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      Ptpn11 Deletion in A Novel Cartilage Cell Causes Metachondromatosis by Activating Hedgehog Signaling

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          Abstract

          SHP2, encoded by PTPN11, is required for survival, proliferation and differentiation of various cell types 1, 2 . Germ line activating mutations in PTPN11 cause Noonan Syndrome, while somatic PTPN11 mutations cause childhood myeloproliferative disease and contribute to some solid tumors. Recently, heterozygous inactivating mutations in PTPN11 were found in metachondromatosis, a rare inherited disorder featuring multiple exostoses, endochondromas, joint destruction and bony deformities 3, 4 . The detailed pathogenesis of this disorder has remained unclear. Here, we used a conditional knockout allele ( Ptpn11 fl ) and Cre recombinase (Cre) transgenic mice to delete Ptpn11 specifically in monocytes, macrophages and osteoclasts (lysozyme M-Cre; LysMCre) or in cathepsin K (Ctsk)-expressing cells, previously thought to be osteoclasts. LysMCre;Ptpn11 fl/fl mice had mild osteopetrosis. Surprisingly, however, CtskCre;Ptpn11 fl/fl mice developed features strikingly similar to metachondromatosis. Lineage tracing revealed a novel population of Ctsk-Cre-expressing cells in the “Perichondrial Groove of Ranvier” that display markers and functional properties consistent with mesenchymal progenitors. Chondroid neoplasms arose from these cells and showed decreased Erk activation, increased Indian Hedgehog (Ihh) and Parathyroid hormone-related protein (Pthrp) expression and excessive proliferation. Shp2-deficient chondroprogenitors had decreased FGF-evoked Erk activation and enhanced Ihh and Pthrp expression, whereas FGFR or MEK inhibitor treatment of chondroid cells increased Ihh and Pthrp expression. Most importantly, Smoothened inhibitor treatment ameliorated metachondromatosis features in CtskCre;Ptpn11 fl/fl mice. Thus, in contrast to its pro-oncogenic role in hematopoietic and epithelial cells, Ptpn11 is a tumor suppressor in cartilage, acting via an FGFR/MEK/ERK-dependent pathway in a novel progenitor cell population to prevent excessive Ihh production.

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          Most cited references30

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          Conditional gene targeting in macrophages and granulocytes using LysMcre mice.

          Conditional mutagenesis in mice has recently been made possible through the combination of gene targeting techniques and site-directed mutagenesis, using the bacteriophage P1-derived Cre/loxP recombination system. The versatility of this approach depends on the availability of mouse mutants in which the recombinase Cre is expressed in the appropriate cell lineages or tissues. Here we report the generation of mice that express Cre in myeloid cells due to targeted insertion of the cre cDNA into their endogenous M lysozyme locus. In double mutant mice harboring both the LysMcre allele and one of two different loxP-flanked target genes tested, a deletion efficiency of 83-98% was determined in mature macrophages and near 100% in granulocytes. Partial deletion (16%) could be detected in CD11c+ splenic dendritic cells which are closely related to the monocyte/macrophage lineage. In contrast, no significant deletion was observed in tail DNA or purified T and B cells. Taken together, LysMcre mice allow for both specific and highly efficient Cre-mediated deletion of loxP-flanked target genes in myeloid cells.
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            Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts.

            Estrogen prevents osteoporotic bone loss by attenuating bone resorption; however, the molecular basis for this is unknown. Here, we report a critical role for the osteoclastic estrogen receptor alpha (ERalpha) in mediating estrogen-dependent bone maintenance in female mice. We selectively ablated ERalpha in differentiated osteoclasts (ERalpha(DeltaOc/DeltaOc)) and found that ERalpha(DeltaOc/DeltaOc) females, but not males, exhibited trabecular bone loss, similar to the osteoporotic bone phenotype in postmenopausal women. Further, we show that estrogen induced apoptosis and upregulation of Fas ligand (FasL) expression in osteoclasts of the trabecular bones of WT but not ERalpha(DeltaOc/DeltaOc) mice. The expression of ERalpha was also required for the induction of apoptosis by tamoxifen and estrogen in cultured osteoclasts. Our results support a model in which estrogen regulates the life span of mature osteoclasts via the induction of the Fas/FasL system, thereby providing an explanation for the osteoprotective function of estrogen as well as SERMs.
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              The control of chondrogenesis.

              Chondrogenesis is the earliest phase of skeletal development, involving mesenchymal cell recruitment and migration, condensation of progenitors, and chondrocyte differentiation, and maturation and resulting in the formation of cartilage and bone during endochondral ossification. This process is controlled exquisitely by cellular interactions with the surrounding matrix, growth and differentiation factors, and other environmental factors that initiate or suppress cellular signaling pathways and transcription of specific genes in a temporal-spatial manner. Vertebrate limb development is controlled by interacting patterning systems involving prominently the fibroblast growth factor (FGF), bone morphogenetic protein (BMP), and hedgehog pathways. Both positive and negative signaling kinases and transcription factors, such as Sox9 and Runx2, and interactions among them determine whether the differentiated chondrocytes remain within cartilage elements in articular joints or undergo hypertrophic maturation prior to ossification. The latter process requires extracellular matrix remodeling and vascularization controlled by mechanisms that are not understood completely. Recent work has revealed novel roles for mediators such as GADD45beta, transcription factors of the Dlx, bHLH, leucine zipper, and AP-1 families, and the Wnt/beta-catenin pathway that interact at different stages during chondrogenesis. (c) 2005 Wiley-Liss, Inc.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                22 July 2013
                17 July 2013
                25 July 2013
                28 August 2014
                : 499
                : 7459
                : 491-495
                Affiliations
                [1 ]Department of Orthopaedics, Brown University Alpert Medical School and Rhode Island Hospital, Providence, RI 02903
                [2 ]Department of Medicine and COBRE Center for Stem Cell Biology, Rhode Island Hospital and Brown University Alpert Medical School, Providence, RI 02903
                [3 ]Department of Pathology and Laboratory Medicine, University of Connecticut Health Center, Farmington, CT 06030
                [4 ]Princess Margaret Cancer Center, University Health Network, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 1L7
                Author notes
                [* ]Corresponding Author: Wentian Yang, M.D., Ph.D., 1 Hoppin Street, Coro 402E, Providence, RI 02903; 401-444-5956 (Phone), wyang@ 123456lifespan.org
                Article
                NIHMS497579
                10.1038/nature12396
                4148013
                23863940
                f084c843-fb15-405c-be8a-993c504cc682

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