title: Effect of dexamethasone prodrug on inflamed temporomandibular joints in juvenile rats.
abstract: BACKGROUND
  Juvenile idiopathic arthritis (JIA) often causes inflammation of the temporomandibular joint (TMJ) and has been treated with both systemic and intra-articular steroids, with concerns about effects on growing bones. In this study, we evaluated the impact of a macromolecular prodrug of dexamethasone (P-DEX) with inflammation-targeting potential applied systemically or directly to the TMJ.
  
  
  METHODS
  Joint inflammation was initiated by injecting two doses of complete Freund's adjuvant (CFA) at 1-month intervals into the right TMJs of 24 growing Sprague-Dawley male rats (controls on left side). Four additional rats were not manipulated. With the second CFA injection, animals received (1) 5 mg of P-DEX intra-articularly (n = 9), (2) 15 mg of P-DEX into the tail vein (n = 7), or (3) nothing in addition to CFA (n = 8). The rats were killed 28 days later and measured by radiography for ramus height (condylar superior to gonion inferior [CsGoInf]), by micro-computed tomography for condylar width (CW) and bone volume/standardized condylar volume (BV/CV), and by histology for retrodiscal inflammatory cells. Inflammation targeting of systemic P-DEX was confirmed by IVIS infrared dye imaging. Inflammation and bone growth were compared between groups using analysis of variance and Pearson's correlations.
  
  
  RESULTS
  CFA caused a significant reduction in CsGoInf (p < 0.05), but neither route of P-DEX administration had an effect on CsGoInf or CW at CFA injection sites. BV/CV was significantly reduced in both inflamed and control condyles as a result of either steroid application (p < 0.05). The inflammatory infiltrate was overwhelmingly lymphocytic, comprising 16.4 ± 1.3 % of the field in CFA alone vs. <0.01 % lymphocytes in contralateral controls (p < 0.0001). Both P-DEX TMJ (10.1 ± 1.2 %) and systemic P-DEX (8.9 ± 1.7 %) reduced lymphocytes (p < 0.002). The total area of inflammatory infiltrate was significantly less in the systemic injection group than in the group that received CFA injections alone (2.6 ± 1.5 mm(2) vs. 8.0 ± 1.3 mm(2); p = 0.009), but not in the group that received intra-articular P-DEX (8.8 ± 1.2 mm(2)).
  
  
  CONCLUSIONS
  High-dose systemic administration of inflammation-targeting P-DEX is more effective than an intra-articular injection in reducing TMJ inflammation, but both routes may affect TMJ bone density.
authors.affiliation: University of Nebraska Medical Center College of Dentistry, 4000 East Campus Loop South, Lincoln, NE, 68583-0740, USA. mitchell.knudsen@unmc.edu.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Knudsen
authors.affiliation: University of Nebraska Medical Center College of Dentistry, 4000 East Campus Loop South, Lincoln, NE, 68583-0740, USA. matt.bury@unmc.edu.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bury
authors.affiliation: Private Practice of Orthodontics, Cheyenne, WY, USA. callie.owen.holwegner@gmail.com.
authors.forename: Callie
authors.initials: C
authors.lastname: Holwegner
authors.affiliation: Pediatric Rheumatology, Children's Hospital, Omaha, NE, USA. areinhardt@childrensomaha.org.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Reinhardt
authors.affiliation: University of Nebraska Medical Center College of Pharmacy, Omaha, NE, USA. fyuan116@hotmail.com.
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.affiliation: University of Nebraska Medical Center College of Pharmacy, Omaha, NE, USA. yzhan2@unmc.edu.
authors.forename: Yijia
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: University of Nebraska Medical Center College of Dentistry, 4000 East Campus Loop South, Lincoln, NE, 68583-0740, USA. pgiannini@unmc.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Giannini
authors.affiliation: Department of Statistics, University of Nebraska, Lincoln, NE, USA. david.marx@unl.edu.
authors.forename: David B
authors.initials: DB
authors.lastname: Marx
authors.affiliation: University of Nebraska Medical Center College of Pharmacy, Omaha, NE, USA. dwang@unmc.edu.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: University of Nebraska Medical Center College of Dentistry, 4000 East Campus Loop South, Lincoln, NE, 68583-0740, USA. rareinha@unmc.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Reinhardt
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001169:Arthritis, Experimental / Q000150:complications / Q000473:pathology*; D001171:Arthritis, Juvenile / Q000150:complications / Q000473:pathology*; D015519:Bone Density / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage* / Q000009:adverse effects; D007270:Injections, Intra-Articular; D007275:Injections, Intravenous; D011355:Prodrugs / Q000008:administration & dosage* / Q000009:adverse effects; D051381:Rats; D013704:Temporomandibular Joint / Q000187:drug effects / Q000473:pathology; D013705:Temporomandibular Joint Disorders / Q000209:etiology / Q000473:pathology*
chemical_list: D000893:Anti-Inflammatory Agents; D011355:Prodrugs; D003907:Dexamethasone