical strain and is implicated in the pathogenesis of disuse bone loss. There are no data on sclerostin in humans. Objective: The aim of the study was to evaluate sclerostin in patients immobilized after stroke, compared with control subjects, and to analyze its relationship with markers of bone formation and resorption. Design: This was a cross-sectional study. Setting and patients: We studied 40 postmenopausal women immobilized after a single episode of stroke 6 months or longer after onset, and 40 postmenopausal women from the general community. Bone status was assessed by quantitative ultrasound measurements at the calcaneus. Bone alkaline phosphatase (b-AP), carboxy-terminal telopeptide of type I collagen (CrossLaps), and sclerostin were evaluated by ELISA. We also used ELISA to measure serum levels of Dickkopf-1, another soluble inhibitor of Wnt/β-catenin signaling, highly expressed by osteocytes. Results: Immobilized patients had higher sclerostin serum levels (median 0.975 ng/ml; 25th to 75th percentiles 0.662–1.490) than controls (median 0.300 ng/ml; 25th to 75th percentiles 0.165–0.400: P < 0.0001) and an increased bone turnover with a more significant rise in bone resorption (CrossLaps) than formation (b-AP) markers. Sclerostin correlated negatively with b-AP (r = −0.911; P < 0.0001) and positively with CrossLaps (r = 0.391; P = 0.012). Dickkopf-1 did not significantly differ between the groups. Patients also had quantitative ultrasound measurements index lower than controls (P < 0.001). Conclusions: This study shows for the first time that long-term immobilized patients present hypersclerostinemia associated with reduced bone formation, and suggests that sclerostin could be a link between mechanical unloading and disuse osteoporosis in humans.

scholarly journals DZNep Promotes Mouse Bone Defect Healing via Enhancing Both Osteogenesis and Osteoclastogenesis

2021 ◽  
Author(s):  
Xiankun Cao ◽  
Wenxin He ◽  
Kewei Rong ◽  
Shenggui Xu ◽  
Zhiqian Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Bone Defect ◽  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Cell Counting ◽  
Nuclear Factor ◽  
Defect Healing ◽  
Bone Defect Healing

Abstract Background: EZH2 (Enhancer of zeste homolog 2) is a novel oncogene that can specifically trimethylate the histone H3 lysine 27 (H3K27me3) to transcriptionally inhibit the expression of downstream tumor-suppressing genes. As a small molecular inhibitor of EZH2, 3-Deazaneplanocin (DZNep) has been widely studied due to the role of tumor suppression. With the roles of epigenetic regulation of bone cells emerged in past decades, the property and molecular mechanism of DZNep on enhancing osteogenesis had been reported and attracted a great deal of attention recently. this study aims to elucidate the role of DZNep on EZH2-H3K27me3 axis and downstream factors during both osteoclasts and osteoblasts formation and the therapeutic possibility of DZNep on bone defect healing.Methods: Bone marrow drived macrophages (BMMs) cells were cultured and their responsiveness to DZNep was evaluated by Cell Counting Kit-8, TRAP staining assay, Bone Resorption Assay, Podosome Actin Belt. Bone marrow drived mesenchymal stem cells (BMSC) were cultured and their responsiveness to DZNep was evaluated by Cell Counting Kit-8, ALP and AR staining assay. The expression of nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), Wnt signaling pathway was determined by qPCR and western blotting. Mouse bone defect models were created, rescued by DZNep injection and the effectiveness was evaluated by X-ray and Micro-CT and Histological staining.Results: Consistent with the previous study that DZNep enhances osteogenesis via Wnt family member 1(Wnt1), Wnt6, and Wnt10a, our results showed that DZNep also promotes osteoblasts differentiation and mineralization through the EZH2-H3K27me3-Wnt4 axis. Furthermore, we identified that DZNep promoted the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast formation via facilitating the phosphorylation of IKKα/β, IκB, and subsequently NF-κB nuclear translocation, which credit to the EZH2-H3K27me3-Foxc1 axis. More importantly, the enhanced osteogenesis and osteoclastogenesis result in accelerated mice bone defect healing in vivo.Conclusion: DZNep targeting EZH2-H3K27me3 axis facilitated the healing of mice bone defect via simultaneously enhancing osteoclastic bone resorption and promoting osteoblastic bone formation.

scholarly journals ASSOCIATION BETWEEN PERIODONTAL DISEASE AND OSTEOPOROSIS

2017 ◽  
Vol 26 (3) ◽  
pp. 107-114
Author(s):  
Dan Piperea-Sianu ◽  
◽  
Adela M. Ceau ◽  
Mara Carsote ◽  
Alexandru G. Croitoru ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Periodontal Disease ◽  
Alveolar Bone ◽  
Serum Levels ◽  
Bone Lysis ◽  
Local Impact ◽  
Systemic Bone Loss

Osteoporosis and periodontal disease (PD) are two chronic diseases, characterized by bone loss, with systemic or local impact (alveolar bone). Both pathologies have a progressive evolution, leading to systemic bone loss in the case of osteoporosis and bone lysis localized in the alveolar bone in the case of periodontal disease. The present paper presents recent data from the literature on the association between periodontal disease and osteoporosis, on the role of cytokines in the bone resorption-apposition imbalance, and on how periodontal disease causes changes in serum levels of cytokines, leading to disorders in the systemic bone formation. We also found it useful, especially for rheumatologists, to outline the extent to which periodontal disease can create a systemic context favorable to the development of osteoporosis.

Inhibition of JAK2/STAT3 signaling suppresses bone marrow stromal cells proliferation and osteogenic differentiation, and impairs bone defect healing

2018 ◽  
Vol 399 (11) ◽  
pp. 1313-1323 ◽  
Author(s):  
Xin Yu ◽  
Zhi Li ◽  
Qilong Wan ◽  
Xin Cheng ◽  
Jing Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Osteogenic Differentiation ◽  
Bone Defect ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Marrow Stromal Cells ◽  
Defect Healing ◽  
Stat3 Signaling ◽  
Bone Defect Healing

Abstract Mesenchymal stem cells (MSCs) undergo osteogenic differentiation during bone defect healing. However, the role of JAK2/STAT3 in the osteogenic differentiation of MSCs and bone defect healing is still not fully understood. In this study, we aimed to analyze the effect of AG490, a JAK2-specific inhibitor, on MSCs proliferation and osteogenic differentiation as well as in bone defect healing. We used AG490 to inhibit the JAK2/STAT3 signaling in a mice bone marrow stromal cells (BMSCs) culture. AG490 inhibited BMSCs proliferation and osteogenic differentiation markers, i.e. Col1α, Alp and Ocn expression in mRNA and protein levels. Inhibition of JAK2 reduced ALP activity and matrix mineralization in BMSCs culture. Inhibition of JAK2 reduced phosphorylation of STAT3, AKT, P38, and JNK phosphorylation. Immunohistochemistry showed high numbers of pJAK2, pSTAT3 and ALP positive cells and AG490 reduced this effect in vivo. Histology and μ-computed tomography (CT) data showed that AG490 treatment inhibits bone regeneration and bone defect healing. Our results clearly showed the inhibitory effect of AG490 on proliferation and osteogenic differentiation of BMSCs, bone regeneration and bone defect healing. Moreover, AG490 inhibited phosphorylation of STAT3, P38, JNK and AKT. This suggests the possible role of JAK2/STAT3 signaling in hypoxia-induced osteogenic differentiation of MSCs and bone defect healing.

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