共查询到20条相似文献,搜索用时 765 毫秒
1.
Mark L. Johnson PhD 《Clinical reviews in bone and mineral metabolism》2006,4(2):97-106
Several lines of evidence have provided compelling support for low-density lipoprotein receptor-related protein 5 (LRP5) and
the canonical Wnt/β-catenin signaling pathway as being important and essential for bone formation. Lrp 5 and its close homolog,
Lrp6, are coreceptors with frizzled for Wnt proteins. Binding of Wnt proteins to Lrp5/6 and frizzled activates the Wnt/β-catenin
signaling pathway. Mutations in Lrp5 have been shown to give rise to human diseases of low bone mass and loss of vision such
as osteoporosis pseudoglioma syndrome (OPPG) and familial exudative vitreoretinopathy (FEVR) as well as several human conditions
with increased bone mass and reduced fracture risk, such as the high bone mass (HBM) phenotype. Although it is well established
that the Lrp5/6-Wnt canonical pathway is important in embryonic growth and development of the skeleton, its role in the adult
skeleton is not clear. Accumulating evidence now supports an important role for Lrp5 in the response of the postnatal skeleton
to mechanical load. Transgenic mice carrying the human HBM mutation (LRP5G171V) have increased sensitivity to load, and mice lacking Lrp5 do not respond to mechanical load. In vivo loading of LRP5G171V mice tibia results in increased osteoprotegerin (OPG) gene expression. Mice with either gain-or loss-of-function mutations
in protein components of the canonical pathway below the level of Lrp5/6 develop high or low bone mass mainly as a consequence
of altered OPG production by osteoblasts, which subsequently alters osteoclastogenesis. Thus, activation of the canonical
Wnt signaling pathway apparently has multiple modes of action on bone cells to regulate bone mass. Given the clear importance
of LRP5 in regulating bone mass, this gene/protein represents a potentially exciting new target for the development of anabolic
agents to treat osteoporosis. 相似文献
2.
Bone remodeling requires osteoblasts and osteoclasts working in concert to maintain a constant bone mass. The dysregulation of signaling pathways that affect osteoblast or osteoclast differentiation or function leads to either osteopenia or high bone mass. The discovery that activating and inactivating mutations in low-density lipoprotein receptor-related protein 5, a putative Wnt coreceptor, led to high bone mass and low bone mass in human beings, respectively, generated a tremendous amount of interest in the possible role of the Wnt signaling pathway in the regulation of bone remodeling. A number of mouse models have been generated to study a collection of Wnt signaling molecules that have been identified as regulators of bone mass. These mouse models help establish the canonical Wnt signaling pathway as a major regulator of chondrogenesis, osteoblastogenesis, and osteoclastogenesis. This review will summarize these advances. 相似文献
3.
Wnts are a large family of growth factors that mediate fundamental biological processes like embryogenesis, organogenesis
and tumorigenesis. These proteins bind to a membrane receptor complex comprised of a frizzled (FZD) G-protein-coupled receptor
(GPCRs) and a low-density lipoprotein (LDL) receptor-related protein (LRP). The formation of this ligand-receptor complex
initiates a number of intracellular signaling cascades that includes the canonical/β-catenin pathway, as well as several GPCR-mediated
noncanonical pathways. In recent years, canonical Wnt signaling has been shown to play a substantial role in the control of
bone formation. Clinical investigations have found that mutations in LRP-5 are associated with bone mineral density and fractures.
For example, loss-of-function mutations in LRP-5 cause osteoporosis pseudoglioma syndrome, while gain-of-function mutations
lead to high bone mass phenotypes. Studies of knockout and transgenic mouse models for Wnt pathway components like Wnt-10b,
LRP-5/6, secreted frizzled-related protein-1, dickkopf-2, Axin-2 and β-catenin have demonstrated that canonical signaling
modulates most aspects of osteoblast physiology including proliferation, differentiation, bone matrix formation/mineralization
and apoptosis as well as coupling to osteoclastogenesis and bone resorption. Future studies in this rapidly growing area of
research should focus on elucidating Wnt/FZD specificity in the control of bone cell function, the role of noncanonical pathways
in skeletal remodeling, and direct effects of Wnts on cells of the osteoclast lineage. 相似文献
4.
