PMID- 28484423 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240207 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 8 DP - 2017 TI - Evaluation of Salivary Cytokines for Diagnosis of both Trauma-Induced and Genetic Heterotopic Ossification. PG - 74 LID - 10.3389/fendo.2017.00074 [doi] LID - 74 AB - PURPOSE: Heterotopic ossification (HO) occurs in the setting of persistent systemic inflammation. The identification of reliable biomarkers can serve as an early diagnostic tool for HO, especially given the current lack of effective treatment strategies. Although serum biomarkers have great utility, they can be inappropriate or ineffective in traumatic acute injuries and in patients with fibrodysplasia ossificans progressiva (FOP). Therefore, the goal of this study is to profile the cytokines associated with HO using a different non-invasive source of biomarkers. METHODS: Serum and saliva were collected from a model of trauma-induced HO (tHO) with hind limb Achilles' tenotomy and dorsal burn injury at indicated time points (pre-injury, 48 h, 1 week, and 3 weeks post-injury) and a genetic non-trauma HO model (Nfatc1-Cre/caAcvr1(fl/wt) ). Samples were analyzed for 27 cytokines using the Bio-Plex assay. Histologic evaluation was performed in Nfatc1-Cre/caAcvr1(fl/wt) mice and at 48 h and 1 week post-injury in burn tenotomy mice. The mRNA expression levels of these cytokines at the tenotomy site were also quantified with quantitative real-time PCR. Pearson correlation coefficient was assessed between saliva and serum. RESULTS: Levels of TNF-alpha and IL-1beta peaked at 48 h and 1 week post-injury in the burn/tenotomy cohort, and these values were significantly higher when compared with both uninjured (p < 0.01, p < 0.03) and burn-only mice (p < 0.01, p < 0.01). Immunofluorescence staining confirmed enhanced expression of IL-1beta, TNF-alpha, and MCP-1 at the tenotomy site 48 h after injury. Monocyte chemoattractant protein-1 (MCP-1) and VEGF was detected in saliva showing elevated levels at 1 week post-injury in our tHO model when compared with both uninjured (p < 0.001, p < 0.01) and burn-only mice (p < 0.005, p < 0.01). The Pearson correlation between serum MCP-1 and salivary MCP-1 was statistically significant (r = 0.9686, p < 0.001) Similarly, the Pearson correlation between serum VEGF and salivary VEGF was statistically significant (r = 0.9709, p < 0.05). CONCLUSION: In this preliminary study, we characterized the diagnostic potential of specific salivary cytokines that may serve as biomarkers for an early-stage diagnosis of HO. This study identified two candidate biomarkers for further study and suggests a novel method for diagnosis in the context of current difficult diagnosis and risks of current diagnostic methods in certain patients. FAU - Sung Hsieh, Hsiao Hsin AU - Sung Hsieh HH AD - Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, MI, USA. AD - Experimental Rheumatology, Radboud University Medical Center, Nijmegen, Netherlands. FAU - Chung, Michael T AU - Chung MT AD - Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, MI, USA. FAU - Allen, Ronald M AU - Allen RM AD - Department of Pathology, University of Michigan, Ann Arbor, MI, USA. FAU - Ranganathan, Kavitha AU - Ranganathan K AD - Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, MI, USA. FAU - Habbouche, Joe AU - Habbouche J AD - Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, MI, USA. FAU - Cholok, David AU - Cholok D AD - Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, MI, USA. FAU - Butts, Jonathan AU - Butts J AD - Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, MI, USA. FAU - Kaura, Arminder AU - Kaura A AD - Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, MI, USA. FAU - Tiruvannamalai-Annamalai, Ramkumar AU - Tiruvannamalai-Annamalai R AD - Department of Pathology, University of Michigan, Ann Arbor, MI, USA. FAU - Breuler, Chris AU - Breuler C AD - Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, MI, USA. FAU - Priest, Caitlin AU - Priest C AD - Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, MI, USA. FAU - Loder, Shawn J AU - Loder SJ AD - Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, MI, USA. FAU - Li, John AU - Li J AD - Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, MI, USA. FAU - Li, Shuli AU - Li S AD - Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, MI, USA. FAU - Stegemann, Jan AU - Stegemann J AD - Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA. FAU - Kunkel, Steven L AU - Kunkel SL AD - Department of Pathology, University of Michigan, Ann Arbor, MI, USA. FAU - Levi, Benjamin AU - Levi B AD - Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, MI, USA. LA - eng GR - R01 HL112897/HL/NHLBI NIH HHS/United States GR - T32 HD007505/HD/NICHD NIH HHS/United States PT - Journal Article DEP - 20170424 PL - Switzerland TA - Front Endocrinol (Lausanne) JT - Frontiers in endocrinology JID - 101555782 PMC - PMC5401868 OTO - NOTNLM OT - biomarkers OT - fibrodysplasia ossificans progresiva OT - heterotopic ossification OT - inflammatory cytokines OT - minimally invasive OT - saliva EDAT- 2017/05/10 06:00 MHDA- 2017/05/10 06:01 PMCR- 2017/01/01 CRDT- 2017/05/10 06:00 PHST- 2017/01/13 00:00 [received] PHST- 2017/03/27 00:00 [accepted] PHST- 2017/05/10 06:00 [entrez] PHST- 2017/05/10 06:00 [pubmed] PHST- 2017/05/10 06:01 [medline] PHST- 2017/01/01 00:00 [pmc-release] AID - 10.3389/fendo.2017.00074 [doi] PST - epublish SO - Front Endocrinol (Lausanne). 2017 Apr 24;8:74. doi: 10.3389/fendo.2017.00074. eCollection 2017.