共查询到20条相似文献,搜索用时 78 毫秒
1.
Adverse Effects of Osteocytic Constitutive Activation of ß‐Catenin on Bone Strength and Bone Growth
下载免费PDF全文
![点击此处可从《Journal of bone and mineral research》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Sixu Chen Jianquan Feng Quanwei Bao Ang Li Bo Zhang Yue Shen Yufeng Zhao Qingshan Guo Junjun Jing Shuxian Lin Zhaowen Zong 《Journal of bone and mineral research》2015,30(7):1184-1194
The activation of the canonical Wnt/β‐catenin signaling pathway in both mesenchymal stem cells and osteoblasts has been demonstrated to increase bone mass, showing promise for the treatment of low bone volume conditions such as osteoporosis. However, the possible side effects of manipulating this pathway have not been fully addressed. Previously, we reported that the constitutive activation of ß‐catenin in osteoblasts impaired vertebral linear growth. In the present study, β‐catenin was constitutively activated in osteocytes by crossing Catnb+/lox(exon 3) mice with dentin matrix protein 1(DMP1)‐Cre transgenic mice, and the effects of this activation on bone mass, bone growth and bone strength were then observed. DMP1‐Cre was found to be predominantly expressed in osteocytes, with weak expression in a small portion of osteoblasts and growth plate chondrocytes. After the activation, the cancellous bone mass was dramatically increased, almost filling the entire bone marrow cavity in long bones. However, bone strength decreased significantly. Thinner and more porous cortical bone along with impaired mineralization were responsible for the decrease in bone strength. Furthermore, the mice showed shorter stature with impaired linear growth of the long bones. Moreover, the concentration of serum phosphate decreased significantly after the activation of ß‐catenin, and a high inorganic phosphate (Pi) diet could partially rescue the phenotype of decreased mineralization level and impaired linear growth. Taken together, the constitutive activation of β‐catenin in osteocytes may increase cancellous bone mass; however, the activation also had adverse effects on bone strength and bone growth. These adverse effects should be addressed before the adoption of any therapeutic clinical application involving adjustment of the Wnt/β‐catenin signaling pathway. © 2015 American Society for Bone and Mineral Research. 相似文献
2.
《Journal of orthopaedic research》2017,35(4):812-819
3.
Protection From Glucocorticoid‐Induced Osteoporosis by Anti‐Catabolic Signaling in the Absence of Sost/Sclerostin
下载免费PDF全文
![点击此处可从《Journal of bone and mineral research》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Amy Y Sato Meloney Cregor Jesus Delgado‐Calle Keith W Condon Matthew R Allen Munro Peacock Lilian I Plotkin Teresita Bellido 《Journal of bone and mineral research》2016,31(10):1791-1802
Excess of glucocorticoids, either due to disease or iatrogenic, increases bone resorption and decreases bone formation and is a leading cause of osteoporosis and bone fractures worldwide. Improved therapeutic strategies are sorely needed. We investigated whether activating Wnt/β‐catenin signaling protects against the skeletal actions of glucocorticoids, using female mice lacking the Wnt/β‐catenin antagonist and bone formation inhibitor Sost. Glucocorticoids decreased the mass, deteriorated the microarchitecture, and reduced the structural and material strength of bone in wild‐type (WT), but not in Sost–/– mice. The high bone mass exhibited by Sost–/– mice is due to increased bone formation with unchanged resorption. However, unexpectedly, preservation of bone mass and strength in Sost–/– mice was due to prevention of glucocorticoid‐induced bone resorption and not to restoration of bone formation. In WT mice, glucocorticoids increased the expression of Sost and the number of sclerostin‐positive osteocytes, and altered the molecular signature of the Wnt/β‐catenin pathway by decreasing the expression of genes associated with both anti‐catabolism, including osteoprotegerin (OPG), and anabolism/survival, such as cyclin D1. In contrast in Sost–/– mice, glucocorticoids did not decrease OPG but still reduced cyclin D1. Thus, in the context of glucocorticoid excess, activation of Wnt/β‐catenin signaling by Sost/sclerostin deficiency sustains bone integrity by opposing bone catabolism despite markedly reduced bone formation and increased apoptosis. This crosstalk between glucocorticoids and Wnt/β‐catenin signaling could be exploited therapeutically to halt resorption and bone loss induced by glucocorticoids and to inhibit the exaggerated bone formation in diseases of unwanted hyperactivation of Wnt/β‐catenin signaling. © 2016 American Society for Bone and Mineral Research. 相似文献
4.
