دورية أكاديمية
Inhibition of Mammalian Target of Rapamycin Signaling with Rapamycin Prevents Trauma-Induced Heterotopic Ossification.
العنوان: | Inhibition of Mammalian Target of Rapamycin Signaling with Rapamycin Prevents Trauma-Induced Heterotopic Ossification. |
---|---|
المؤلفون: | Qureshi AT; Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland., Dey D; Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland., Sanders EM; Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland., Seavey JG; Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland; Department of Surgery, Uniformed Services University and the Walter Reed National Military Medical Center, Bethesda, Maryland., Tomasino AM; Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland., Moss K; Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland., Wheatley B; Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland; Department of Surgery, Uniformed Services University and the Walter Reed National Military Medical Center, Bethesda, Maryland., Cholok D; Department of Surgery, University of Michigan Health Systems, Ann Arbor, Michigan., Loder S; Department of Surgery, University of Michigan Health Systems, Ann Arbor, Michigan., Li J; Department of Surgery, University of Michigan Health Systems, Ann Arbor, Michigan., Levi B; Department of Surgery, University of Michigan Health Systems, Ann Arbor, Michigan., Davis TA; Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland; Department of Surgery, Uniformed Services University and the Walter Reed National Military Medical Center, Bethesda, Maryland. Electronic address: thomas.davis@usuhs.edu. |
المصدر: | The American journal of pathology [Am J Pathol] 2017 Nov; Vol. 187 (11), pp. 2536-2545. Date of Electronic Publication: 2017 Oct 10. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 0370502 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1525-2191 (Electronic) Linking ISSN: 00029440 NLM ISO Abbreviation: Am J Pathol Subsets: MEDLINE |
أسماء مطبوعة: | Publication: 2011-: New York : Elsevier Original Publication: Philadelphia [etc.] American Assn. of Pathologists [etc.] |
مواضيع طبية MeSH: | Bone and Bones/*drug effects , Ossification, Heterotopic/*prevention & control , Osteogenesis/*drug effects , Sirolimus/*pharmacology , TOR Serine-Threonine Kinases/*antagonists & inhibitors, Animals ; Blast Injuries/complications ; Bone and Bones/pathology ; Disease Models, Animal ; Male ; Ossification, Heterotopic/pathology ; Osteogenesis/genetics ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism ; X-Ray Microtomography/methods |
مستخلص: | A pressing clinical need exists for 63% to 65% of combat-wounded service members and 11% to 20% of civilians who develop heterotopic ossification (HO) after blast-related extremity injury and traumatic injuries, respectively. The mammalian target of rapamycin pathway is a central cellular sensor of injury. We evaluated the prophylactic effects of rapamycin, a selective inhibitor of mammalian target of rapamycin signaling, on HO formation in a rat model of blast-related, polytraumatic extremity injury. Rapamycin was administered intraperitoneally daily for 14 days at 0.5 mg/kg or 2.5 mg/kg. Ectopic bone formation was monitored by micro-computed tomography and confirmed by histologic examination. Connective tissue progenitor cells, platelet-derived growth factor receptor-α-positive cells, and α-smooth muscle actin-positive blood vessels were assayed at postoperative day 7 by colony formation and immunofluorescence. Early gene expression changes