Blocking CTGF/CCN2 reverses neural fibrosis and sensorimotor declines in a rat model of overuse-induced median mononeuropathy.
Animals
Anterior Horn Cells
/ drug effects
Antibodies, Monoclonal, Humanized
/ pharmacology
Connective Tissue Growth Factor
/ antagonists & inhibitors
Disease Models, Animal
Drug Evaluation, Preclinical
Estradiol
/ blood
Female
Fibrosis
Ganglia, Spinal
/ drug effects
Median Neuropathy
/ blood
Myelin Sheath
/ drug effects
Rats, Sprague-Dawley
dysfunction
median nerve
overuse injury
work-related musculoskeletal disorders
Journal
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
ISSN: 1554-527X
Titre abrégé: J Orthop Res
Pays: United States
ID NLM: 8404726
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
14
01
2020
revised:
24
04
2020
accepted:
29
04
2020
pubmed:
8
5
2020
medline:
2
2
2021
entrez:
8
5
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32379362
doi: 10.1002/jor.24709
pmc: PMC7647961
mid: NIHMS1601908
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
CCN2 protein, rat
0
Connective Tissue Growth Factor
139568-91-5
Estradiol
4TI98Z838E
pamrevlumab
QS5F6VTS0O
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2396-2408Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR056019
Pays : United States
Informations de copyright
© 2020 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.
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