PURPOSE OF REVIEW: The Wnt signaling pathway has been a major focus of effort in the bone field for the past 5 years. This review will examine some of the seminal findings that have brought us to our current understanding of the role of this pathway in bone metabolism. RECENT FINDINGS: The Wnt/beta-catenin signaling pathway has been shown to play a major role in bone cell differentiation, proliferation and apoptosis. It is a critical component of bone mass regulation and required for bone to respond to mechanical loading. The pathway is tightly regulated by a number of modulator proteins. Mutations in pathway components that result in aberrant regulation are involved in a number of bone diseases. SUMMARY: Understanding the role that the Wnt signaling pathways play in the regulation of bone metabolism offers great promise for the developmental of new paradigms and pharmaceutical strategies for the treatment of various diseases such as osteoporosis, rheumatoid arthritis and osteoarthritis. Progress in this regard has already been made. 相似文献
5.
Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice 总被引:9,自引:0,他引:9 下载免费PDF全文
Clément-Lacroix P Ai M Morvan F Roman-Roman S Vayssière B Belleville C Estrera K Warman ML Baron R Rawadi G 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(48):17406-17411
One of the well characterized cell biologic actions of lithium is the inhibition of glycogen synthase kinase-3beta and the consequent activation of canonical Wnt signaling. Because deficient Wnt signaling has been implicated in disorders of reduced bone mass, we tested whether lithium could improve bone mass in mice. We gavage-fed lithium chloride to 8-week-old mice from three different strains (Lrp5(-/-), SAMP6, and C57BL/6) and assessed the effect on bone metabolism after 4 weeks of therapy. Lrp5(-/-) mice lack the Wnt coreceptor low-density lipoprotein receptor-related protein 5 and have markedly reduced bone mass. Lithium, which is predicted to act downstream of this receptor, restored bone metabolism and bone mass to near wild-type levels in these mice. SAMP6 mice have accelerated osteoporosis due to inadequate osteoblast renewal. Lithium significantly improved bone mass in these mice and in wild-type C57BL/6 mice. We found that lithium activated canonical Wnt signaling in cultured calvarial osteoblasts from Lrp5(-/-) mice ex vivo and that lithium-treated mice had increased expression of Wnt-responsive genes in their bone marrow cells in vivo. These data lead us to conclude that lithium enhances bone formation and improves bone mass in mice and that it may do so via activation of the canonical Wnt pathway. Lithium has been used safely and effectively for over half a century in the treatment of bipolar illness. Prospective studies in patients receiving lithium should determine whether it also improves bone mass in humans. 相似文献
6.
The Wnt/beta-catenin pathway regulates multiple biological events during embryonic development, including bone formation. Fracture repair recapitulates some of the processes of normal bone development, such as the formation of bone from a cartilaginous template, and many cell-signaling pathways that underlie bone development are activated during the repair process. The Wnt/beta-catenin signaling pathway is activated during fracture repair, and dysregulation of this pathway alters the normal bone-healing response. In early pluripotent mesenchymal stem cells, Wnt/beta-catenin signaling needs to be precisely regulated to facilitate the differentiation of osteoblasts; by contrast, beta-catenin is not needed for chondrocyte differentiation. Once mesenchymal stem cells are committed to the osteoblast lineage, activation of Wnt/beta-catenin signaling enhances bone formation. This activity suggests that the Wnt/beta-catenin pathway is a therapeutic target during bone repair. Indeed, treatments that activate Wnt/beta-catenin signaling, such as lithium, increase bone density and also enhance healing. 相似文献
7.
