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A Comprehensive overview of Skeletal Phenotypes Associated with Alterations in Wnt/β-catenin Signaling in Humans and Mice

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Bone Research 2013年第1期1卷 27-71页

作者： Kevin A.Maupin Casey J.Droscha bart o.williams Program for Skeletal Pathobiology and Center for Tumor Metastasis Van Andel Research Institute333 Bostwick NEGrand RapidsMI 49503USA

The Wnt signaling pathway plays key roles in differentiation and development and alterations in this signaling pathway are causally associated with numerous human diseases. While several laboratories were examining roles for Wnt signaling in skeletal development during the 1990s, interest in the pathway rose exponentially when three key papers were published in 2001-2002. one report found that loss of the Wnt co-receptor, Low-density lipoprotein related protein-5 （LRPS）, was the underlying genetic cause of the syndrome osteoporosis pseudoglioma （oPPG）. oPPG is characterized by early-onset osteoporosis causing increased susceptibility to debilitating fractures. Shortly thereafter, two groups reported that individuals carrying a specific point mutation in LRP5 （G171V） develop high-bone mass. Subsequent to this, the causative mechanisms for these observations heightened the need to understand the mechanisms by which Wnt signaling controlled bone development and homeostasis and encouraged significant investment from biotechnology and pharmaceutical companies to develop methods to activate Wnt signaling to increase bone mass to treat osteoporosis and other bone disease. In this review, we will briefly summarize the cellular mechanisms underlying Wnt signaling and discuss the observations related to oPPG and the high-bone mass disorders that heightened the appreciation of the role of Wnt signaling in normal bone development and homeostasis. We will then present a comprehensive overview of the core components of the pathway with an emphasis on the phenotypes associated with mice carrying genetically engineered mutations in these genes and clinical observations that further link alterations in the pathway to changes in human bone.

关键词： Wnt signaling mouse models Lrp5/Lrp6 -catenin skeletal phenotypes

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Enhanced cortical bone expansion in Lgals3-deficient mice during aging

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Bone Research 2018年第1期6卷 95-106页

作者： Kevin A.Maupin Kevin Weaver Alexis Bergsma Cheryl Christie Zhendong A.Zhong Tao Yang bart o.williams Center for Cancer and Cell Biology Program for Skeletal Disease and Tumor Microenvironment Van Andel Research Institute

Imbalances between bone formation and bone resorption, which can occur due to aging or sex hormone deprivation, result in decreased bone mass and an increased risk of fracture. Previous studies have suggested that the β-galactoside binding lectin,galectin-3, is involved in bone remodeling. We compared bone parameters of mice having null alleles of the galectin-3 gene(Lgals3-Ko) with those of their wild-type littermates. Lgals3 deficiency increased cortical bone expansion at 36 weeks(wk) and preserved or enhanced bone mass in both male and female mutant mice. In addition, female Lgals3-Ko mice were protected from age-related loss of trabecular bone. Histomorphometry and ex vivo primary cell differentiation assays showed increased osteoblastogenesis with little-to-no effect on osteoclastogenesis, suggesting the increased bone mass phenotype is primarily due to increased anabolism. our study identifies galectin-3 as a negative regulator of bone formation and suggests that disruption of galectin-3 may be useful in preventing bone loss during aging.

关键词： Lgals3-Ko their wild-type Histomorphometry

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Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy

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Bone Research 2018年第2期6卷 167-176页

作者： Babita Madan Mitchell J.McDonald Gabrielle E.Foxa Cassandra R.Diegel bart o.williams David M.Virshup Program in Cancer and Stem Cell Biology Duke-NUS Medical School Center for Cancer and Cell Biology and Program for Skeletal Disease and Tumor Microenvironment Van Andel Research Institute Department of Pediatrics Duke University

