Altered spinal MicroRNA-146a and the microRNA-183 cluster contribute to osteoarthritic pain in knee joints

Xin Li, Jeffrey S. Kroin, Ranjan Kc, Gary Gibson, Di Chen, Grant T. Corbett, Kalipada Pahan, Sana Fayyaz, Jae Sung Kim, Andre J. Van Wijnen, Joon Suh, Su Gwan Kim, Hee Jeong Im

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

The objective of this study was to examine whether altered expression of microRNAs in central nervous system components is pathologically linked to chronic knee joint pain in osteoarthritis. A surgical animal model for knee joint OA was generated by medial meniscus transection in rats followed by behavioral pain tests. Relationships between pathological changes in knee joint and development of chronic joint pain were examined by histology and imaging analyses. Alterations in microRNAs associated with OA-evoked pain sensation were determined in bilateral lumbar dorsal root ganglia (DRG) and the spinal dorsal horn by microRNA array followed by individual microRNA analyses. Gain- and loss-of-function studies of selected microRNAs (miR-146a and miR-183 cluster) were conducted to identify target pain mediators regulated by these selective microRNAs in glial cells. The ipsilateral hind leg displayed significantly increased hyperalgesia after 4 weeks of surgery, and sensitivity was sustained for the remainder of the 8-week experimental period (F = 341, p < 0.001). The development of OA-induced chronic pain was correlated with pathological changes in the knee joints as assessed by histological and imaging analyses. MicroRNA analyses showed that miR-146a and the miR-183 cluster were markedly reduced in the sensory neurons in DRG (L4/L5) and spinal cord from animals experiencing knee joint OA pain. The downregulation of miR-146a and/or the miR-183 cluster in the central compartments (DRG and spinal cord) are closely associated with the upregulation of inflammatory pain mediators. The corroboration between decreases in these signature microRNAs and their specific target pain mediators were further confirmed by gain- and loss-of-function analyses in glia, the major cellular component of the central nervous system (CNS). MicroRNA therapy using miR-146a and the miR-183 cluster could be powerful therapeutic intervention for OA in alleviating joint pain and concomitantly regenerating peripheral knee joint cartilage.

Original languageEnglish (US)
Pages (from-to)2512-2522
Number of pages11
JournalJournal of Bone and Mineral Research
Volume28
Issue number12
DOIs
StatePublished - Dec 2013

Keywords

  • knee joint pain
  • microglial cells
  • micrornas
  • osteoarthritis

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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    Li, X., Kroin, J. S., Kc, R., Gibson, G., Chen, D., Corbett, G. T., Pahan, K., Fayyaz, S., Kim, J. S., Van Wijnen, A. J., Suh, J., Kim, S. G., & Im, H. J. (2013). Altered spinal MicroRNA-146a and the microRNA-183 cluster contribute to osteoarthritic pain in knee joints. Journal of Bone and Mineral Research, 28(12), 2512-2522. https://doi.org/10.1002/jbmr.2002