Increased CCN2, substance P and tissue fibrosis are associated with sensorimotor declines in a rat model of repetitive overuse injury

  • Paul W. Fisher
  • Yingjie Zhao
  • Mario C. Rico
  • Vicky S. Massicotte
  • Christine K. Wade
  • Judith Litvin
  • Geoffrey M. Bove
  • Steven N. Popoff
  • Mary F. Barbe


Key clinical features of cumulative trauma disorders include pain, muscle weakness, and tissue fibrosis, although the etiology is still under investigation. Here, we characterized the temporal pattern of altered sensorimotor behaviors and inflammatory and fibrogenic processes occurring in forearm muscles and serum of young adult, female rats performing an operant, high repetition high force (HRHF) reaching and grasping task for 6, 12, or 18 weeks. Palmar mechanical sensitivity, cold temperature avoidance and spontaneous behavioral changes increased, while grip strength declined, in 18-week HRHF rats, compared to controls. Flexor digitorum muscles had increased MCP-1 levels after training and increased TNFalpha in 6-week HRHF rats. Serum had increased IL-1beta, IL-10 and IP-10 after training. Yet both muscle and serum inflammation resolved by week 18. In contrast, IFNγ increased at week 18 in both muscle and serum. Given the anti-fibrotic role of IFNγ, and to identify a mechanism for the continued grip strength losses and behavioral sensitivities, we evaluated the fibrogenic proteins CCN2, collagen type I and TGFB1, as well as the nociceptive/fibrogenic peptide substance P. Each increased in and around flexor digitorum muscles and extracellular matrix in the mid-forearm, and in nerves of the forepaw at 18 weeks. CCN2 was also increased in serum at week 18. At a time when inflammation had subsided, increases in fibrogenic proteins correlated with sensorimotor declines. Thus, muscle and nerve fibrosis may be critical components of chronic work-related musculoskeletal disorders. CCN2 and substance P may serve as potential targets for therapeutic intervention, and CCN2 as a serum biomarker of fibrosis progression.


Collagen type I Cumulative trauma disorder Fibrosis IFNgamma Overuse injury TGFB1 



Connective tissue growth factor


Extracellular matrix


Food-restricted control


Glyceraldehyde 3-phosphate dehydrogenase


Granulocyte colony stimulating factor


Granulocyte-macrophage colony stimulating factor


Growth regulated oncogene alpha / keratinocyte-derived chemokine


High repetition high force


Interferon gamma




Interferon gamma-induced protein 10


Macrophage inflammatory protein


Monocyte chemoattractant protein 1


Normal control


The United States Occupational Safety and Health Administration


Regulated on activation normal T cell expressed and secreted


Substance P


Transforming growth factor beta


Trained to high force


Tumor necrosis factor alpha


Vascular endothelial growth factor


Work-related musculoskeletal disorders



Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number AR056019 to MFB. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors would like to thank Michele Harris and Mamta Amin for their aid in the behavioral experiments, Mamta Amin for performing the immunohistochemistry, and Shreya Amin for sectioning the tissues.

Statement of financial disclosure and conflict of interest: None of the authors have any conflicts of interest issues to declare.

Supplementary material

12079_2015_263_Fig7_ESM.gif (440 kb)
Supplemental Figure 1

Pre-absorption control staining demonstrating antibody specificity in flexor digitorum muscle (M), tendon (T) or extracellular matrix tissues from HRHF rats. DAPI (blue) used as nuclear stain. (A1, B1) CCN2 antibody staining after preabsorption with CCN2 recombinant protein. (A2,B2) DAPI staining in same sections. (C1, D1) COL1 antibody staining after preabsorption with Collagen type 1 purified rat protein. (C2,D2) DAPI staining in same sections. (E1, F1) IFN antibody staining after preabsorption with IFN rat recombinant protein. (E2,F2) DAPI staining in same sections. (G1, H1) TGFB1 antibody staining after preabsorption with TGFB1 rat recombinant protein. (G2,H2) DAPI staining in same sections. (I1, J1) Substance P (SubP) antibody staining after preabsorption with full length SubP peptide. (I2,J2) DAPI staining in same sections. (GIF 439 kb)

12079_2015_263_MOESM1_ESM.tif (4.6 mb)
High resolution image (TIFF 4705 kb)
12079_2015_263_Fig8_ESM.gif (112 kb)
Supplemental Figure 2

No primary antibody control staining in which serum was substituted for the primary antibody, showing no staining with donkey anti-goat Cy3 or donkey anti-mouse secondary antibodies alone in the same section of a flexor digitorum muscle from an 18 week HRHF rat. DAPI (blue) used as nuclear stain. (GIF 112 kb)

12079_2015_263_MOESM2_ESM.tif (932 kb)
High resolution image (TIFF 931 kb)


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Copyright information

© The International CCN Society 2015

Authors and Affiliations

  • Paul W. Fisher
    • 1
  • Yingjie Zhao
    • 1
  • Mario C. Rico
    • 2
  • Vicky S. Massicotte
    • 1
  • Christine K. Wade
    • 3
  • Judith Litvin
    • 1
  • Geoffrey M. Bove
    • 4
  • Steven N. Popoff
    • 1
  • Mary F. Barbe
    • 1
  1. 1.Department of Anatomy and Cell BiologyTemple University School of MedicinePhiladelphiaUSA
  2. 2.Sol Sherry Thrombosis Research CenterTemple University School of MedicinePhiladelphiaUSA
  3. 3.Department of Physical TherapyThomas Jefferson UniversityPhiladelphiaUSA
  4. 4.Department of Biomedical SciencesUniversity of New England COMBiddefordUSA

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