Dysregulated Wnt signaling is associated with the pathogenesis of cancers, fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy in various pre-clinical models of these disorders. one of the key challenges in developing targeted anti-cancer drugs is to balance efficacy with on-target toxicity. Given the crucial role Wnts play in the differentiation of osteoblasts and osteoclasts, acute inhibition of Wnt signaling is likely to affect bone homeostasis. In this study, we evaluated the skeletal effect of small molecule inhibitor of an o-acyl transferase porcupine（PoRCN） that prevents Wnt signaling by blocking the secretion of all Wnts. Micro-computed tomography and histomorphometric evaluation revealed that the bones of mice treated with two structurally distinct PoRCN inhibitors LGK974 and ETC-1922159（ETC-159） had loss-of-bone volume and density within 4 weeks of exposure. This decreased bone mass was associated with a significant increase in adipocytes within the bone marrow. Notably,simultaneous administration of a clinically approved anti-resorptive, alendronate, a member of the bisphosphonate family,mitigated loss-of-bone mass seen upon ETC-159 treatment by regulating activity of osteoclasts and blocking accumulation of bone marrow adipocytes. our results support the addition of bone protective agents when treating patients with PoRCN *** of bone toxicity can extend the therapeutic utility of Wnt pathway inhibitors.

关键词： Wnt ETC Bone loss Wnt inhibition mitigated concurrent alendronate therapy

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Skeletal metastasis:treatments,mouse models,and the Wnt signaling

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Chinese Journal of Cancer 2013年第7期32卷 380-396页

作者： Kenneth C.Valkenburg Matthew R.Steensma bart o.williams Zhendong Zhong Center for Skeletal Disease Research Van Andel Research Institute333 Bostwick Ave.NEGrand RapidsMI 49503USA orthopedic oncology Spectrum Health145 Michigan St.NEGrand RapidsMI 49503USA

Skeletal metastases result in significant morbidity and *** is particularly true of cancers with a strong predilection for the bone,such as breast,prostate,and lung *** is currently no reliable cure for skeletal metastasis,and palliative therapy options are *** Wnt signaling pathway has been found to play an integral role in the process of skeletal metastasis and may be an important clinical *** experimental models of skeletal metastasis have been used to find new biomarkers and test new *** this review,we discuss pathologic process of bone metastasis,the roles of the Wnt signaling,and the available experimental models and treatments.

关键词：治疗小鼠模型 Wnt信号通路信令实验模型生物标志物前列腺癌病理过程

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Inhibiting WNT secretion reduces high bone mass caused by Sost loss-of-function or gain-of-function mutations in Lrp5

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Bone Research 2023年第3期11卷 595-606页

作者： Cassandra R.Diegel Ina Kramer Charles Moes Gabrielle E.Foxa Mitchell J.McDonald Zachary B.Madaj Sabine Guth Jun Liu Jennifer L.Harris Michaela Kneissel bart o.williams Department of Cell Biology Van Andel Institute333 Bostwick Ave.NEGrand RapidsMI 49503USA Diseases of Aging and Regenerative Medicine Novartis Institutes for Biomedical ResearchCH-4002 BaselSwitzerland Bioinformatics and Biostatistics Core Van Andel Institute333 Bostwick Ave.NEGrand RapidsMI 49503USA oncology Novartis Institutes for Biomedical ResearchSan DiegoCA 92121USA

Proper regulation of Wnt signaling is critical for normal bone development and *** in several Wnt signaling components,which increase the activity of the pathway in the skeleton,cause high bone mass in human subjects and mouse *** bone mass is often accompanied by severe headaches from increased intracranial pressure,which can lead to fatality and loss of vision or hearing due to the entrapment of cranial *** addition,progressive forehead bossing and mandibular overgrowth occur in almost all *** that would provide symptomatic relief in these subjects are ***-mediated palmitoylation is necessary for Wnt secretion and binding to the frizzled *** inhibition of porcupine is a highly selective method of Wnt signaling *** treated three different mouse models of high bone mass caused by aberrant Wnt signaling,including homozygosity for loss-of-function in Sost,which models sclerosteosis,and two strains of mice carrying different point mutations in Lrp5(equivalent to human G171V and A214V),at 3 months of age with porcupine inhibitors for 5–6 *** significantly reduced both trabecular and cortical bone mass in all three *** demonstrates that porcupine inhibition is potentially therapeutic for symptomatic relief in subjects who suffer from these disorders and further establishes that the continued production of Wnts is necessary for sustaining high bone mass in these models.