Chuwen Lin Xuan Jiang Zhongquan Dai Xizhi Guo Tujun Weng Jun Wang Yinghui Li Guoyin Feng Xiang Gao PhD Lin He PhD 《Journal of bone and mineral research》2009,24(10):1651-1661
Reduced mechanical stress leads to bone loss, as evidenced by disuse osteoporosis in bedridden patients and astronauts. Osteocytes have been identified as major cells responsible for mechanotransduction; however, the mechanism underlying the response of bone to mechanical unloading remains poorly understood. In this study, we found that mechanical unloading of wildtype mice caused decrease of Wnt/β‐catenin signaling activity accompanied by upregulation of Sost. To further analyze the causal relationship among these events, Sost gene targeting mice were generated. We showed that sclerostin selectively inhibited Wnt/β‐catenin in vivo, and sclerostin suppressed the activity of osteoblast and viability of osteoblasts and osteocytes. Interestingly, Sost?/? mice were resistant to mechanical unloading‐induced bone loss. Reduction in bone formation in response to unloading was also abrogated in the mutant mice. Moreover, in contrast to wildtype mice, Wnt/β‐catenin signaling was not altered by unloading in Sost?/? mice. Those data implied that sclerostin played an essential role in mediating bone response to mechanical unloading, likely through Wnt/β‐catenin signaling. Our findings also indicated sclerostin is a promising target for preventing disuse osteoporosis. 相似文献
5.
Thyroid hormone regulates terminal differentiation of growth plate chondrocytes in part through modulation of the Wnt/β‐catenin signaling pathway. Insulin‐like growth factor 1 (IGF‐1) has been described as a stabilizer of β‐catenin, and thyroid hormone is a known stimulator of IGF‐1 receptor expression. The purpose of this study was to test the hypothesis that IGF‐1 signaling is involved in the interaction between the thyroid hormone and the Wnt/β‐catenin signaling pathways in regulating growth plate chondrocyte proliferation and differentiation. The results show that IGF‐1 and the IGF‐ receptor (IGF1R) stimulate Wnt‐4 expression and β‐catenin activation in growth plate chondrocytes. The positive effects of IGF‐1/IGF1R on chondrocyte proliferation and terminal differentiation are partially inhibited by the Wnt antagonists sFRP3 and Dkk1. T3 activates IGF‐1/IGF1R signaling and IGF‐1‐dependent PI3K/Akt/GSK‐3β signaling in growth plate chondrocytes undergoing proliferation and differentiation to prehypertrophy. T3‐mediated Wnt‐4 expression, β‐catenin activation, cell proliferation, and terminal differentiation of growth plate chondrocytes are partially prevented by the IGF1R inhibitor picropodophyllin as well as by the PI3K/Akt signaling inhibitors LY294002 and Akti1/2. These data indicate that the interactions between thyroid hormone and β‐catenin signaling in regulating growth plate chondrocyte proliferation and terminal differentiation are modulated by IGF‐1/IGF1R signaling through both the Wnt and PI3K/Akt signaling pathways. While chondrocyte proliferation may be triggered by the IGF‐1/IGF1R‐mediated PI3K/Akt/GSK3β pathway, cell hypertrophy is likely due to activation of Wnt/β‐catenin signaling, which is at least in part initiated by IGF‐1 signaling or the IGF‐1‐activated PI3K/Akt signaling pathway. © 2010 American Society for Bone and Mineral Research 相似文献
6.
