Blocking CTGF/CCN2 reverses neural fibrosis and sensorimotor declines in a rat model of overuse‐induced median mononeuropathy

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Abstract
Encapsulation of median nerves is a hallmark of overuse‐induced median mononeuropathy and contributes to functional declines. We tested if an antibody against CTGF/CCN2 (termed FG‐3019 or Pamrevlumab) reduces established neural fibrosis and sensorimotor declines in a clinically relevant rodent model of overuse in which median mononeuropathy develops. Young adult female rats performed a high repetition high force (HRHF) lever‐pulling task for 18 weeks. Rats were then euthanised at 18 weeks (HRHF untreated), or rested and systemically treated for 6 weeks with either an anti‐CCN2 monoclonal antibody (HRHF‐Rest/FG‐3019) or IgG (HRHF‐Rest/IgG), with results compared with nontask control rats. Neuropathology was evident in HRHF‐untreated and HRHF‐Rest/IgG rats as increased perineural collagen deposition and degraded myelin basic protein (dMBP) in median nerves, and increased substance P in lower cervical dorsal root ganglia (DRG), compared with controls. Both groups showed functional declines, specifically, decreased sensory conduction velocity in median nerves, noxious cold temperature hypersensitivity, and grip strength declines, compared with controls. There were also increases of ATF3‐immunopositive nuclei in ventral horn neurons in HRHF‐untreated rats, compared with controls (which showed none). FG‐3019‐treated rats showed no increase above control levels of perineural collagen or dMBP in median nerves, Substance P in lower cervical DRGs, or ATF3‐immunopositive nuclei in ventral horns, and similar median nerve conduction velocities and thermal sensitivity, compared with controls. We hypothesize that neural fibrotic processes underpin the sensorimotor declines by compressing or impeding median nerves during movement, and that inhibiting fibrosis using an anti‐CCN2 treatment reverses these effects.
Funding Information
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR056019)

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