Staphylococcal enterotoxin C2 expedites bone consolidation in distraction osteogenesis

Distraction osteogenesis (DO) technique could be used to manage large‐size bone defect successfully, but DO process usually requires long duration of bone consolidation. Innovative approaches for augmenting bone consolidation are of great need. Staphylococcal enterotoxin C2 (SEC2) has been found to suppress osteoclastogenesis of mesenchymal stem cells in vitro. In this study, we investigated the effect of SEC2 on proliferation and osteogenic differentiation of rat bone marrow derived mesenchymal stem cells (rBMSCs). Further, we locally administrated SEC2 (10 ng/ml) or PBS into the distraction gap in Sprague–Dawley male rat DO model every 3 days till termination at 3 and 6 weeks. The regenerates were subjected to X‐rays, micro‐computed tomography, mechanical testing, histology, and immunohischemistry examinations to assess new bone quality. SEC2 had no effect on cell viability. The calcium deposition was remarkably increased and osteogenic marker genes were significantly up‐regulated in rBMSCs treated with SEC2. In rat DO model, SEC2 group had higher bone volume/total tissue volume in the regenerates. At 6 weeks, mechanical properties were significantly higher in SEC2‐treated tibiae comparing to the control group. Histological analysis confirmed that the new bone had improved quality in SEC2 treated group, where the osteocalcin and osterix expression in the regenerates was up‐regulated, indicating faster bone formation. The current study demonstrated that SEC2 local injection promotes osteogenesis and enhanced bone consolidation in DO. The findings support application of SEC2 as a potential novel strategy to expedite bone consolidation in patients undergoing DO treatment. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1215–1225, 2017.

[1]  S. Midha,et al.  Osteogenic signaling on silk-based matrices. , 2016, Biomaterials.

[2]  Y. Chai,et al.  Management of hypertrophic nonunion with failure of internal fixation by distraction osteogenesis. , 2015, Injury.

[3]  Yuxin Sun,et al.  Joint distraction attenuates osteoarthritis by reducing secondary inflammation, cartilage degeneration and subchondral bone aberrant change. , 2015, Osteoarthritis and cartilage.

[4]  Kai-Ming Chan,et al.  mir-21 Overexpressing Mesenchymal Stem Cells Accelerate Fracture Healing in a Rat Closed Femur Fracture Model , 2015, BioMed research international.

[5]  L. Cui,et al.  Salvianolic acid B promotes osteogenesis of human mesenchymal stem cells through activating ERK signaling pathway. , 2014, The international journal of biochemistry & cell biology.

[6]  Xiao Zhu,et al.  Staphylococcal enterotoxin C2 promotes osteogenesis and suppresses osteoclastogenesis of human mesenchymal stem cells. , 2014, Experimental cell research.

[7]  J. Friederichs,et al.  Clinical course, complication rate and outcome of segmental resection and distraction osteogenesis after chronic tibial osteitis. , 2013, Injury.

[8]  S. Beyea,et al.  Enhancement of bone consolidation in mandibular distraction osteogenesis: a contemporary review of experimental studies involving adjuvant therapies. , 2013, Journal of plastic, reconstructive & aesthetic surgery : JPRAS.

[9]  Liangliang Xu,et al.  Cellular retinol-binding protein 1 (CRBP-1) regulates osteogenenesis and adipogenesis of mesenchymal stem cells through inhibiting RXRα-induced β-catenin degradation. , 2012, The international journal of biochemistry & cell biology.

[10]  M. Macoritto,et al.  Interferon‐γ plays a role in bone formation in vivo and rescues osteoporosis in ovariectomized mice , 2011, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[11]  L. Qin,et al.  Impaired bone healing pattern in mice with ovariectomy-induced osteoporosis: A drill-hole defect model. , 2011, Bone.

[12]  S. Rutz,et al.  Regulation and functions of the IL-10 family of cytokines in inflammation and disease. , 2011, Annual review of immunology.

[13]  Hideo Orimo,et al.  The mechanism of mineralization and the role of alkaline phosphatase in health and disease. , 2010, Journal of Nippon Medical School = Nippon Ika Daigaku zasshi.

[14]  B. de Crombrugghe,et al.  Positive Regulation of Adult Bone Formation by Osteoblast‐Specific Transcription Factor Osterix , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[15]  Xiaogang Wang,et al.  Enhancement of superantigen activity and antitumor response of staphylococcal enterotoxin C2 by site-directed mutagenesis , 2009, Cancer Immunology, Immunotherapy.

[16]  M. Macoritto,et al.  Autocrine Regulation of Interferon γ in Mesenchymal Stem Cells Plays a Role in Early Osteoblastogenesis , 2009, Stem cells.