The genetics of low-density lipoprotein receptor-related protein 5 in bone: a story of extremes 总被引:1,自引:0,他引:1
A few years ago, human genetic studies provided compelling evidence that the low-density lipoprotein receptor-related protein 5 (LRP5) is involved in the regulation of bone homeostasis because pathogenic LRP5 mutations were found in monogenic conditions with abnormal bone density. On the one hand, the osteoporosis pseudoglioma syndrome results from loss of function of LRP5, whereas on the other hand, gain-of-function mutations in LRP5 cause conditions with an increased bone density. On the molecular level, these types of mutations result in disturbed (respectively, decreased and increased) canonical Wnt signaling, an important metabolic pathway in osteoblasts during embryonic and postnatal osteogenesis. This signaling cascade is activated by binding of Wnt ligand to the Frizzled/LRP5 receptor complex. In addition to the involvement of LRP5 in conditions with extreme bone phenotypes, the genetic profile of this gene has also been shown to contribute to the determination of bone density in the general population. Quite a number of studies already demonstrated that common polymorphic variants in LRP5 are associated with bone mineral density and consequently osteoporosis, a multifactorial trait with low bone mass and porous bone structure. These genetic studies together with results obtained from in vitro and in vivo studies emphasize the importance of LRP5 and canonical Wnt signaling in the regulation of bone homeostasis. Therefore, unraveling the exact mechanisms of this signaling cascade has become an important area in bone research. This review focuses on the genetics of LRP5 and summarizes the findings on monogenic bone conditions as well as the current knowledge of its involvement in the pathogenesis of osteoporosis. 相似文献
8.
The Wnt signaling pathway has recently been demonstrated to play an important role in regulation of bone formation. LRP5 is thought to signal through the canonical Wnt pathway. In humans, LRP5 loss-of-function mutations lead to low bone mass with fractures, while LRP5 gain-of-function mutations lead to high bone mass, thus identifying LRP5 as an important regulator of bone mass. Patients with sclerosteosis have a severe skeletal disorder with progressive bone overgrowth due to a loss of function of the SOST gene, which implicates its role as a suppressor of bone formation. Recent study revealed that SOST is a BMP antagonist with unique ligand specificity, negatively regulating bone formation by repressing BMP-induced osteoblast differentiation or function or both. 相似文献
9.
高骨量疾病骨硬化症(sclerosteosis)和Van Buchem病由SOST基因表达缺失导致.由于SOST基因突变导致骨硬化蛋白不能表达或功能缺陷,可造成该病患者的过度骨形成,其作用机制与抑制Wnt信号转导通路相关.骨硬化蛋白通过与该通路共受体LRP5/6结合来阻断Wnt通路,进而对成骨细胞分化及矿化起抑制作用.由于骨硬化蛋白在抑制骨形成起关键作用且仅在骨组织表达,其单克隆抗体可用于治疗低骨量疾病如骨质疏松. 相似文献
10.
Eveline BoudinIgor Fijalkowski PhD Elke PitersWim Van Hul PhD 《Seminars in arthritis and rheumatism》2013
Objectives
The Wnt signaling pathway is a key pathway in various processes, including bone metabolism. In this review, current knowledge of all extracellular modulators of the canonical Wnt signaling in bone metabolism is summarized and discussed.Methods
The PubMed database was searched using the following keywords: canonical Wnt signaling, β-catenin bone metabolism, BMD, osteoblast, osteoporosis, Wnt, LRPs, Frizzleds, sFRPs, sclerostin or SOST, dickkopfs, Wif1, R-spondins, glypicans, SOST-dc1 and kremen, all separately as well as in different combinations.Results
Canonical Wnt signaling is considered to be one of the major pathways regulating bone formation. Consequently, a large number of studies were performed to elucidate the role of numerous proteins in canonical Wnt signaling and bone metabolism. These studies led to the identification of novel modulators of the pathway like the R-spondin and glypican protein families. Furthermore novel insights are gained in the regulatory role of the different Wnt proteins. Finally, due to its function in bone formation, the pathway is an interesting target for the development of therapeutics for osteoporosis and other bone diseases. In this review, we discuss the promising results of the Wnt modulators sclerostin, Dkk1 and sFRP1 as targets for osteoporosis treatment.Conclusion
The increasing number of studies into the exact function of all proteins in the canonical Wnt pathway in general and in bone metabolism already led to novel insights in the regulation of the canonical Wnt pathway. In this review we covered the current knowledge of all extracellular modulators of canonical Wnt signaling. 相似文献11.