Mei Zhu Dezhi Tang Qiuqian Wu Suyang Hao Mo Chen Chao Xie Randy N Rosier Regis J O'Keefe Michael Zuscik Di Chen 《Journal of bone and mineral research》2009,24(1):12-21
Osteoarthritis (OA) is a degenerative joint disease, and the mechanism of its pathogenesis is poorly understood. Recent human genetic association studies showed that mutations in the Frzb gene predispose patients to OA, suggesting that the Wnt/β‐catenin signaling may be the key pathway to the development of OA. However, direct genetic evidence for β‐catenin in this disease has not been reported. Because tissue‐specific activation of the β‐catenin gene (targeted by Col2a1‐Cre) is embryonic lethal, we specifically activated the β‐catenin gene in articular chondrocytes in adult mice by generating β‐catenin conditional activation (cAct) mice through breeding of β‐cateninfx(Ex3)/fx(Ex3) mice with Col2a1‐CreERT2 transgenic mice. Deletion of exon 3 of the β‐catenin gene results in the production of a stabilized fusion β‐catenin protein that is resistant to phosphorylation by GSK‐3β. In this study, tamoxifen was administered to the 3‐ and 6‐mo‐old Col2a1‐CreERT2;β‐cateninfx(Ex3)/wt mice, and tissues were harvested for histologic analysis 2 mo after tamoxifen induction. Overexpression of β‐catenin protein was detected by immunostaining in articular cartilage tissues of β‐catenin cAct mice. In 5‐mo‐old β‐catenin cAct mice, reduction of Safranin O and Alcian blue staining in articular cartilage tissue and reduced articular cartilage area were observed. In 8‐mo‐old β‐catenin cAct mice, cell cloning, surface fibrillation, vertical clefting, and chondrophyte/osteophyte formation were observed. Complete loss of articular cartilage layers and the formation of new woven bone in the subchondral bone area were also found in β‐catenin cAct mice. Expression of chondrocyte marker genes, such as aggrecan, Mmp‐9, Mmp‐13, Alp, Oc, and colX, was significantly increased (3‐ to 6‐fold) in articular chondrocytes derived from β‐catenin cAct mice. Bmp2 but not Bmp4 expression was also significantly upregulated (6‐fold increase) in these cells. In addition, we also observed overexpression of β‐catenin protein in the knee joint samples from patients with OA. These findings indicate that activation of β‐catenin signaling in articular chondrocytes in adult mice leads to the premature chondrocyte differentiation and the development of an OA‐like phenotype. This study provides direct and definitive evidence about the role of β‐catenin in the development of OA. 相似文献
7.
Haijun Tian Tangjun Zhou Hongfang Chen Chenshuang Li Ziyue Jiang Lifeng Lao Suzana Assad Kahn Maria Eugenia Leite Duarte Jie Zhao Michael D. Daubs Zorica Buser Elsa J. Brochmann Jeffrey C. Wang Samuel S. Murray 《Journal of orthopaedic research》2019,37(7):1638-1648
The correlation between BMP‐2 and osteosarcoma growth has gained increased interest in the recent years, however, there is still no consensus. In this study, we tested the effects of BMP‐2 on osteosarcoma cells through both in vitro and in vivo experiments. The effect of BMP‐2 on the proliferation, migration and invasion of osteosarcoma cells was tested in vitro. Subcutaneous and intratibial tumor models were used for the in vivo experiments in nude mice. The effects of BMP‐2 on EMT of osteosarcoma cells and the Wnt/β‐catenin signaling pathway were also tested using a variety of biochemical methods. In vitro tests did not show a significant effect of BMP‐2 on tumor cell proliferation. However, BMP‐2 increased the mobility of tumor cells and the invasion assay demonstrated that BMP‐2 promoted invasion of osteosarcoma cells in vitro. In vivo animal study showed that BMP‐2 dramatically enhanced tumor growth. We also found that BMP‐2 induced EMT of osteosarcoma cells. The expression levels of Axin2 and Dkk‐1 were both down regulated by BMP‐2 treatment, while β‐catenin, c‐myc and Cyclin‐D1 were all upregulated. The expression of Wnt3α and p‐GSK‐3β were also significantly upregulated indicating that the Wnt/β‐catenin signaling pathway was activated during the EMT of osteosarcoma driven by BMP‐2. From this study, we can conclude that BMP‐2 significantly promotes growth of osteosarcoma cells (143B, MG63), and enhances mobility and invasiveness of tumor cells as demonstrated in vitro. The underlying mechanism might be that BMP‐2 promotes EMT of osteosarcoma through the Wnt/β‐catenin signaling pathway. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1638–1648, 2019. 相似文献
8.
