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      Activation of hedgehog signaling in mesenchymal stem cells induces cartilage and bone tumor formation via Wnt/β-Catenin

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          Abstract

          Indian Hedgehog (IHH) signaling, a key regulator of skeletal development, is highly activated in cartilage and bone tumors. Yet deletion of Ptch1, encoding an inhibitor of IHH receptor Smoothened (SMO), in chondrocyte or osteoblasts does not cause tumorigenesis. Here, we show that Ptch1 deletion in mice Prrx1 +mesenchymal stem/stromal cells (MSCs) promotes MSC proliferation and osteogenic and chondrogenic differentiation but inhibits adipogenic differentiation. Moreover, Ptch1 deletion led to development of osteoarthritis-like phenotypes, exostoses, enchondroma, and osteosarcoma in Smo-Gli1/2-dependent manners. The cartilage and bone tumors are originated from Prrx1 + lineage cells and express low levels of osteoblast and chondrocyte markers, respectively. Mechanistically, Ptch1 deletion increases the expression of Wnt5a/6 and leads to enhanced β-Catenin activation. Inhibiting Wnt/β-Catenin pathway suppresses development of skeletal anomalies including enchondroma and osteosarcoma. These findings suggest that cartilage/bone tumors arise from their early progenitor cells and identify the Wnt/β-Catenin pathway as a pharmacological target for cartilage/bone neoplasms.

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          Bone and cartilage tumors are among the most common tumors in the skeleton, often affecting the limbs. Bone tumors, also called osteosarcomas, usually occur in growing children and teenagers, and they are often resistant to conventional chemo- and radio-therapies. Surgery is the only treatment option, but this can lead to long-lasting damage that impairs the quality of life of these patients. Thus, there is a need to find new drug targets for these diseases. Unfortunately, no good laboratory-based systems exist that mimic these human cancers, hindering research into these tumors.

          One way to create a laboratory-based model for cartilage tumors and osteosarcomas is to reproduce the signaling that is present in the human tumors in a mouse. A signaling pathway called Hedgehog signaling is overactive in human cartilage and bone tumors. The activity of this pathway can be increased by deleting a gene called Ptch1; but mice do not form tumors when this gene is deleted in their mature cartilage and bone cells.

          Now, Deng, Li et al. report that deleting Ptch1 in mesenchymal stem cells, early-stage cells that can give rise to cartilage and bone cells, generates a mouse model for osteosarcoma and cartilage tumors. The mice with these Ptch1 deficient cells developed tumors with overactive Hedgehog signaling in cartilage and bone. Deng, Li et al. also performed biochemical experiments to show that Hedgehog signaling turned on another signaling pathway called Wnt signaling. Treating the mice that had mesenchymal cells lacking Ptch1 with a drug that inhibits Wnt signaling reduced the growth of cartilage and bone tumors.

          These data suggest that deleting Ptch1 in mouse mesenchymal stem cells can mimic human cartilage tumors and osteosarcomas. More experiments will be needed to explain how the Hedgehog and Wnt signaling pathways interact in these tumors. Finally, further studies will need to investigate if inhibiting Wnt signaling might become a useful therapy for human patients with osteosarcoma in the future.

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          Most cited references24

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          Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes.

          Osteoblasts and chondrocytes are involved in building up the vertebrate skeleton and are thought to differentiate from a common mesenchymal precursor, the osteo-chondroprogenitor. Although numerous transcription factors involved in chondrocyte and osteoblast differentiation have been identified, little is known about the signals controlling lineage decisions of the two cell types. Here, we show by conditionally deleting beta-catenin in limb and head mesenchyme that beta-catenin is required for osteoblast lineage differentiation. Osteoblast precursors lacking beta-catenin are blocked in differentiation and develop into chondrocytes instead. In vitro experiments demonstrate that this is a cell-autonomous function of beta-catenin in an osteoblast precursor. Furthermore, detailed in vivo and in vitro loss- and gain-of-function analyses reveal that beta-catenin activity is necessary and sufficient to repress the differentiation of mesenchymal cells into Runx2- and Sox9-positive skeletal precursors. Thus, canonical Wnt/beta-catenin signaling is essential for skeletal lineage differentiation, preventing transdifferentiation of osteoblastic cells into chondrocytes.
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            Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog.