Ram Babu Undi Usha Gutti Itishri Sahu Shilpa Sarvothaman Satya Ratan Pasupuleti Ravinder Kandi Ravi Kumar Gutti 《Indian journal of hematology & blood transfusion》2016,32(2):123-134
Hematopoietic stem cells (HSCs) are a unique population of bone marrow cells which are responsible for the generation of various blood cell lineages. One of the significant characteristics of these HSCs is to self-renew, while producing differentiating cells for normal hematopoiesis. Deregulation of self-renewal and differentiation leads to the hematological malignancies. Several pathways are known to be involved in the maintenance of HSC fate among which Wnt signaling is a crucial pathway which controls development and cell fate determination. Wnt signaling also plays a major role in differentiation, self-renewal and maintenance of HSCs. Wnt ligands activate three major pathways including planar cell polarity, Wnt/β-catenin and Wnt/Ca2+. It has been shown that Wnt/β-catenin or canonical pathway regulates cell proliferation, survival and differentiation in HSCs, deregulation of this pathway leads to hematological malignancies. Wnt non-canonical pathway regulates calcium signaling and planar cell polarity. In this review, we discuss various signaling pathways induced by Wnt ligands and their potential role in hematopoiesis. 相似文献
12.
Edwards CM Edwards JR Lwin ST Esparza J Oyajobi BO McCluskey B Munoz S Grubbs B Mundy GR 《Blood》2008,111(5):2833-2842
There is increasing evidence to suggest that the Wnt signaling pathway plays a critical role in the pathogenesis of myeloma bone disease. In the present study, we determined whether increasing Wnt signaling within the bone marrow microenvironment in myeloma counteracts development of osteolytic bone disease. C57BL/KaLwRij mice were inoculated intravenously with murine 5TGM1 myeloma cells, resulting in tumor growth in bone and development of myeloma bone disease. Lithium chloride (LiCl) treatment activated Wnt signaling in osteoblasts, inhibited myeloma bone disease, and decreased tumor burden in bone, but increased tumor growth when 5TGM1 cells were inoculated subcutaneously. Abrogation of beta-catenin activity and disruption of Wnt signaling in 5TGM1 cells by stable overexpression of a dominant-negative TCF4 prevented the LiCl-induced increase in subcutaneous growth but had no effect on LiCl-induced reduction in tumor burden within bone or on osteolysis in myeloma-bearing mice. Together, these data highlight the importance of the local microenvironment in the effect of Wnt signaling on the development of myeloma bone disease and demonstrate that, despite a direct effect to increase tumor growth at extraosseous sites, increasing Wnt signaling in the bone marrow microenvironment can prevent the development of myeloma bone disease and inhibit myeloma growth within bone in vivo. 相似文献
13.
14.
Diseases of Wnt signaling 总被引:4,自引:0,他引:4
The Wnt signaling pathways play fundamental roles in the differentiation, proliferation, death and function of many cells
and as a result are involved in critical developmental, growth and homeostatic processes in animals. There are four currently
known pathways of Wnt signaling; the so-called canonical or Wnt/β-catenin pathway, the Wnt/Ca+2 pathway involving Protein Kinase A, the planar cell polarity pathway and a pathway involving Protein Kinase C that functions
in muscle myogenesis. The best studied of these is the Wnt/β-catenin pathway. The Wnts are an evolutionarily highly conserved
family of genes/proteins. Control of the Wnt pathways is modulated by a number of the proteins that either interact with the
Wnt ligands directly, or with the low density lipoprotein-receptor related proteins (LRP) 5 and 6 that along with one of several
Frizzled proteins function as co-receptors for the Wnt ligands. Aberrant regulation resulting as a consequence of mutations
in any of several components of the Wnt pathway and/or protein modulators of the pathway have been shown to cause a wide spectrum
of diseases. This review will briefly touch on various diseases of Wnt signaling including cancer, aortic valve calcification
and several bone related phenotypes. Our emerging understanding of Wnt signaling offers great hope that new molecular based
screening tests and pharmaceutical agents that selectively target this pathway will be developed to diagnose and treat these
diseases in the future.
