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      Knockdown Indian Hedgehog (Ihh) does not delay Fibular Fracture Healing in genetic deleted Ihh mice and pharmaceutical inhibited Ihh Mice

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          Abstract

          The objective of this study was to determine if Ihh is required for fracture healing. Fibular fracture was created in adult Col2a1-CreER T2; Ihh fl / fl mice. Ihh fl / fl mice received Tamoxifen (TM) to delete Ihh. WT mice received Cyclopamine to inhibit Hh pathway. Callus tissue properties and Ihh pathway were analyzed at 1, 2, and 3 weeks post-fracture by X-ray, micro-CT, mechanical test, RT-PCR and immunohistochemistry. Deleted Ihh was evidenced by the occurrence of growth plate closure in the Ihh fl/fl mice by X-ray 3 weeks after TM treatment. All mice showed fracture healing at 3 weeks post-operation. Histology analysis indicated that, compared to the control, cartilage area was less in fracture sites from Ihh deficient animals by either genetic deletion or drug inhibition at 1 and 2 weeks post-fracture. Ihh immunostaining and its mRNA level were diminished in the fracture callus in Ihh reduced mice. There was no significant difference in BV/TV, BMD and mechanical test. Interruption to Ihh pathway by either genetic or pharmaceutical approach didn’t affect fibular fracture healing in these mice. This surprised finding implicates that the deleted Ihh does not affect fracture healing in this model.

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          Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion

          Frédéric Varnat, Arnaud Duquet, Monica Malerba … (2009)
          Human colon cancers often start as benign adenomas through loss of APC, leading to enhanced βCATENIN (βCAT)/TCF function. These early lesions are efficiently managed but often progress to invasive carcinomas and incurable metastases through additional changes, the nature of which is unclear. We find that epithelial cells of human colon carcinomas (CCs) and their stem cells of all stages harbour an active HH-GLI pathway. Unexpectedly, they acquire a high HEDGEHOG-GLI (HH-GLI) signature coincident with the development of metastases. We show that the growth of CC xenografts, their recurrence and metastases require HH-GLI function, which induces a robust epithelial-to-mesenchymal transition (EMT). Moreover, using a novel tumour cell competition assay we show that the self-renewal of CC stem cells in vivo relies on HH-GLI activity. Our results indicate a key and essential role of the HH-GLI1 pathway in promoting CC growth, stem cell self-renewal and metastatic behavior in advanced cancers. Targeting HH-GLI1, directly or indirectly, is thus predicted to decrease tumour bulk and eradicate CC stem cells and metastases.
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            Developmental roles and clinical significance of hedgehog signaling.

            Andrew McMahon, Philip W Ingham, Clifford J. Tabin (2002)
            Cell signaling plays a key role in the development of all multicellular organisms. Numerous studies have established the importance of Hedgehog signaling in a wide variety of regulatory functions during the development of vertebrate and invertebrate organisms. Several reviews have discussed the signaling components in this pathway, their various interactions, and some of the general principles that govern Hedgehog signaling mechanisms. This review focuses on the developing systems themselves, providing a comprehensive survey of the role of Hedgehog signaling in each of these. We also discuss the increasing significance of Hedgehog signaling in the clinical setting.
            Article 0 comments Cited 149 times – based on 0 reviews     Review now
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              Evolution of the internal fixation of long bone fractures. The scientific basis of biological internal fixation: choosing a new balance between stability and biology.

              Stephan Perren (2002)
              The advent of 'biological internal fixation' is an important development in the surgical management of fractures. Locked nailing has demonstrated that flexible fixation without precise reduction results in reliable healing. While external fixators are mainly used today to provide temporary fixation in fractures after severe injury, the internal fixator offers flexible fixation, maintaining the advantages of the external fixator but allowing long-term treatment. The internal fixator resembles a plate but functions differently. It is based on pure splinting rather than compression. The resulting flexible stabilisation induces the formation of callus. With the use of locked threaded bolts, the application of the internal fixator foregoes the need of adaptation of the shape of the splint to that of the bone during surgery. Thus, it is possible to apply the internal fixator as a minimally invasive percutaneous osteosynthesis (MIPO). Minimal surgical trauma and flexible fixation allow prompt healing when the blood supply to bone is maintained or can be restored early. The scientific basis of the fixation and function of these new implants has been reviewed. The biomechanical aspects principally address the degree of instability which may be tolerated by fracture healing under different biological conditions. Fractures may heal spontaneously in spite of gross instability while minimal, even non-visible, instability may be deleterious for rigidly fixed small fracture gaps. The theory of strain offers an explanation for the maximum instability which will be tolerated and the minimal degree required for induction of callus formation. The biological aspects of damage to the blood supply, necrosis and temporary porosity explain the importance of avoiding extensive contact of the implant with bone. The phenomenon of bone loss and stress protection has a biological rather than a mechanical explanation. The same mechanism of necrosis-induced internal remodelling may explain the basic process of direct healing.
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                Author and article information

                Contributors
                Chuan Xiang: xcml7275@163.com
                Lei Wei: leiwei43@hotmail.com
                Journal
                Journal ID (nlm-ta): Sci Rep
                Journal ID (iso-abbrev): Sci Rep
                Title: Scientific Reports
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2045-2322
                Publication date (Electronic): 9 July 2018
                Publication date PMC-release: 9 July 2018
                Publication date Collection: 2018
                Volume: 8
                Electronic Location Identifier: 10351
                Affiliations
                [1 ]GRID grid.452845.a, The Second Hospital of Shanxi Medical University, ; Taiyuan, 030001 China
                [2 ]ISNI 0000 0004 1798 6662, GRID grid.415644.6, Shaoxing People’s Hospital, ; Shaoxing, China
                [3 ]GRID grid.452244.1, Affiliated Hospital of Guizhou Medical University, ; Guiyang, China
                [4 ]ISNI 0000000121845633, GRID grid.215352.2, University of Texas at San Antonio, ; San Antonio, TX USA
                [5 ]GRID grid.464460.4, The third people’s Hospital of Hubei Province, ; Wuhan, China
                [6 ]ISNI 0000 0004 1936 9094, GRID grid.40263.33, Department of Orthopedics, , Warren Alpert Medical School of Brown University/RIH, ; Providence, RI USA
                Article
                Publisher ID: 28657
                DOI: 10.1038/s41598-018-28657-7
                PMC ID: 6037729
                PubMed ID: 29985470
                SO-VID: e205b750-7ccb-4fa7-8c4f-70e6dd9c1fd4
                Copyright © © The Author(s) 2018
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 8 December 2017
                Date accepted : 22 June 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100004480, Natural Science Foundation of Shanxi Province (Shanxi Province Natural Science Foundation);
                Award ID: 201605D211024
                Award ID: 20150313012-6
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100004492, National Youth Foundation of China;
                Award ID: 81601949
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000069, U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS);
                Award ID: R01AR059142
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 81572098
                Award ID: 81772415
                Award Recipient :
                Categories
                Subject: Article
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                issue-copyright-statement © The Author(s) 2018

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