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      Reg Gene Expression in Periosteum after Fracture and Its In Vitro Induction Triggered by IL-6

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          Abstract

          The periosteum is a thin membrane that surrounds the outer surface of bones and participates in fracture healing. However, the molecular signals that trigger/initiate the periosteal reaction are not well established. We fractured the rat femoral bone at the diaphysis and fixed it with an intramedullary inserted wire, and the expression of regenerating gene ( Reg) I, which encodes a tissue regeneration/growth factor, was analyzed. Neither bone/marrow nor muscle showed Reg I gene expression before or after the fracture. By contrast, the periosteum showed an elevated expression after the fracture, thereby confirming the localization of Reg I expression exclusively in the periosteum around the fractured areas. Expression of the Reg family increased after the fracture, followed by a decrease to basal levels by six weeks, when the fracture had almost healed. In vitro cultures of periosteal cells showed no Reg I expression, but the addition of IL-6 significantly induced Reg I gene expression. The addition of IL-6 also increased the cell number and reduced pro-apoptotic gene expression of Bim. The increased cell proliferation and reduction in Bim gene expression were abolished by transfection with Reg I siRNA, indicating that these IL-6-dependent effects require the Reg I gene expression. These results indicate the involvement of the IL-6/Reg pathway in the osteogenic response of the periosteum, which leads to fracture repair.

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          Most cited references49

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          Skeletal Cell Fate Decisions Within Periosteum and Bone Marrow During Bone Regeneration

          Bone repair requires the mobilization of adult skeletal stem cells/progenitors to allow deposition of cartilage and bone at the injury site. These stem cells/progenitors are believed to come from multiple sources including the bone marrow and the periosteum. The goal of this study was to establish the cellular contributions of bone marrow and periosteum to bone healing in vivo and to assess the effect of the tissue environment on cell differentiation within bone marrow and periosteum. Results show that periosteal injuries heal by endochondral ossification, whereas bone marrow injuries heal by intramembranous ossification, indicating that distinct cellular responses occur within these tissues during repair. Next, lineage analyses were used to track the fate of cells derived from periosteum, bone marrow, and endosteum, a subcompartment of the bone marrow. Skeletal progenitor cells were found to be recruited locally and concurrently from periosteum and/or bone marrow/endosteum during bone repair. Periosteum and bone marrow/endosteum both gave rise to osteoblasts, whereas the periosteum was the major source of chondrocytes. Finally, results show that intrinsic and environmental signals modulate cell fate decisions within these tissues. In conclusion, this study sheds light into the origins of skeletal stem cells/progenitors during bone regeneration and indicates that periosteum, endosteum, and bone marrow contain pools of stem cells/progenitors with distinct osteogenic and chondrogenic potentials that vary with the tissue environment.
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            Callus mineralization and maturation are delayed during fracture healing in interleukin-6 knockout mice.

            IL-6 is a pleiotropic cytokine involved in cell signaling in the musculoskeletal system, but its role in bone healing remains uncertain. The purpose of this study was to examine the role of IL-6 in fracture healing. Eight-week-old male C57BL/6 and IL-6 -/- mice were subjected to transverse, mid-diaphyseal osteotomies on the right femora. Sacrifice time points were 1, 2, 4, or 6 weeks post-fracture (N=14 per group). Callus tissue properties was analyzed by microcomputed tomography (micro-CT) and Fourier transform infrared imaging spectroscopy (FT-IRIS). Cartilage and collagen content, and osteoclast density were measured histologically. In intact unfractured bone, IL-6 -/- mice had reduced crystallinity, mineral/matrix ratio, tissue mineral density (TMD), and bone volume fraction (BVF) compared to wildtype mice. This suggests that there was an underlying deficit in baseline bone quality in IL-6 -/- mice. At 2 weeks post-fracture, the callus of IL-6 -/- mice had reduced crystallinity and mineral/matrix ratio. These changes were less evident at 4 weeks. At 2 weeks, the callus of the IL-6 -/- mice had an increased tissue mineral density (TMD), an increased cartilage and collagen content, and reduced osteoclast density compared to these parameters in wildtype mice. By 4 and 6 weeks, these parameters were no longer different between the two strains of mice. In conclusion, IL-6 -/- mice had delayed callus maturity, mineralization, and remodeling compared with the callus of the wildtype mice. These effects were transient indicating that the role of IL-6 appears to be most important in the early stages of fracture healing.
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              Bone development and its relation to fracture repair. The role of mesenchymal osteoblasts and surface osteoblasts

              F. Shapiro (2008)
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                27 October 2017
                November 2017
                : 18
                : 11
                : 2257
                Affiliations
                [1 ]Department of Orthopedic Surgery, Nara City Hospital, 1-50-1 Higashikidera-cho, Nara, Nara 630-8305, Japan; yatohma@ 123456naramed-u.ac.jp
                [2 ]Department of Orthopedic Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan; yatanaka@ 123456naramed-u.ac.jp
                [3 ]Department of Biochemistry, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan; yoshiko-dohi@ 123456aroma.ocn.ne.jp (Y.D.); rshobatake@ 123456naramed-u.ac.jp (R.S.); uchiyama0403@ 123456naramed-u.ac.jp (T.U.); maikot@ 123456naramed-u.ac.jp (M.T.); hajime-ohgushi@ 123456aist.go.jp (H.O.)
                [4 ]Department of Diagnostic Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
                [5 ]Department of Laboratory Medicine and Pathology, National Hospital Organization Kinki-chuo Chest Medical Center, 1180 Nagasone-cho, Kita-ku, Sakai, Osaka 591-8025, Japan
                [6 ]Department of Orthopedic Surgery, Ookuma Hospital, 2-17-13 Kuise-honmachi, Amagasaki, Hyogo 660-0814, Japan
                Author notes
                [* ]Correspondence: shintksw@ 123456naramed-u.ac.jp ; Tel.: +81-744-22-3051 (ext. 2227); Fax: +81-744-24-9525
                Author information
                https://orcid.org/0000-0002-4066-0199
                https://orcid.org/0000-0002-2300-611X
                Article
                ijms-18-02257
                10.3390/ijms18112257
                5713227
                29077068
                ac714d80-83f2-48ab-9e1f-c4526daccd60
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 12 September 2017
                : 24 October 2017
                Categories
                Article

                Molecular biology
                bone regeneration,fracture,reg (regenerating gene),il-6,periosteum,bim
                Molecular biology
                bone regeneration, fracture, reg (regenerating gene), il-6, periosteum, bim

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