Lige Song Minlin Liu Noriaki Ono F Richard Bringhurst Henry M Kronenberg Jun Guo 《Journal of bone and mineral research》2012,27(11):2344-2358
Wnt signaling is essential for osteogenesis and also functions as an adipogenic switch, but it is not known if interrupting wnt signaling via knockout of β‐catenin from osteoblasts would cause bone marrow adiposity. Here, we determined whether postnatal deletion of β‐catenin in preosteoblasts, through conditional cre expression driven by the osterix promoter, causes bone marrow adiposity. Postnatal disruption of β‐catenin in the preosteoblasts led to extensive bone marrow adiposity and low bone mass in adult mice. In cultured bone marrow–derived cells isolated from the knockout mice, adipogenic differentiation was dramatically increased, whereas osteogenic differentiation was significantly decreased. As myoblasts, in the absence of wnt/β‐catenin signaling, can be reprogrammed into the adipocyte lineage, we sought to determine whether the increased adipogenesis we observed partly resulted from a cell‐fate shift of preosteoblasts that had to express osterix (lineage‐committed early osteoblasts), from the osteoblastic to the adipocyte lineage. Using lineage tracing both in vivo and in vitro we showed that the loss of β‐catenin from preosteoblasts caused a cell‐fate shift of these cells from osteoblasts to adipocytes, a shift that may at least partly contribute to the bone marrow adiposity and low bone mass in the knockout mice. These novel findings indicate that wnt/β‐catenin signaling exerts control over the fate of lineage‐committed early osteoblasts, with respect to their differentiation into osteoblastic versus adipocytic populations in bone, and thus offers potential insight into the origin of bone marrow adiposity. © 2012 American Society for Bone and Mineral Research. 相似文献
9.
Deletion of a Single β‐Catenin Allele in Osteocytes Abolishes the Bone Anabolic Response to Loading
下载免费PDF全文
![点击此处可从《Journal of bone and mineral research》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Behzad Javaheri Amber Rath Stern Nuria Lara Mark Dallas Hong Zhao Ying Liu Lynda F Bonewald Mark L Johnson 《Journal of bone and mineral research》2014,29(3):705-715
The Wnt/β‐catenin signaling pathway is essential for bone cell viability and function and for skeletal integrity. To determine if β‐catenin in osteocytes plays a role in the bone anabolic response to mechanical loading, 18‐ to 24‐week‐old osteocyte β‐catenin haploinsufficient mice (Dmp1‐Cre × β‐catenin fl/ + ; HET cKO) were compared with their β‐catenin fl/fl (control) littermates. Trabecular bone volume (BV/TV) was significantly less (58.3%) in HET cKO females versus controls, whereas male HET cKO and control mice were not significantly different. Trabecular number was significantly less in HET cKO mice compared with controls for both genders, and trabecular separation was greater in female HET cKO mice. Osteoclast surface was significantly greater in female HET cKO mice. Cortical bone parameters in males and females showed subtle or no differences between HET cKO and controls. The right ulnas were loaded in vivo at 100 cycles, 2 Hz, 2500 µ?, 3 days per week for 3 weeks, and the left ulnas served as nonloaded controls. Calcein and alizarin complexone dihydrate were injected 10 days and 3 days before euthanization, respectively. Micro‐computed tomography (µCT) analysis detected an 8.7% and 7.1% increase in cortical thickness in the loaded right ulnas of male and female control mice, respectively, compared with their nonloaded left ulnas. No significant increase in new cortical bone formation was observed in the HET cKO mice. Histomorphometric analysis of control mice showed a significant increase in endocortical and periosteal mineral apposition rate (MAR), bone‐formation rate/bone surface (BFR/BS), BFR/BV, and BFR/TV in response to loading, but no significant increases were detected in the loaded HET cKO mice. These data show that deleting a single copy of β‐catenin in osteocytes abolishes the anabolic response to loading, that trabecular bone in females is more severely affected and suggest that a critical threshold of β‐catenin is required for bone formation in response to mechanical loading. © 2014 American Society for Bone and Mineral Research 相似文献
10.
11.
12.
