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
RESEARCH ARTICLE

Abstract

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.

Keywords

Collagen type I Cumulative trauma disorder Fibrosis IFNgamma Overuse injury TGFB1 

Abbreviations

CCN2

Connective tissue growth factor

ECM

Extracellular matrix

FRC

Food-restricted control

GAPDH

Glyceraldehyde 3-phosphate dehydrogenase

G-CSF

Granulocyte colony stimulating factor

GM-CSF

Granulocyte-macrophage colony stimulating factor

GRO/KC

Growth regulated oncogene alpha / keratinocyte-derived chemokine

HRHF

High repetition high force

IFNγ

Interferon gamma

IL-

Interleukin

IP-10

Interferon gamma-induced protein 10

MIP-

Macrophage inflammatory protein

MCP-1

Monocyte chemoattractant protein 1

NC

Normal control

OSHA

The United States Occupational Safety and Health Administration

RANTES

Regulated on activation normal T cell expressed and secreted

subP

Substance P

TGFB1

Transforming growth factor beta

TRHF

Trained to high force

TNFalpha

Tumor necrosis factor alpha

VEGF

Vascular endothelial growth factor

WMSDs

Work-related musculoskeletal disorders

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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