An erratum to this article can be found at 相似文献
15.
Auld KL Berasi SP Liu Y Cain M Zhang Y Huard C Fukayama S Zhang J Choe S Zhong W Bhat BM Bhat RA Brown EL Martinez RV 《Journal of molecular endocrinology》2012,48(2):177-191
Based on its homology to the estrogen receptor and its roles in osteoblast and chondrocyte differentiation, the orphan nuclear receptor estrogen-related receptor α (ERRα (ESRRA)) is an intriguing therapeutic target for osteoporosis and other bone diseases. The objective of this study was to better characterize the molecular mechanisms by which ERRα modulates osteoblastogenesis. Experiments from multiple systems demonstrated that ERRα modulates Wnt signaling, a crucial pathway for proper regulation of bone development. This was validated using a Wnt-luciferase reporter, where ERRα showed co-activator-dependent (peroxisome proliferator-activated receptor gamma co-activator 1α, PGC-1α) stimulatory effects. Interestingly, knockdown of ERRα expression also enhanced WNT signaling. In combination, these data indicated that ERRα could serve to either activate or repress Wnt signaling depending on the presence or absence of its co-activator PGC-1α. The observed Wnt pathway modulation was cell intrinsic and did not alter β-catenin nuclear translocation but was dependent on DNA binding of ERRα. We also found that expression of active ERRα correlated with Wnt pathway effects on osteoblastic differentiation in two cell types, consistent with a role for ERRα in modulating the Wnt pathway. In conclusion, this work identifies ERRα, in conjunction with co-activators such as PGC-1α, as a new regulator of the Wnt-signaling pathway during osteoblast differentiation, through a cell-intrinsic mechanism not affecting β-catenin nuclear translocation. 相似文献
16.
Peter V. N. Bodine John A. Robinson Ramesh A. Bhat Julia Billiard Frederick J. Bex Barry S. Komm 《Clinical reviews in bone and mineral metabolism》2006,4(2):73-96
Regulation of canonical Wnt signaling in osteoblasts has been shown to play an important role in bone formation. Loss-of-function
mutations in the Wnt co-receptor, low-density lipoprotein receptor-related protein (LRP)5, cause osteoporosis pseudoglioma
syndrome in humans, whereas gain-of-function mutations like G171V lead to high bone mass phenotypes. Mouse models of these
conditions have enabled the mechanisms of LRP5 action on bone to be elucidated, and allation of additional pathway components
like LRP6, Wnt-10b, and the antagonist secreted frizzled-related protein (sFRP)-1 has extended our understanding of Wnt action
in the skeleton. LRP5−/− mice exhibit decreased trabecular bone volume (TBV) at an early age owing to reduced osteoblast proliferation and activity,
whereas transgenic LRP5G171V/+ mice demonstrate increased TBV at a young age owing to reduced osteoblast and osteocyte apoptosis. Canonical Wnt signaling
also plays a role in mechanosensory stimulation of osteoblasts in vitro, and the LRP5G171V/+ transgenic mice are resistant to disuse-induced bone loss. LRP6−/+ mice display diminished TBV indicating that LRP5 and LRP6 are both required for optimal osteoblast function. Wnt-10b−/− mice also exhibit reduced TBV, demonstrating that this is one of the ligands that controls bone formation. In contrast, sFRP-1−/− mice show heightened TBV, but not until adulthood when enhanced osteoblast proliferation, differentiation and activity, as
well as diminished osteoblast and osteocyte apoptosis are observed. sFRP-1 also modulates osteoclast formation in vitro, and
other family members like sFRP-4 are able to control phosphate metabolism in vivo. Moreover, anabolic factors like bone morphogenetic
protein-2 and parathyroid hormone appear to at least partly control bone formation through intersection with Wnt signaling.