were determined by low-density microarray. There was significant attenuation of 1) total new bone and soft tissue ectopic bone with 0.5 mg/kg (38.5% and 14.7%) and 2.5 mg/kg rapamycin (90.3% and 82.9%), respectively, 2) connective tissue progenitor cells, 3) platelet-derived growth factor receptor-α-positive cells, 4) α-smooth muscle actin-positive blood vessels, and 5) of key extracellular matrix remodeling (CD44, Col1a1, integrins), osteogenesis (Sp7, Runx2, Bmp2), inflammation (Cxcl5, 10, IL6, Ccl2), and angiogenesis (Angpt2) genes. No wound healing complications were noted. Our data demonstrate the efficacy of rapamycin in inhibiting blast trauma-induced HO by a multipronged mechanism. (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.) |
References: | Bone Joint J. 2015 Apr;97-B(4):572-6. (PMID: 25820900) J Bone Joint Surg Am. 2009 May;91(5):1084-91. (PMID: 19411456) Proc Natl Acad Sci U S A. 1995 May 23;92(11):4947-51. (PMID: 7539137) Clin Orthop Relat Res. 2015 Sep;473(9):2840-7. (PMID: 25822455) J Orthop Res. 2017 Nov;35(11):2397-2406. (PMID: 28390182) Matrix Biol. 2001 Jan;19(8):707-15. (PMID: 11223330) J Am Acad Orthop Surg. 2006;14(10 Spec No.):S191-7. (PMID: 17003198) Int J Cardiol. 2017 Jul 1;238:79-91. (PMID: 28433555) J Cell Sci. 2009 Oct 15;122(Pt 20):3589-94. (PMID: 19812304) Clin Orthop Relat Res. 2015 Sep;473(9):2831-9. (PMID: 25754758) Curr Rev Musculoskelet Med. 2015 Sep;8(3):290-7. (PMID: 26104316) Clin Orthop Relat Res. 2014 Sep;472(9):2845-54. (PMID: 24879568) J Bone Miner Res. 2015 Feb;30(2):369-78. (PMID: 25196701) Bone Joint Res. 2012 Aug 01;1(8):192-7. (PMID: 23610689) J Surg Orthop Adv. 2010 Spring;19(1):54-61. (PMID: 20371008) Carbohydr Polym. 2012 Jul 1;89(3):723-39. (PMID: 24750856) J Cell Physiol. 2018 Jan;233(1):516-529. (PMID: 28300280) Eur J Pharmacol. 2016 Nov 15;791:235-243. (PMID: 27600020) Nephrol Dial Transplant. 2007 Sep;22 Suppl 8:viii61-viii65. (PMID: 17890266) Mol Cell Proteomics. 2017 Jun;16(6):982-997. (PMID: 28408662) Mol Cell Biol. 2017 Mar 17;37(7):. (PMID: 28069737) Crit Rev Oncol Hematol. 2013 Aug;87(2):101-11. (PMID: 23838481) Mol Cell Biol. 2002 Oct;22(20):7004-14. (PMID: 12242281) BMC Musculoskelet Disord. 2015 Oct 26;16:321. (PMID: 26503103) Proc Natl Acad Sci U S A. 2016 Jan 19;113(3):E338-47. (PMID: 26721400) Am J Physiol Endocrinol Metab. 2013 May 15;304(10):E1042-52. (PMID: 23531613) Cell. 2012 Apr 13;149(2):274-93. (PMID: 22500797) J Bone Joint Surg Am. 2011 Jun 15;93(12):1122-31. (PMID: 21776549) J Cell Sci. 1992 Dec;103 ( Pt 4):1111-6. (PMID: 1487493) Bone. 2016 Sep;90:159-67. (PMID: 27368930) J Orthop Trauma. 2014 Apr;28(4):232-7. (PMID: 24658066) Drug Des Devel Ther. 2015 Sep 09;9:5169-83. (PMID: 26392752) Bone. 2013 Sep;56(1):119-26. (PMID: 23727270) J Am Acad Orthop Surg. 2004 Mar-Apr;12(2):116-25. (PMID: 15089085) J Bone Joint Surg Am. 2007 Mar;89(3):476-86. (PMID: 17332095) Aging (Albany NY). 2017 Apr;9(4):1326-1340. (PMID: 28455969) Mech Dev. 2002 Feb;111(1-2):61-73. (PMID: 11804779) Acta Histochem Cytochem. 2011 Apr 28;44(2):113-8. (PMID: 21614172) |
معلومات مُعتمدة: | K08 GM109105 United States GM NIGMS NIH HHS |
المشرفين على المادة: | EC 2.7.11.1 (TOR Serine-Threonine Kinases) W36ZG6FT64 (Sirolimus) |
تواريخ الأحداث: | Date Created: 20171015 Date Completed: 20171128 Latest Revision: 20211204 |
رمز التحديث: | 20221213 |
مُعرف محوري في PubMed: | PMC5809339 |
DOI: | 10.1016/j.ajpath.2017.07.010 |
PMID: | 29029772 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1525-2191 |
---|---|
DOI: | 10.1016/j.ajpath.2017.07.010 |