关键词： homeostasis function mass

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LRP6 in mesenchymal stem cells is required for bone formation during bone growth and bone remodeling

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Bone Research 2014年第1期2卷 43-54页

作者： Changjun Li bart o.williams Xu Cao Mei Wan Department of orthopaedic Surgery Johns Hopkins University School of Medicine Center for Skeletal Disease and Tumor Metastasis and Laboratory of Cell Signaling and Carcinogenesis Van Andel Research Institute

Lipoprotein receptor-related protein 6 （LRP6） plays a critical role in skeletal development and homeostasis in adults. However, the role of LRP6 in mesenchymal stem cells （MSCs）, skeletal stem cells that give rise to osteoblastic lineage, is unknown. In this study, we generated mice lacking LRP6 expression specifically in nestin＋ MSCs by crossing nestin-Cre mice with LRP6 flox mice and investigated the functional changes of bone marrow MSCs and skeletal alterations. Mice with LRP6 deletion in nestin＋ cells demonstrated reductions in body weight and body length at I and 3 months of age. Bone architecture measured by microCT （uCT） showed a significant reduction in bone mass in both trabecular and cortical bone of homozygous and heterozygous LRP6 mutant mice. A dramatic reduction in the numbers of osteoblasts but much less significant reduction in the numbers of osteoclasts was observed in the mutant mice. osterix＋ osteoprogenitors and osteocalcin＋ osteoblasts significantly reduced at the secondary spongiosa area, but only moderately decreased at the primary spongiosa area in mutant mice. Bone marrow MSCs from the mutant mice showed decreased colony forming, cell viability and cell proliferation. Thus, LRP6 in bone marrow MSCs is essential for their survival and proliferation, and therefore, is a key positive regulator for bone formation during skeletal growth and remodeling.

关键词： bone LRP6 in mesenchymal stem cells is required for bone formation during bone growth and bone remodeling stem

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Characterization of genetically engineered mouse models carrying Col2a1-cre-induced deletions of Lrp5 and/or Lrp6

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Bone Research 2015年第4期3卷 235-245页

作者： Cassie A Schumacher Danese M Joiner Kennen D Less Melissa oosterhouse Drewry bart o.williams Center for Cancer and Cell Biology Program in Skeletal Disease and Tumor MicroenvironmentVan Andel Research Institute

Mice carrying Collagen2a1-cre-mediated deletions of Lrp5 and/or Lrp6 were created and *** lacking either gene alone were viable and fertile with normal knee *** in which both Lrp5 and Lrp6 were conditionally ablated via Collagen2al-cre-mediated deletion displayed severe defects in skeletal development during *** addition,adult mice carrying Collagen2al-cre-mediated deletions of Lrp5 and/or Lrp6 displayed low bone mass suggesting that the Collagen2a1-cre transgene was active in cells that subsequently differentiated into *** both embryonic skeletal development and establishment of adult bone mass,Lrp5 and Lrp6 carry out redundant functions.

关键词： carrying Collagen displayed deletion engineered transgene viable embryogenesis redundant embryonic

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Mice with a heterozygous Lrp6 deletion have impaired fracture healing

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Bone Research 2016年第2期4卷 101-109页

作者： Travis A Burgers Juan F Vivanco Juraj zahatnansky Andrew J Vander Moren James J Mason bart o.williams Center for Cancer and Cell Biology Program for Skeletal Disease and Tumor Microenvironment Van Andel Research Institute Grand Rapids MhUSA Faculfad de Ingenieria y Ciencias Adolfo Ib6fiez University Vifia del Mar Chile padnos College of Engineering and Computing Grand Valley State University Grand Rapids MI USA

Bone fracture non-unions, the failure of a fracture to heal, occur in 10%-20% of fractures and are a costly and debilitating clinical problem. The Wnt/fl-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 （LRP6）, a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density. As fracture healing closely models embryonic skeletal development, we investigated the process of fracture healing in mice heterozygous for Lrp6 （Lrp6~/-） and hypothesized that the heterozygous deletion of Lrp6 would impair fracture healing. Mid-diaphyseal femur fractures were induced in Lrp6~^- mice and wild-type controls （Lrp6~/~）. Fractures were analyzed using micro-computed tomography （~CT） scans, biomechanical testing, and histological analysis. Lrp6~/- mice had significantly decreased stiffness and strength at 28 days post fracture （PF） and significantly decreased BV/TV, total density, immature bone density, and mature area within the callus on day-14 and -21 PF; they had significantly increased empty callus area at days 14 and 21 PF. our results demonstrate that the heterozygous deletion of Lrp6 impairs fracture healing, which suggests that Lrp6 has a role in fracture healing.