            The differentiation of mesenchymal cells into chondrocytes and chondrocyte proliferation and maturation are fundamental steps in skeletal development. Runx2 is essential for osteoblast differentiation and is involved in chondrocyte maturation. Although chondrocyte maturation is delayed in Runx2-deficient (Runx2(-/-)) mice, terminal differentiation of chondrocytes does occur, indicating that additional factors are involved in chondrocyte maturation. We investigated the involvement of Runx3 in chondrocyte differentiation by generating Runx2-and-Runx3-deficient (Runx2(-/-)3(-/-)) mice. We found that chondrocyte differentiation was inhibited depending on the dosages of Runx2 and Runx3, and Runx2(-/-)3(-/-) mice showed a complete absence of chondrocyte maturation. Further, the length of the limbs was reduced depending on the dosages of Runx2 and Runx3, due to reduced and disorganized chondrocyte proliferation and reduced cell size in the diaphyses. Runx2(-/-)3(-/-) mice did not express Ihh, which regulates chondrocyte proliferation and maturation. Adenoviral introduction of Runx2 in Runx2(-/-) chondrocyte cultures strongly induced Ihh expression. Moreover, Runx2 directly bound to the promoter region of the Ihh gene and strongly induced expression of the reporter gene driven by the Ihh promoter. These findings demonstrate that Runx2 and Runx3 are essential for chondrocyte maturation and that Runx2 regulates limb growth by organizing chondrocyte maturation and proliferation through the induction of Ihh expression.
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              Sequential roles of Hedgehog and Wnt signaling in osteoblast development.

              Signals that govern development of the osteoblast lineage are not well understood. Indian hedgehog (Ihh), a member of the hedgehog (Hh) family of proteins, is essential for osteogenesis in the endochondral skeleton during embryogenesis. The canonical pathway of Wnt signaling has been implicated by studies of Lrp5, a co-receptor for Wnt proteins, in postnatal bone mass homeostasis. In the present study we demonstrate that beta-catenin, a central player in the canonical Wnt pathway, is indispensable for osteoblast differentiation in the mouse embryo. Moreover, we present evidence that Wnt signaling functions downstream of Ihh in development of the osteoblast lineage. Finally Wnt7b is identified as a potential endogenous ligand regulating osteogenesis. These data support a model that integrates Hh and Wnt signaling in the regulation of osteoblast development.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Role: Senior Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                04 September 2019
                2019
                : 8
                : e50208
                Affiliations
                [1 ]deptBio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders Shanghai Jiao Tong University, Ministry of Education ShanghaiChina
                [2 ]deptMetabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease Shanghai Jiao Tong University Affiliated Sixth People's Hospital ShanghaiChina
                [3 ]deptDepartment of Developmental Biology Harvard School of Dental Medicine BostonUnited States
                [4 ]deptState Key Laboratory of Oncogenes and Related Genes, Bio-X-Renji Hospital Research Center, School of Medicine Renji Hospital, Shanghai Jiao Tong University ShanghaiChina
                California Institute of Technology United States
                California Institute of Technology United States
                California Institute of Technology United States
                The University of Hong Kong Hong Kong
                Author notes
                [†]

                These authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-1427-2678
                http://orcid.org/0000-0003-3933-887X
                https://orcid.org/0000-0002-3913-1062
                Article
                50208
                10.7554/eLife.50208
                6764825
                31482846
                258e6109-7e59-46f3-9bfc-5bfece1dc77c
                © 2019, Deng et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 15 July 2019
                : 31 August 2019
                Funding
                Funded by: National Key Research and Development Program of China;
                Award ID: 2017YFA0103602
                Award Recipient :
                Funded by: National Key Research and Development Program of China;
                Award ID: 2018YFA0800803
                Award Recipient :
                Funded by: National Natural Science Foundation of China;
                Award ID: 81520108012
                Award Recipient :
                Funded by: National Natural Science Foundation of China;
                Award ID: 91542120
                Award Recipient :
                Funded by: Columbia University;
                Award ID: Schaefer Research Scholarship
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Cancer Biology
                Cell Biology
                Custom metadata
                Cartilage and bone tumors arise from chondrocyte or osteoblast progenitors but not differentiated cells or multipotent mesenchymal stem cells (MSCs) via the IHH-Wnt/β-Catenin pathway.

                Life sciences
                hedgehog,bone tumor,mesenchymal stem cell,mouse
                Life sciences
                hedgehog, bone tumor, mesenchymal stem cell, mouse

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