Shiguang Liu Wenping Song Joseph H Boulanger Wen Tang Yves Sabbagh Brian Kelley Russell Gotschall Susan Ryan Lucy Phillips Katie Malley Xiaohong Cao Tai‐He Xia Gehua Zhen Xu Cao Hong Ling Paul C Dechow Teresita M Bellido Steven R Ledbetter Susan C Schiavi 《Journal of bone and mineral research》2014,29(5):1141-1157
Altered bone turnover is a key pathologic feature of chronic kidney disease‐mineral and bone disorder (CKD‐MBD). Expression of TGF‐β1, a known regulator of bone turnover, is increased in bone biopsies from individuals with CKD. Similarly, TGF‐β1 mRNA and downstream signaling is increased in bones from jck mice, a model of high‐turnover renal osteodystrophy. A neutralizing anti‐TGF‐β antibody (1D11) was used to explore TGF‐β's role in renal osteodystrophy. 1D11 administration to jck significantly attenuated elevated serum osteocalcin and type I collagen C‐telopeptides. Histomorphometric analysis indicated that 1D11 administration increased bone volume and suppressed the elevated bone turnover in a dose‐dependent manner. These effects were associated with reductions in osteoblast and osteoclast surface areas. Micro‐computed tomography (µCT) confirmed the observed increase in trabecular bone volume and demonstrated improvements in trabecular architecture and increased cortical thickness. 1D11 administration was associated with significant reductions in expression of osteoblast marker genes (Runx2, alkaline phosphatase, osteocalcin) and the osteoclast marker gene, Trap5. Importantly, in this model, 1D11 did not improve kidney function or reduce serum parathyroid hormone (PTH) levels, indicating that 1D11 effects on bone are independent of changes in renal or parathyroid function. 1D11 also significantly attenuated high‐turnover bone disease in the adenine‐induced uremic rat model. Antibody administration was associated with a reduction in pSMAD2/SMAD2 in bone but not bone marrow as assessed by quantitative immunoblot analysis. Immunostaining revealed pSMAD staining in osteoblasts and osteocytes but not osteoclasts, suggesting 1D11 effects on osteoclasts may be indirect. Immunoblot and whole genome mRNA expression analysis confirmed our previous observation that repression of Wnt/β‐catenin expression in bone is correlated with increased osteoclast activity in jck mice and bone biopsies from CKD patients. Furthermore, our data suggest that elevated TGF‐β may contribute to the pathogenesis of high‐turnover disease partially through inhibition of β‐catenin signaling. © 2014 American Society for Bone and Mineral Research. 相似文献
13.
FAK Promotes Osteoblast Progenitor Cell Proliferation and Differentiation by Enhancing Wnt Signaling
下载免费PDF全文
![点击此处可从《Journal of bone and mineral research》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Chunhui Sun Hebao Yuan Li Wang Xiaoxi Wei Linford Williams Paul H Krebsbach Jun‐Lin Guan Fei Liu 《Journal of bone and mineral research》2016,31(12):2227-2238
Decreased bone formation is often associated with increased bone marrow adiposity. The molecular mechanisms that are accountable for the negative correlation between bone mass and bone marrow adiposity are incompletely understood. Focal adhesion kinase (FAK) has critical functions in proliferation and differentiation of many cell types; however, its roles in osteoblast lineage cells are largely unknown. We show herein that mice lacking FAK in Osterix‐expressing cells exhibited decreased osteoblast number and low bone mass as well as increased bone marrow adiposity. The decreased bone mass in FAK‐deficient mice was accounted for by decreased proliferation, compromised osteogenic differentiation, and increased adipogenic differentiation of bone marrow Osterix‐expressing cells resulting from downregulation of Wnt/β‐catenin signaling due to the reduced expression of canonical Wnt ligands. In contrast, FAK loss in calvarial preosteoblasts had no adverse effect on their proliferation and osteogenic differentiation and these cells had intact Wnt/β‐catenin signaling. © 2016 American Society for Bone and Mineral Research. 相似文献
14.
