title: Development of a Rat Model of Mechanically Induced Tunable Pain and Associated Temporomandibular Joint Responses.
abstract: OBJECTIVE
  Although mechanical overloading of the temporomandibular joint (TMJ) is implicated in TMJ osteoarthritis (OA) and orofacial pain, most experimental models of TMJ-OA induce only acute and resolving pain, which do not meaningfully simulate the pathomechanisms of TMJ-OA in patients with chronic pain. The aim of this study was to adapt an existing rat model of mechanically induced TMJ-OA, to induce persistent orofacial pain by altering only the jaw-opening force, and to measure the expression of common proxies of TMJ-OA, including degradation and inflammatory proteins, in the joint.
  
  
  METHODS
  TMJ-OA was mechanically induced in a randomized, prospective study using 2 magnitudes of opening loads in separate groups (ie.,. 2-N, 3.5-N and sham control [no load]). Steady mouth opening was imposed daily (60 minutes/day for 7 days) in female Holtzman rats, followed by 7 days of rest, and orofacial sensitivity was measured throughout the loading and rest periods. Joint structure and extent of degeneration were assessed at day 14 and expression of matrix metalloproteinase-13 (MMP-13), hypoxia-inducible factor-1α (HIF-1α), and tumor necrosis factor-α (TNF-α) in articular cartilage was evaluated by immunohistochemistry and quantitative densitometry methods at day 7 between the 2 loading and control groups. Statistical differences of orofacial sensitivity and chondrocyte expression between loading groups were computed and significance was set at a P value less than .05.
  
  
  RESULTS
  Head-withdrawal thresholds for the 2 loading groups were significantly decreased during loading (P < .0001), but that decrease remained through day 14 only for the 3.5-N group (P < .00001). At day 14, TMJs from the 2-N and 3.5-N groups exhibited truncation of the condylar cartilage, typical of TMJ-OA. In addition, a 3.5-N loading force significantly upregulated MMP-13 (P < .0074), with nearly a 2-fold increase in HIF-1α (P < .001) and TNF-α (P < .0001) at day 7, in 3.5-N loaded joints over those loaded by 2 N.
  
  
  CONCLUSIONS
  Unlike a 2-N loading force, mechanical overloading of the TMJ using a 3.5-N loading force induced constant and nonresolving pain and the upregulation of inflammatory markers only in the 3.5-N group, suggesting that these markers could predict the maintenance of persistent orofacial pain. As such, the development of a tunable experimental TMJ-OA model that can separately induce acute or persistent orofacial pain using similar approaches provides a platform to better understand the pathomechanisms involved and possibly to evaluate potential treatment strategies for patients with painful TMJ-OA.
authors.affiliation: Graduate Student, Department of Bioengineering, University of Pennsylvania, Philadelphia, PA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Kartha
authors.affiliation: Undergraduate Student, Department of Bioengineering, University of Pennsylvania, Philadelphia, PA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Assistant Professor, Department of Oral and Maxillofacial Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA. Electronic address: eric.granquist@uphs.upenn.edu.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Granquist
authors.affiliation: Professor, Department of Bioengineering; Associate Dean, Undergraduate Education, School of Engineering and Applied Science; Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Winkelstein
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D002358:Cartilage, Articular / Q000737:chemistry / Q000473:pathology; D019902:Chondrocytes / Q000737:chemistry / Q000473:pathology; D059350:Chronic Pain / Q000209:etiology* / Q000378:metabolism; D004195:Disease Models, Animal; D005157:Facial Pain / Q000209:etiology* / Q000378:metabolism; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis; D008335:Mandibular Condyle / Q000737:chemistry / Q000473:pathology; D053509:Matrix Metalloproteinase 13 / Q000032:analysis; D010003:Osteoarthritis / Q000209:etiology* / Q000378:metabolism; D011897:Random Allocation; D016059:Range of Motion, Articular / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012677:Sensation / Q000502:physiology; D013314:Stress, Mechanical; D013705:Temporomandibular Joint Disorders / Q000209:etiology* / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014409:Tumor Necrosis Factor-alpha; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat