scholarly journals An antibody against Siglec-15 promotes bone formation and fracture healing by increasing TRAP+ mononuclear cells and PDGF-BB secretion

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Gehua Zhen ◽  
Yang Dan ◽  
Ruomei Wang ◽  
Ce Dou ◽  
Qiaoyue Guo ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Fracture Healing ◽  
Knockout Mice ◽  
Mononuclear Cells ◽  
Neutralizing Antibody ◽  
Conditional Knockout ◽  
Anabolic Effect ◽  
Antibody Treatment ◽  
Conditional Knockout Mice

AbstractOsteoporosis (OP) is a common age-related disease characterized by a deterioration of bone mass and structure that predisposes patients to fragility fractures. Pharmaceutical therapies that promote anabolic bone formation in OP patients and OP-induced fracture are needed. We investigated whether a neutralizing antibody against Siglec-15 can simultaneously inhibit bone resorption and stimulate bone formation. We found that the multinucleation of osteoclasts was inhibited in SIGLEC-15 conditional knockout mice and mice undergoing Siglec-15 neutralizing antibody treatment. The secretion of platelet-derived growth factor-BB (PDGF-BB), the number of tartrate-resistant acid phosphatase-positive (TRAP+) mononuclear cells, and bone formation were significantly increased in the SIGLEC-15 conditional knockout mice and antibody-treated mice. The anabolic effect of the Siglec-15 neutralizing antibody on bone formation was blunted in mice with Pdgfb deleted in TRAP+ cells. These findings showed that the anabolic effect of the Siglec-15 neutralizing antibody was mediated by elevating PDGF-BB production of TRAP+ mononuclear cells. To test the therapeutic potential of the Siglec-15 neutralizing antibody, we injected the antibody in an ovariectomy-induced osteoporotic mouse model, which mimics postmenopausal osteoporosis in women, and in two fracture healing models because fracture is the most serious health consequence of osteoporosis. The Siglec-15 neutralizing antibody effectively reduced bone resorption and stimulated bone formation in estrogen deficiency-induced osteoporosis. Of note, the Siglec-15 neutralizing antibody promoted intramembranous and endochondral ossification at the damaged area of cortical bone in fracture healing mouse models. Thus, the Siglec-15 neutralizing antibody shows significant translational potential as a novel therapy for OP and bone fracture.

scholarly journals Core-binding factor beta is required for osteoblast differentiation during fibula fracture healing

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Tuanmao Guo ◽  
Yanli Xing ◽  
Zhongning Chen ◽  
Xianhong Wang ◽  
Haiyun Zhu ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Knockout Mice ◽  
Osteoblast Differentiation ◽  
Conditional Knockout ◽  
Core Binding Factor ◽  
Fibula Fracture ◽  
Conditional Knockout Mice ◽  
Binding Factor ◽  
Collagen Ii ◽  
Core Binding Factor Beta

Abstract Background Growing evidence has implicated core-binding factor beta (Cbfb) as a contributor to osteoblast differentiation, which plays a key role in fracture healing. Herein, we aimed to assess whether Cbfb affects osteoblast differentiation after fibula fracture. Methods Initially, we established a Cbfb conditional knockout mouse model for subsequent studies. Immunohistochemical staining was conducted to detect the expression of proliferating cell nuclear antigen (PCNA) and collagen II in the fracture end. Next, we isolated and cultured osteoblasts from specific Cbfb conditional knockout mice for BrdU analysis, alkaline phosphatase (ALP) staining, and von Kossa staining to detect osteoblast viability, differentiation, and mineralization, respectively. Western blot analysis and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to detect the expression of osteoblast differentiation-related genes. Results The Cbfb conditional knockout mice exhibited downregulated expression of PCNA and collagen II, reduced ALP activity, and mineralization, as well as diminished expression of osteoblast differentiation-related genes. Further, Cbfb knockout exerted no obvious effects on osteoblast proliferation. Conclusions Overall, these results substantiated that Cbfb could promote fibula fracture healing and osteoblast differentiation and thus provided a promising therapeutic target for clinical treatment of fibula fracture.

