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RNA interference therapy for autosomal dominant osteopetrosis type 2. Towards the preclinical development
Autosomal Dominant Osteopetrosis type 2 (ADO2) is a rare bone disease characterized by dense and brittle bones due to impairment of osteoclast bone resorption. Dominant negative mutations of the CLCN7 gene affect about 70% of ADO2 patients. ADO2 has no cure and our recent work established that it is suitable for gene silencing by a specific small interfering RNA that does not affect the normal mRNA, thus inducing a condition of pseudo-haplosufficiency and rescuing the bone phenotype. We performed a systematic study to test the likelihood that the therapy could progress towards clinical trials, treating Clcn7G213R/WT ADO2 m...
Source: Bone - February 28, 2018 Category: Orthopaedics Authors: Antonio Maurizi, Mattia Capulli, Rajvi Patel, Annabel Curle, Nadia Rucci, Anna Teti Tags: Full Length Article Source Type: research

Src siRNA prevents corticosteroid-associated osteoporosis in a rabbit model
In an established steroid-associated osteonecrosis (SAON) rabbit model we found recently that blockage Src by siRNA could improve reconstructive repair of osteonecrosis via enhancing osteogenesis and inhibiting bone resorption. The current study investigated if blocking Src was able to prevent steroid-associated osteoporosis (SAOP) in the same SAON animal model. Rabbits were treated with pulsed lipopolysaccharide (LPS) and corticosteroid methylprednisolone (MPS). At 2, 4, 6weeks after induction, Src siRNA, control siRNA and saline were intramedullary injected into proximal femur, respectively.
Source: Bone - November 17, 2015 Category: Orthopaedics Authors: Li-Zhen Zheng, Xin-Luan Wang, Hui-Juan Cao, Shi-Hui Chen, Le Huang, Ling Qin Tags: Original Full Length Article Source Type: research

CCN4/WISP-1 positively regulates chondrogenesis by controlling TGF-β3 function
The CCN family of proteins plays important roles in development and homeostasis of bone and cartilage. To understand the role of CCN4 in chondrogenesis, human bone marrow stromal cells (hBMSCs) were transduced with CCN4 adenovirus (adCCN4) or siRNA to CCN4 (siCCN4) in the presence or absence of transforming growth factor-β3 (TGF-β3). Overexpression of CCN4 enhanced TGF-β3-induced SMAD2/3 phosphorylation and chondrogenesis of hBMSCs in an in vitro assay using a micromass culture model. On the other hand, knockdown of CCN4 inhibited the TGF-β3-induced SMAD2/3 phosphorylation and synthesis of cartilage matrix in micromass cultures of hBMSCs.
Source: Bone - November 7, 2015 Category: Orthopaedics Authors: Yuya Yoshioka, Mitsuaki Ono, Azusa Maeda, Tina M. Kilts, Emilio Satoshi Hara, Hany Khattab, Junji Ueda, Eriko Aoyama, Toshitaka Oohashi, Masaharu Takigawa, Marian F. Young, Takuo Kuboki Tags: Original Full Length Article Source Type: research

Caspase-2 Modulates Osteoclastogenesis through Down-Regulating Oxidative Stress
In this study, we show that Casp-2 is involved in osteoclastogenesis. Protein levels of Casp-2 decrease during the differentiation of macrophages to osteoclasts. Furthermore, siRNA-mediated Casp-2 knockdown in osteoclast precursors or differentiation of bone marrow macrophage (BMM) precursors from Casp2-/- mice result in increased osteoclast numbers and tartrate-resistant acid phosphatase (TRAP) activity.
Source: Bone - March 19, 2015 Category: Orthopaedics Authors: Danielle A. Callaway, Manuel A. Riquelme, Ramaswamy Sharma, Marisa Lopez-Cruzan, Brian A. Herman, Jean X. Jiang Tags: Original Full Length Article Source Type: research

Src blockage by siRNA inhibits VEGF-induced vascular hyperpemeability and osteoclast activity – an mechanism study for preventing destructive repair of osteonecrosis
Destructive repair is the pathological feature of ONFH characterized with the elevated vascular permeability and persistent bone resorption, which is associated with higher VEGF expression, activated c-Src, and vascular leakage. Activated c-Src also participates in mediating endothelial permeability and osteoclasts activity. However, the molecular mechanism of the VEGF and c-Src contributing to the destructive repair process remains unknown. The purpose of this study is to delineate the role of VEGF and c-Src in triggering destructive repair of osteonecrosis in vitro, as well as to elucidate if VEGF mediating vascular perm...
Source: Bone - December 29, 2014 Category: Orthopaedics Authors: Hui-Juan Cao, Li-Zhen Zheng, Nan Wang, Lin-Ying Wang, Ye Li, Dan Li, Yu-Xiao Lai, Xin-Luan Wang, Ling Qin Tags: Original Full Length Article Source Type: research

Src blockage by siRNA inhibits VEGF-induced vascular hyperpemeability and osteoclast activity– an mechanism study for preventing destructive repair of osteonecrosis
Destructive repair is the pathological feature of ONFH characterized with the elevated vascular permeability and persistent bone resorption, which is associated with higher VEGF expression, activated c-Src, and vascular leakage. Activated c-Src also participates in mediating endothelial permeability and osteoclasts activity. However, the molecular mechanism of the VEGF and c-Src contributing to the destructive repair process remains unknown. The purpose of this study is to delineate the role of VEGF and c-Src in triggering destructive repair of osteonecrosis in vitro, as well as to elucidate if VEGF mediating vascular perm...
Source: Bone - December 29, 2014 Category: Orthopaedics Authors: Hui-Juan Cao, Li-Zhen Zheng, Nan Wang, Lin-Ying Wang, Ye Li, Dan Li, Yu-Xiao Lai, Xin-Luan Wang, Ling Qin Source Type: research

E2F1 effects on osteoblast differentiation and mineralization are mediated through up-regulation of frizzled-1
We examined the role of E2F1 in FZD1 promoter activation and osteoblast differentiation and mineralization. A putative E2F1 binding site in the FZD1 promoter region was initially identified in silico and characterized further in Saos2 cells in vitro by chromatin immunoprecipitation (ChIP), electrophoretic mobility shift (EMSA) and promoter reporter assays. Over-expression of E2F1 transactivated the FZD1 promoter and increased endogenous FZD1 mRNA and protein levels in Saos2 cells. Over-expression of E2F1 in Saos2 cells up-regulated osteoblast differentiation markers alkaline phosphatase (ALP), type I collagen α (COL1A), a...
Source: Bone - September 17, 2013 Category: Orthopaedics Authors: Shibing Yu, Laura M Yerges-Armstrong, Yanxia Chu, Joseph M. Zmuda, Yingze Zhang Tags: Original Articles Source Type: research