دورية أكاديمية
أعرض في EDS

Targeted stimulation of retinoic acid receptor-γ mitigates the formation of heterotopic ossification in an established blast-related traumatic injury model.

التفاصيل البيبلوغرافية
العنوان: Targeted stimulation of retinoic acid receptor-γ mitigates the formation of heterotopic ossification in an established blast-related traumatic injury model.
المؤلفون: Pavey GJ; Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, MD, United States; USU-Walter Reed Surgery, Walter Reed National Military Medical Center, Bethesda, MD, United States., Qureshi AT; Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, MD, United States., Tomasino AM; Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, MD, United States., Honnold CL; Department of Pathology, Naval Medical Research Center, Silver Spring, MD, United States., Bishop DK; Department of Wound Infections, Naval Medical Research Center, Silver Spring, MD, United States., Agarwal S; Department of Surgery, University of Michigan Health System, Ann Arbor, MI, United States., Loder S; Department of Surgery, University of Michigan Health System, Ann Arbor, MI, United States., Levi B; Department of Surgery, University of Michigan Health System, Ann Arbor, MI, United States., Pacifici M; Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia, PA, United States., Iwamoto M; Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia, PA, United States., Potter BK; Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, MD, United States; USU-Walter Reed Surgery, Walter Reed National Military Medical Center, Bethesda, MD, United States., Davis TA; Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, MD, United States; USU-Walter Reed Surgery, Walter Reed National Military Medical Center, Bethesda, MD, United States. Electronic address: thomas.a.davis196.ctr@mail.mil., Forsberg JA; Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, MD, United States; USU-Walter Reed Surgery, Walter Reed National Military Medical Center, Bethesda, MD, United States.
المصدر: Bone [Bone] 2016 Sep; Vol. 90, pp. 159-67. Date of Electronic Publication: 2016 Jun 28.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Country of Publication: United States NLM ID: 8504048 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2763 (Electronic) Linking ISSN: 18732763 NLM ISO Abbreviation: Bone Subsets: MEDLINE
أسماء مطبوعة: Publication: New York : Elsevier Science
Original Publication: Elmsford, NY : Pergamon Press, c1985-
مواضيع طبية MeSH: Blast Injuries/*drug therapy , Ossification, Heterotopic/*drug therapy , Receptors, Retinoic Acid/*metabolism , Wounds and Injuries/*drug therapy, Animals ; Blast Injuries/complications ; Blast Injuries/pathology ; Chondrogenesis/drug effects ; Chondrogenesis/genetics ; Disease Models, Animal ; Gene Expression Regulation/drug effects ; Male ; Ossification, Heterotopic/pathology ; Osteogenesis/drug effects ; Osteogenesis/genetics ; Pyrazoles/pharmacology ; Pyrazoles/therapeutic use ; Rats, Sprague-Dawley ; Stilbenes/pharmacology ; Stilbenes/therapeutic use ; Wound Healing/drug effects ; Wounds and Injuries/complications ; Wounds and Injuries/pathology ; Retinoic Acid Receptor gamma
مستخلص: Heterotopic ossification (HO) involves formation of endochondral bone at non-skeletal sites, is prevalent in severely wounded service members, and causes significant complications and delayed rehabilitation. As common prophylactic treatments such as anti-inflammatory drugs and irradiation cannot be used after multi-system combat trauma, there is an urgent need for new remedies. Previously, we showed that the retinoic acid receptor γ agonist Palovarotene inhibited subcutaneous and intramuscular HO in mice, but those models do not mimic complex combat injury. Thus, we tested Palovarotene in our validated rat trauma-induced HO model that involves blast-related limb injury, femoral fracture, quadriceps crush injury, amputation and infection with methicillin-resistant Staphylococcus aureus from combat wound infections. Palovarotene was given orally for 14days at 1mg/kg/day starting on post-operative day (POD) 1 or POD-5, and HO amount, wound dehiscence and related processes were monitored for up to 84days post injury. Compared to vehicle-control animals, Palovarotene significantly decreased HO by 50 to 60% regardless of when the treatment started and if infection was present. Histological analyses showed that Palovarotene reduced ectopic chondrogenesis, osteogenesis and angiogenesis forming at the injury site over time, while fibrotic tissue was often present in place of ectopic bone. Custom gene array data verified that while expression of key chondrogenic and osteogenic genes was decreased within soft tissues of residual limb in Palovarotene-treated rats, expression of cartilage catabolic genes was increased, including matrix metalloproteinase-9. Importantly, Palovarotene seemed to exert moderate inhibitory effects on wound healing, raising potential safety concerns related to dosing and timing. Our data show for the first time that Palovarotene significantly inhibits HO triggered by blast injury and associated complications, strongly indicating that it may prevent HO in patients at high risk such as those sustaining combat injuries and other forms of blast trauma.
(Published by Elsevier Inc.)
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معلومات مُعتمدة: F32 AR066499 United States AR NIAMS NIH HHS; K08 GM109105 United States GM NIGMS NIH HHS; L30 AR066947 United States AR NIAMS NIH HHS; R01 AR056837 United States AR NIAMS NIH HHS
فهرسة مساهمة: Keywords: Animal model; Bioburden; Blast overpressure exposure; Endochondral ossification; Heterotopic ossification; Prophylaxis; Retinoic acid receptor-γ agonist; Traumatic extremity injury
المشرفين على المادة: 0 (Pyrazoles)
0 (Receptors, Retinoic Acid)
0 (Stilbenes)
28K6I5M16G (Palovarotene)
تواريخ الأحداث: Date Created: 20160703 Date Completed: 20171218 Latest Revision: 20231213
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC5546218
DOI: 10.1016/j.bone.2016.06.014
PMID: 27368930
قاعدة البيانات: MEDLINE
الوصف
تدمد:1873-2763
DOI:10.1016/j.bone.2016.06.014