[17]  T. Rosol,et al.  Interferon-γ Targets Cancer Cells and Osteoclasts to Prevent Tumor-associated Bone Loss and Bone Metastases* , 2009, Journal of Biological Chemistry.

[18]  Meng Li,et al.  Staphylococcal enterotoxin C injection in combination with ascorbic acid promotes the differentiation of bone marrow-derived mesenchymal stem cells into osteoblasts in vitro. , 2008, Biochemical and biophysical research communications.

[19]  D. Graves,et al.  Molecular Mechanisms Controlling Bone Formation during Fracture Healing and Distraction Osteogenesis , 2008, Journal of dental research.

[20]  T. Clemens,et al.  Activation of the hypoxia-inducible factor-1α pathway accelerates bone regeneration , 2008, Proceedings of the National Academy of Sciences.

[21]  Lei Sun,et al.  The pilot study of anti-tumor effects versus immunosuppression of staphylococcal enterotoxin C , 2007, Cancer biology & therapy.

[22]  L. Qin,et al.  Changes of microstructure and mineralized tissue in the middle and late phase of osteoporotic fracture healing in rats. , 2007, Bone.

[23]  C. Chung,et al.  Expression and Role of Interleukin-6 in Distraction Osteogenesis , 2007, Calcified Tissue International.

[24]  Q. Tu,et al.  Osterix enhances proliferation and osteogenic potential of bone marrow stromal cells. , 2006, Biochemical and biophysical research communications.

[25]  Xu Ming-kai,et al.  Gene expression and function study of fusion immunotoxin anti-Her-2-scFv—SEC2 in Escherichia coli , 2006, Applied Microbiology and Biotechnology.

[26]  K. Omoe,et al.  Characterization of Novel Staphylococcal Enterotoxin-Like Toxin Type P , 2005, Infection and Immunity.

[27]  G. Xiao,et al.  Gene transfer of the Runx2 transcription factor enhances osteogenic activity of bone marrow stromal cells in vitro and in vivo. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[28]  W Lehmann,et al.  The role of angiogenesis in a murine tibial model of distraction osteogenesis. , 2004, Bone.

[29]  Hongchuan Jin,et al.  In vitro biological activities of transmembrane superantigen staphylococcal enterotoxin A fusion protein , 2004, Cancer Immunology, Immunotherapy.

[30]  D. Graves,et al.  Impaired Fracture Healing in the Absence of TNF‐α Signaling: The Role of TNF‐α in Endochondral Cartilage Resorption , 2003 .

[31]  L. Suva,et al.  Interleukin-1 and Tumor Necrosis Factor Antagonists Attenuate Ethanol-Induced Inhibition of Bone Formation in a Rat Model of Distraction Osteogenesis , 2002, Journal of Pharmacology and Experimental Therapeutics.

[32]  H. Tsuchiya,et al.  Osteosarcoma around the knee. Intraepiphyseal excision and biological reconstruction with distraction osteogenesis. , 2002, The Journal of bone and joint surgery. British volume.

[33]  J. Deng,et al.  The Novel Zinc Finger-Containing Transcription Factor Osterix Is Required for Osteoblast Differentiation and Bone Formation , 2002, Cell.

[34]  S. Ralston,et al.  Cytokine‐Induced Nitric Oxide Inhibits Bone Resorption by Inducing Apoptosis of Osteoclast Progenitors and Suppressing Osteoclast Activity , 1997, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[35]  G. Karsenty,et al.  Osf2/Cbfa1: A Transcriptional Activator of Osteoblast Differentiation , 1997, Cell.

[36]  H. Tsuchiya,et al.  Limb salvage using distraction osteogenesis. A classification of the technique. , 1997, The Journal of bone and joint surgery. British volume.

[37]  G. Plautz,et al.  Treatment of intracranial tumors by systemic transfer of superantigen-activated tumor-draining lymph node T cells. , 1996, Cancer research.

[38]  I. Shapiro,et al.  The phosphatidylinositol‐glycolipid anchor on alkaline phosphatase facilitates mineralization initiation in vitro , 1995, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[39]  W. Davis,et al.  Characterization of novel type C staphylococcal enterotoxins: biological and evolutionary implications , 1993, Infection and immunity.

[40]  P. Marrack,et al.  The staphylococcal enterotoxins and their relatives. , 1990, Science.

[41]  G A Ilizarov,et al.  The tension-stress effect on the genesis and growth of tissues: Part II. The influence of the rate and frequency of distraction. , 1989, Clinical orthopaedics and related research.

[42]  T A Einhorn,et al.  Impaired fracture healing in the absence of TNF-alpha signaling: the role of TNF-alpha in endochondral cartilage resorption. , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.