Ankyrin-G heterozygous conditional knockout mice display increased sensitivity to social defeat stress

2021 ◽  
Author(s):  
Zachary A. Cordner ◽  
Seva G. Khambadkone ◽  
Shanshan Zhu ◽  
Justin Bai ◽  
Rasadokht Forati ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Social Defeat ◽  
Conditional Knockout ◽  
Social Defeat Stress ◽  
Conditional Knockout Mice ◽  
Ankyrin G ◽  
Increased Sensitivity

Reduced hippocampal ten-eleven translocation 3 (Tet3) protein expression in Tet3 conditional knockout mice

2021 ◽  
Vol 26 (5) ◽  
pp. 1425-1425
Author(s):  
Cláudia Antunes ◽  
Jorge D. Da Silva ◽  
Sónia Guerra-Gomes ◽  
Nuno D. Alves ◽  
Fábio Ferreira ◽  
...  
Keyword(s):  
Protein Expression ◽  
Knockout Mice ◽  
Conditional Knockout ◽  
Conditional Knockout Mice

scholarly journals Ultrastructural pathological changes in the cochlear cells of connexin 26 conditional knockout mice

2013 ◽  
Vol 8 (4) ◽  
pp. 1029-1036 ◽  
Author(s):  
LAN LIN ◽  
YUN-FENG WANG ◽  
SHU-YI WANG ◽  
SHAO-FENG LIU ◽  
ZHANG YU ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Conditional Knockout ◽  
Connexin 26 ◽  
Pathological Changes ◽  
Conditional Knockout Mice

scholarly journals Endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice

Blood ◽  
2017 ◽  
Vol 129 (4) ◽  
pp. 405-414 ◽  
Author(s):  
Susanna Canali ◽  
Kimberly B. Zumbrennen-Bullough ◽  
Amanda B. Core ◽  
Chia-Yu Wang ◽  
Manfred Nairz ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Bone Morphogenetic Protein ◽  
Knockout Mice ◽  
Iron Homeostasis ◽  
Conditional Knockout ◽  
Conditional Knockout Mice ◽  
Morphogenetic Protein ◽  
Key Points ◽  
Paracrine Actions ◽  
Bone Morphogenetic Protein 6

Key Points Endothelial Bmp6 conditional knockout mice exhibit hemochromatosis, whereas hepatocyte and macrophage Bmp6 conditional knockout mice do not. Our data support a model in which EC Bmp6 has paracrine actions on hepatocyte hemojuvelin to regulate hepcidin production.

scholarly journals Epithelial (E)-Cadherin is a Novel Mediator of Platelet Aggregation and Clot Stability

2019 ◽  
Vol 119 (05) ◽  
pp. 744-757 ◽  
Author(s):  
Vanessa Scanlon ◽  
Alexandra Teixeira ◽  
Tarun Tyagi ◽  
Siying Zou ◽  
Ping-Xia Zhang ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Knockout Mice ◽  
Glycogen Synthase ◽  
Conditional Knockout ◽  
Platelet Production ◽  
Conditional Knockout Mice ◽  
Clot Stability ◽  
E Cadherin

AbstractCadherins play a major role in mediating cell–cell adhesion, which shares many parallels with platelet–platelet interactions during aggregate formation and clot stabilization. Platelets express epithelial (E)-cadherin, but its contribution to platelet function and/or platelet production is currently unknown. To assess the role of E-cadherin in platelet production and function in vitro and in vivo, we utilized a megakaryocyte-specific E-cadherin knockout mouse model. Loss of E-cadherin in megakaryocytes does not affect megakaryocyte maturation, platelet number or size. However, platelet dysfunction in the absence of E-cadherin is revealed when conditional knockout mice are challenged with acute antibody-mediated platelet depletion. Unlike wild-type mice that recover fully, knockout mice die within 72 hours post-antibody administration, likely from haemorrhage. Furthermore, conditional knockout mice have prolonged tail bleeding times, unstable clot formation, reduced clot retraction and reduced fibrin deposition in in vivo injury models. Murine platelet aggregation in vitro in response to thrombin and thrombin receptor activating peptide is compromised in E-cadherin null platelets, while aggregation in response to adenosine diphosphate (ADP) is not significantly different. Consistent with this, in vitro aggregation of primary human platelets in response to thrombin is decreased by an inhibitory E-cadherin antibody. Integrin activation and granule secretion in response to ADP and thrombin are not affected in E-cadherin null platelets, but Akt and glycogen synthase kinase 3β (GSK3β) activation are attenuated, suggesting a that E-cadherin contributes to aggregation, clot stabilization and retraction that is mediated by phosphoinositide 3-kinase/Akt/GSK3β signalling. In summary, E-cadherin plays a salient role in platelet aggregation and clot stability.

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