Thomas F. Chan Denis Couchourel Élie Abed Aline Delalandre Nicolas Duval Daniel Lajeunesse 《Journal of bone and mineral research》2011,26(7):1399-1410
The Wnt signaling pathway is crucial for osteogenesis and regulates terminal osteoblast differentiation. Although osteoarthritic (OA) osteoblasts show an abnormal phenotype and poor in vitro mineralization, the mechanism leading to this situation still remains unknow. Recent evidence indicates that Wnt signaling may be altered in OA osteoblasts. In this study we determined whether an alteration of the Wnt/β‐catenin signaling pathway is responsible for the abnormal phenotype of OA osteoblasts. Expression of the Wnt signaling antagonist Dickkopf‐1 (DKK1) was similar in normal and OA osteoblasts, whereas DKK2 expression was higher in OA osteoblasts than in normal osteoblasts. OA osteoblasts showed a decrease of Wnt3a‐dependent Wnt/β‐catenin signaling, measured by the TOPflash reporter assay and by Western blot analysis, compared with normal osteoblasts. Correcting DKK2 levels in OA osteoblasts by siRNA techniques enhanced Wnt/β‐catenin signaling. Elevated DKK2 levels could be explained by elevated transforming growth factor β1 (TGF‐β1) in OA osteoblasts, and exogenous TGF‐β1 increased DKK2 expression in normal osteoblasts, whereas ablating TGF‐β1 expression in OA osteoblasts reduced DKK2 expression. Inhibiting TGF‐β1 or DKK2 expression corrected the abnormal phenotype of OA osteoblasts. In vitro mineralization of OA osteoblasts also was increased by DKK2 siRNA. We conclude that elevated TGF‐β1 levels in OA osteoblasts can stimulate DKK2 expression, which, in turn, is responsible, at least in part, for their abnormal phenotype. © 2011 American Society for Bone and Mineral Research. 相似文献
15.
16.
Wnt Signaling Inhibits Osteoclast Differentiation by Activating Canonical and Noncanonical cAMP/PKA Pathways
下载免费PDF全文
![点击此处可从《Journal of bone and mineral research》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Megan M Weivoda Ming Ruan Christine M Hachfeld Larry Pederson Alan Howe Rachel A Davey Jeffrey D Zajac Yasuhiro Kobayashi Bart O Williams Jennifer J Westendorf Sundeep Khosla Merry Jo Oursler 《Journal of bone and mineral research》2016,31(1):65-75
17.
Inducible Activation of FGFR2 in Adult Mice Promotes Bone Formation After Bone Marrow Ablation
下载免费PDF全文
![点击此处可从《Journal of bone and mineral research》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Wei Xu Fengtao Luo Quan Wang Qiaoyan Tan Junlan Huang Siru Zhou Zuqiang Wang Xianding Sun Liang Kuang Min Jin Nan Su Wanling Jiang Liang Chen Huabing Qi Ying Zhu Bo Chen Hangang Chen Shuai Chen Yu Gao Xiaoling Xu Chuxia Deng Lin Chen Yangli Xie Xiaolan Du 《Journal of bone and mineral research》2017,32(11):2194-2206
Apert syndrome is one of the most severe craniosynostoses, resulting from gain‐of‐function mutations in fibroblast growth factor receptor 2 (FGFR2). Previous studies have shown that gain‐of‐function mutations of FGFR2 (S252W or P253R) cause skull malformation of human Apert syndrome by affecting both chondrogenesis and osteogenesis, underscoring the key role of FGFR2 in bone development. However, the effects of FGFR2 on bone formation at the adult stage have not been fully investigated. To investigate the role of FGFR2 in bone formation, we generated mice with tamoxifen‐inducible expression of mutant FGFR2 (P253R) at the adult stage. Mechanical bone marrow ablation (BMX) was performed in both wild‐type and Fgfr2 mutant (MT) mice. Changes in newly formed trabecular bone were assessed by micro‐computed tomography and bone histomorphometry. We found that MT mice exhibited increased trabecular bone formation and decreased bone resorption after BMX accompanied with a remarkable increase in bone marrow stromal cell recruitment and proliferation, osteoblast proliferation and differentiation, and enhanced Wnt/β‐catenin activity. Furthermore, pharmacologically inhibiting Wnt/β‐catenin signaling can partially reverse the increased trabecular bone formation and decreased bone resorption in MT mice after BMX. Our data demonstrate that gain‐of‐function mutation in FGFR2 exerts a Wnt/β‐catenin‐dependent anabolic effect on trabecular bone by promoting bone formation and inhibiting bone resorption at the adult stage. © 2017 American Society for Bone and Mineral Research. 相似文献
18.
