In Vivo Analysis of Wnt Signaling in Bone

Department of Genetics and Development, Columbia University, New York, New York, United States
Endocrinology (Impact Factor: 4.5). 06/2007; 148(6):2630-4. DOI: 10.1210/en.2006-1372
Source: PubMed


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.

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    • "During new bone layer formation, osteoblasts differentiate into terminal stage osteocytes. The canonical Wnt signaling pathway plays a crucial role in normal bone development[21,858687888990919293949596in the regulation of both osteoblasts and osteoclasts (Figure 2). In osteoblasts, Wnt signaling influences three major developmental functions: the commitment of MSCs to an osteoblast stem cell type; stimulation of osteoblast proliferation; and promotion of osteoblast and osteocyte survival[ "

    Full-text · Dataset · Jan 2016
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    • "Bone anabolic stimuli activate this pathway and human mutations of components along this pathway underscore its crucial role in bone accrual and maintenance. However, the cell responsible for orchestrating Wnt anabolic actions has remained elusive, as activation of Wnt/β-catenin signaling in preosteoblasts or osteoblasts inhibits resorption without increasing bone forma- tion[33]. This new evidence now showed that, in contrast, activation of canonical Wnt signaling in osteocytes [dominant active (da)βcat Ot mice] induces bone anabolism and triggers Notch signaling without affecting survival[32•]. "
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    ABSTRACT: For many years osteocytes have been the forgotten bone cells and considered as inactive spectators buried in the bone matrix. We now know that osteocytes detect and respond to mechanical and hormonal stimuli to coordinate bone resorption and bone formation. Osteocytes are currently considered a major source of molecules that regulate the activity of osteoclasts and osteoblasts, such as RANKL and sclerostin, and genetic and pharmacological manipulations of either molecule markedly affect bone homeostasis. Besides playing a role in physiological bone homeostasis, accumulating evidence supports the notion that dysregulation of osteocyte function and alteration of osteocyte lifespan underlies the pathophysiology of skeletal disorders characterized by loss bone mass and increased bone fragility, as well as the damaging effects of cancer in bone. In this review, we highlight some of these investigations and discuss novel observations that demonstrate that osteocytes, far from being passive cells entombed in the bone, are critical for bone function and maintenance.
    Full-text · Article · Oct 2015
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    • "The application of differentiation therapy for solid tumours has been hindered by the absence of developmental models of cancer progression that correlate cancer subtypes to stages of normal development. Osteosarcoma cells share many similar features to undifferentiated osteoprogenitors including a high proliferative capacity, resistance to apoptosis and similar expression profiles of many osteogenic markers such as connective tissue growth factor, runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), osterix and osteocalcin [9], [10]. Increasing evidence suggests that osteosarcoma cells can be induced to mature osteoblasts by certain compounds, including retinoic acid [11]. "
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    ABSTRACT: Osteosarcoma, one of the most common malignant bone tumours, is generally considered a differentiation disease caused by genetic and epigenetic disruptions in the terminal differentiation of osteoblasts. Novel therapies based on the non-cytotoxic induction of cell differentiation-responsive pathways could represent a significant advance in treating osteosarcoma; however, effective pharmaceuticals to induce differentiation are lacking. In the present study, we investigated the effect of hyperoside, a flavonoid compound, on the osteoblastic differentiation of U2OS and MG63 osteosarcoma cells in vitro. Our results demonstrated that hyperoside inhibits the proliferation of osteosarcoma cells by inducing G0/G1 arrest in the cell cycle, without causing obvious cell death. Cell migration assay further suggested that hyperoside could inhibit the invasion potential of osteosarcoma cells. Additionally, osteopontin and runt-related transcription factor 2 protein levels and osteocalcin activation were upregulated dramatically in hyperoside-treated osteosarcoma cells, suggesting that hyperoside may stimulates osteoblastic differentiation in osteosarcoma cells. This differentiation was accompanied by the activation of transforming growth factor (TGF)-β and bone morphogenetic protein-2, suggesting that the hyperoside-induced differentiation involves the TGF-β signalling pathway. To our knowledge, this study is the first to evaluate the differentiation effect of hyperoside in osteosarcoma cells and assess the possible potential for hyperoside treatment as a future therapeutic approach for osteosarcoma differentiation therapy.
    Full-text · Article · Jul 2014 · PLoS ONE
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