关键词： bone Mice with a heterozygous Lrp6 deletion have impaired fracture healing

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^(99m)TC-Methylene diphosphonate uptake at injury site correlates with osteoblast differentiation and mineralization during bone healing in mice

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Bone Research 2015年第2期3卷 92-99页

作者： Zhendong A Zhong Anderson Peck Shihong Li Jeff Van oss John Snider Casey J Droscha Tingtung A Chang bart o.williams Center for Skeletal Disease Research Van Andel Research Institute Department of Internal Medicine Center for Musculoskeletal Health UC Davis Medical Center Small Animal Imaging Facility Van Andel Research Institute

99mTc-Methylene diphosphonate （99mTc-MDP） is widely used in clinical settings to detect bone abnormalities. However, the mechanism of 99mTc-MDP uptake in bone is not well elucidated. In this study, we utilized a mouse tibia injury model, single-photon emission computed tomography （gamma scintigraphy or SPECT）, ex vivo micro-computed tomography, and histology to monitor 99mTc-MDP uptake in injury sites during skeletal healing. In an ex vivo culture system, calvarial cells were differentiated into osteoblasts with osteogenic medium, pulsed with 99mTc-MDP at different time points, and quantitated for 99mTc-MDP uptake with a gamma counter. We demonstrated that 99mTc-MDP uptake in the injury sites corresponded to osteoblast generation in those sites throughout the healing process. The 99mTc-MDP uptake within the injury sites peaked on day 7 post-injury, while the injury sites were occupied by mature osteoblasts also starting from day 7. ~mTc-MDP uptake started to decrease 14 days post-surgery, when we observed the highest level of bony tissue in the injury sites. We also found that 99mTc-MDP uptake was associated with osteoblast maturation and mineralization in vitro. This study provides direct and biological evidence for 99mTc-MDP uptake in osteoblasts during bone healing in vivo and in vitro.

关键词： MDP bone TC-Methylene diphosphonate uptake at injury site correlates with osteoblast differentiation and mineralization during bone healing in mice SPECT

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Dissolved organic matter tracers reveal contrasting characteristics across high arsenic aquifers in Cambodia:A fluorescence spectroscopy study

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Geoscience Frontiers 2019年第5期10卷 1653-1667页

作者： Laura A. Richards Dan J. Lapworth Daniel Magnone Daren C. Gooddy Lee Chambers Peter J. williams bart E. van Dongen David A. Polya School of Earth and Environmental Sciences and williamson Research Centre for Molecular Environmental Science The University of ManchesterWilliamson BuildingOxford RoadManchesterM13 9PLUK British Geological Survey Maclean BuildingWallingfordOxfordshireOX10 8BBUK Lancaster Environment Centre Lancaster UniversityLancaster LA1 4YQUK Present address: School of Geography University of LincolnBrayford PoolLincolnLincolnshireLN6 7 TSUK Present address: Department of Civil and Environmental Engineering University of StrathclydeGlasgow G1 1XJUK

organic matter in the environment is involved in many biogeochemical processes,including the mobilization of geogenic trace elements,such as arsenic,into *** this paper we present the use of fluorescence spectroscopy to characterize the dissolved organic matter (DoM) pool in heavily arsenicaffected groundwaters in Kandal Province,*** fluorescence DoM (fDoM) characteristics between contrasting field areas of differing dominant lithologies were compared and linked to other hydrogeochemical parameters,including arsenic and dissolved methane as well as selected sedimentary ***-corrected fluorescence indices were used to characterize depth profiles and compare field *** fDoM was generally dominated by terrestrial humic and fulvic-like components,with relatively small contributions from microbially-derived,tryptophan-like *** fDoM from sand-dominated sequences typically contained lower tryptophan-like,lower fulvic-like and lower humic-like components,was less bioavailable,and had higher humification index than clay-dominated *** concentrations were strongly correlated with fDoM bioavailability as well as with tryptophan-like components,suggesting that groundwater methane in these arsenic-prone aquifers is likely of biogenic origin.A comparison of fDoM tracers with sedimentary oM tracers is consistent with the hypothesis that external,surface-derived contributions to the aqueous DoM pool are an important control on groundwater hydrogeochemistry.

关键词： Arsenic Fluorescence spectroscopy organic matter characterization Parallel factor analysis (PARAFAC) Groundwater quality

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