19.
Allogeneic demineralized bone is used extensively as a clinical graft material because it has osteo/chondroinductive and osteoconductive properties. Demineralized bone powder (DBP) induces chondrogenic differentiation of human dermal fibroblasts (hDFs) in three‐dimensional collagen cultures, but the initiating mechanisms have not been fully characterized nor has it been shown that bone morphogenetic proteins (BMPs) recapitulate DBP's effects on target cells. Among the many signaling pathways regulated in hDFs by DBP prior to in vitro chondrogenesis, there are changes in Wnts and their receptors that may contribute to DBP actions. This study tests the hypothesis that DBP modulation of Wnt signaling entails both BMP and TGF‐β pathways. We compared the effects of DBP, TGF‐β1, or BMP‐2 on Wnt signaling components in hDFs by Wnt signaling macroarray, RT‐PCR, in situ hybridization, and Western immunoblot analyses. Many effects of DBP on Wnt signaling components were not shared by BMP‐2, and likewise DBP effects on Wnt genes and β‐catenin only partially required the TGF‐β pathway, as shown by selective inhibition of TGF‐β/activin receptor‐like kinase. The analyses revealed that 64% (16/25) of the Wnt signaling components regulated by DBP were regulated similarly by the sum of effects by BMP‐2 and by TGF‐β1. In conclusion, signaling mechanisms of inductive DBP in human dermal fibroblasts involve the modulation of multiple Wnt signals through both BMP and TGF‐β pathways. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 554–560, 2013 相似文献
20.
Dieudonné FX Marion A Marie PJ Modrowski D 《Journal of bone and mineral research》2012,27(10):2118-2129
Alterations of Wnt signaling appear to be involved in the pathogenesis of osteosarcoma, presenting mutations of adenomatous polyposis coli (APC) and epigenetic downregulation of Wnt inhibitory factor 1. However, the precise role of Wnt effectors in the bone cancer progression remains unclear. We previously showed that Wnt/β‐catenin/T‐cell factor (TCF) activation are responsible for the repression of syndecan‐2, a key modulator of apoptosis and chemosensitivity in osteosarcoma cells, suggesting a role of Wnt signaling in chemoresistance. In this study, we investigated the functional relationship between syndecan‐2, Wnt/β‐catenin/TCF signaling and chemosensitivity in these cells. To this goal, we selected resistant osteosarcoma cells from sensitive human cell lines using repeated exposures to doxorubicin. In doxorubicin‐responsive but not in doxorubicin‐resistant‐derived cells syndecan‐2 expression was upregulated by doxorubicin treatment. Moreover, syndecan‐2 overexpression restored the sensitivity to doxorubicin in resistant‐derived cells. We found that syndecan‐2 induction by doxorubicin is forkhead box protein O3A (Foxo3a)‐dependent. Foxo3a overexpression resulted in increased syndecan‐2 expression in sensitive and resistant‐derived cells. Doxorubicin modulated Foxo3a binding on syndecan‐2 gene promoter and induced Foxo‐dependent inhibition of Wnt/TCF activity. Conversely, β‐catenin/TCF activation impaired syndecan‐2 induction by doxorubicin, indicating that Wnt signaling is competing with the action of the cytotoxic drug. However, β‐catenin was also found to be required for Foxo3a activity. Consistently, Dickkopf 1 (DKK1) and secreted frizzled‐related protein 1 (sFRP‐1) altered doxorubicin action in sensitive cells, whereas inhibition of TCF activity strongly decreased cell viability and increased sensitivity to doxorubicin in sensitive and resistant cells. TCF inhibition also increased the effect of doxorubicin treatment in an orthotopic bone tumor model in mice. Altogether, these data provide evidence that the repression of syndecan‐2 by Wnt/β‐catenin/TCF signaling contributes to the resistance of osteosarcoma cells to doxorubicin and suggest that TCF inhibition may represent a novel therapeutic strategy in osteosarcoma. © 2012 American Society for Bone and Mineral Research. 相似文献