Finally, new components of the Wnt pathways like the orphan tyrosine kinase receptor Ror2 have recently been identified as
modulators of osteoblast physiology. Thus, Wnt signaling plays a substantial role in the regulation of bone and mineral metabolism.
Future research will provide for a better understanding of the mechanisms for Wnt action in the skeleton. 相似文献
17.
Wnt信号通路是由经典及非经典两类通路组成的一个复杂的蛋白网络,其在骨代谢疾病和肿瘤疾病等研究中至关重要.对于骨代谢疾病早期报道多集中于经典信号通路,但随着研究的不断深入,非经典Wnt信号通路在调控骨稳态(骨形成和骨吸收)中的作用日益受到关注.本文对非经典Wnt配体及其在骨稳态中的作用进行阐述,了解非经典Wnt信号的靶向调控为治疗骨质疏松症等骨稳态失衡相关疾病提供潜在研究方法及新的靶点. 相似文献
18.
Regard JB Cherman N Palmer D Kuznetsov SA Celi FS Guettier JM Chen M Bhattacharyya N Wess J Coughlin SR Weinstein LS Collins MT Robey PG Yang Y 《Proceedings of the National Academy of Sciences of the United States of America》2011,108(50):20101-20106
Skeletal dysplasias are common disabling disorders characterized by aberrant growth of bone and cartilage leading to abnormal skeletal structures and functions, often attributable to defects in skeletal progenitor cells. The underlying molecular and cellular mechanisms of most skeletal dysplasias remain elusive. Although the Wnt/β-catenin signaling pathway is required for skeletal progenitor cells to differentiate along the osteoblastic lineage, inappropriately elevated levels of signaling can also inhibit bone formation by suppressing osteoblast maturation. Here, we investigate interactions of the four major Gα protein families (Gα(s), Gα(i/o), Gα(q/11), and Gα(12/13)) with the Wnt/β-catenin signaling pathway and identify a causative role of Wnt/β-catenin signaling in fibrous dysplasia (FD) of bone, a disease that exhibits abnormal differentiation of skeletal progenitor cells. The activating Gα(s) mutations that cause FD potentiated Wnt/β-catenin signaling, and removal of Gα(s) led to reduced Wnt/β-catenin signaling and decreased bone formation. We further show that activation of Wnt/β-catenin signaling in osteoblast progenitors results in an FD-like phenotype and reduction of β-catenin levels rescued differentiation defects of FD patient-derived stromal cells. Gα proteins may act at the level of β-catenin destruction complex assembly by binding Axin. Our results indicate that activated Gα proteins differentially regulate Wnt/β-catenin signaling but, importantly, are not required core components of Wnt/β-catenin signaling. Our data suggest that activated Gα proteins are playing physiologically significant roles during both skeletal development and disease by modulating Wnt/β-catenin signaling strength. 相似文献
19.
Maripat Corr 《Clinical rheumatology》2014,33(6):759-762
The mechanisms that lead to bony fusion in ankylosing spondylitis (AS) are yet to be fully defined. In recent years, there have been several advances in our understanding of this complex disease. Here, the potential impact of the Wnt signaling pathway will be discussed. This pathway is involved in bone morphogenesis and homeostasis. Perturbations in the normal regulation have been implicated in abnormal bone formation (e.g., osteophytes). Levels of Wnt regulatory proteins like Dickkopf have been investigated as potential biomarkers of disease. This pathway might be involved in other aspects of this disease including T cell activation and differentiation, and in bone marrow adipogenesis. The pathways leading to the unique pathology and bony fusion in AS are complex and the Wnt pathway might play a critical contributing role. 相似文献