title: Temporal gene expression profiling of the rat knee joint capsule during immobilization-induced joint contractures.
abstract: BACKGROUND
  Contractures of the knee joint cause disability and handicap. Recovering range of motion is recognized by arthritic patients as their preference for improved health outcome secondary only to pain management. Clinical and experimental studies provide evidence that the posterior knee capsule prevents the knee from achieving full extension. This study was undertaken to investigate the dynamic changes of the joint capsule transcriptome during the progression of knee joint contractures induced by immobilization. We performed a microarray analysis of genes expressed in the posterior knee joint capsule following induction of a flexion contracture by rigidly immobilizing the rat knee joint over a time-course of 16 weeks. Fold changes of expression values were measured and co-expressed genes were identified by clustering based on time-series analysis. Genes associated with immobilization were further analyzed to reveal pathways and biological significance and validated by immunohistochemistry on sagittal sections of knee joints.
  
  
  RESULTS
  Changes in expression with a minimum of 1.5 fold changes were dominated by a decrease in expression for 7732 probe sets occurring at week 8 while the expression of 2251 probe sets increased. Clusters of genes with similar profiles of expression included a total of 162 genes displaying at least a 2 fold change compared to week 1. Functional analysis revealed ontology categories corresponding to triglyceride metabolism, extracellular matrix and muscle contraction. The altered expression of selected genes involved in the triglyceride biosynthesis pathway; AGPAT-9, and of the genes P4HB and HSP47, both involved in collagen synthesis, was confirmed by immunohistochemistry.
  
  
  CONCLUSIONS
  Gene expression in the knee joint capsule was sensitive to joint immobility and provided insights into molecular mechanisms relevant to the pathophysiology of knee flexion contractures. Capsule responses to immobilization was dynamic and characterized by modulation of at least three reaction pathways; down regulation of triglyceride biosynthesis, alteration of extracellular matrix degradation and muscle contraction gene expression. The posterior knee capsule may deploy tissue-specific patterns of mRNA regulatory responses to immobilization. The identification of altered expression of genes and biochemical pathways in the joint capsule provides potential targets for the therapy of knee flexion contractures.
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Rd, Ottawa, ON, K1H 8M5, Canada. wong.kayleigh@gmail.com.
authors.forename: Kayleigh
authors.initials: K
authors.lastname: Wong
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Medical Campus, 801 Massachusetts Ave., Crosstown 3rd floor, Boston, MA, 02118, USA. jennysun@bu.edu.
authors.forename: Fangui
authors.initials: F
authors.lastname: Sun
authors.affiliation: The Ottawa Hospital Rehabilitation Centre, 505 Smyth Rd., Ottawa, ON, K1H 8M2, Canada. gtrudel@Ottawahospital.on.ca.|Bone and Joint Research Laboratory, Faculty of Medicine, 451 Smyth Rd., Ottawa, ON, K1H 8M5, Canada. gtrudel@Ottawahospital.on.ca.
authors.forename: Guy
authors.initials: G
authors.lastname: Trudel
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Medical Campus, 801 Massachusetts Ave., Crosstown 3rd floor, Boston, MA, 02118, USA. sebas@bu.edu.
authors.forename: Paola
authors.initials: P
authors.lastname: Sebastiani
authors.affiliation: Department of Biology, Faculty of Science, University of Ottawa, 30 Marie Curie, Ottawa, ON, K1N 6N5, Canada. olaneuvi@uottawa.ca.
authors.forename: Odette
authors.initials: O
authors.lastname: Laneuville
mesh_terms: D000818:Animals; D003094:Collagen / Q000096:biosynthesis; D003286:Contracture / Q000378:metabolism / Q000503:physiopathology*; D005109:Extracellular Matrix / Q000378:metabolism; D020869:Gene Expression Profiling; D007103:Immobilization; D007150:Immunohistochemistry; D007719:Knee Joint / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D046228:Microarray Analysis; D009119:Muscle Contraction / Q000502:physiology; D016059:Range of Motion, Articular; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000096:biosynthesis
chemical_list: D014280:Triglycerides; D003094:Collagen