Molecular landscape of arthrofibrosis: Microarray and bioinformatic analysis of the temporal expression of 380 genes during contracture genesis.
OBJECTIVE
Inflammatory changes are suspected in the pathophysiology of arthrofibrosis formation and require early molecular examination. Here, we assessed the hypothesis that early inflammatory genes are related to arthrofibrosis by ascertaining gene expression during the early stages of contracture genesis in an animal model.


METHODS
Joint trauma was incited surgically in a cohort of rabbits (n=36) knees followed by immobilization in a model of contracture. Six groups of 6 rabbits were sacrificed at multiple time points (0, 6, 12, 24, 72h and 2weeks). Microarray expression and RT-qPCR profiling were performed to determine genes that are significantly up or downregulated. Bioinformatic analysis was carried out to understand which biological programs and functional groups of genes are modulated in arthrofibrosis.


RESULTS
Gene expression profiling revealed a large number biologically relevant genes (>100) that are either upregulated or downregulated by at least a 1.5 fold (log2) during the first two weeks after joint injury during contracture development. Gene ontology analysis identified molecular pathways and programs that act during the course of fibrosis and joint contracture. Our main finding is that the development of contractures occur concomitant with modulation of genes mediating inflammatory responses, ECM remodeling and the epithelial-to-mesenchymal transition.


CONCLUSIONS
The genesis of joint contracture reflects an imbalance between pro- and anti-fibrotic expression. Our study indicates that inflammatory genes may be involved in the process of contracture genesis and initiated at relatively early stages. Our findings also may inform clinical practice in the future by suggesting potential therapeutic targets in preventing the long-term development of arthrofibrosis.
Department of Orthopedic Surgery and Orthopedic Biomechanics Laboratory, Mayo Clinic, Rochester, United States. Electronic address: morrey.mark@mayo.edu.
Mark E
ME
Morrey
Department of Orthopedic Surgery and Orthopedic Biomechanics Laboratory, Mayo Clinic, Rochester, United States.
Matthew P
MP
Abdel
Department of Orthopedic Surgery and Orthopedic Biomechanics Laboratory, Mayo Clinic, Rochester, United States.
Scott M
SM
Riester
Department of Orthopedic Surgery and Orthopedic Biomechanics Laboratory, Mayo Clinic, Rochester, United States.
Amel
A
Dudakovic
Department of Orthopedic Surgery and Orthopedic Biomechanics Laboratory, Mayo Clinic, Rochester, United States.
Andre J
AJ
van Wijnen
Department of Orthopedic Surgery and Orthopedic Biomechanics Laboratory, Mayo Clinic, Rochester, United States.
Bernard F
BF
Morrey
Department of Orthopedic Surgery and Orthopedic Biomechanics Laboratory, Mayo Clinic, Rochester, United States.
Joaquin
J
Sanchez-Sotelo
D000818:Animals; D003286:Contracture / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005260:Female; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011817:Rabbits; D059467:Transcriptome
Animal model; Arthrofibrosis; Contracture; Genes; Microarray