Musculoskeletal disorders (MSDs) are a leading cause of long-term pain and physical disability worldwide, with diagnoses including tendinopathies, nerve compression injuries, and muscle and joint disorders. MSDs are the 2nd greatest cause of disability globally and have increased 45% worldwide, according to the 2010 Global Burden of Disease Study. In 2012, work-related MSDs accounted for 34% of all lost work time, workplace injuries and illnesses in the U.S., at a cost of over $100 billion annually. The pathophysiology of these chronic disorders is incompletely understood, and, thus, effective treatments are still under investigation. A tissue fibrosis hypothesis is supported by clinical studies examining biopsies from patients with chronic MSDs. This fibrosis is hypothesized to be a key factor in the motor dysfunction, increased discomfort and pain observed in these patients. Unfortunately, recovery from tissue fibrosis is slow or even irreversible. Therefore, our goal here is to use our well-established rodent model in which prolonged performance of high demand reaching and handle-pulling tasks initially induces early injury and inflammation, but later, significant fibrosis in nerves, muscles and tendons, changes accompanied by pain and motor dysfunction as in patients with MSDs. We propose to examine 3 signaling pathways with the goal of reversing fibrotic tissue changes occurring in our pre-clinical model of overuse-MSDs: CTGF, IFN-?, and SubP-NK-1 pathways. It is well documented that Connective Tissue Growth Factor (CTGF)/CCN2 are markedly increased in various fibrotic diseases where they play essential roles in mediating the excessive matrix deposition that causes the fibrosis. CTGF/CCN2 has emerged as an attractive therapeutic target in treating fibrotic diseases. Therefore, in Aim 1, we will examine if an anti-CTGF drug (FG-3019) reduces tissue fibrosis and sensorimotor declines in rats that have performed a high repetition high force (HRHF) task for 18 weeks. We hypothesize that blocking HRHF-induced increases in CTGF will reverse fibrotic tissue changes in muscle, tendons and nerves, and sensorimotor declines occurring as a consequence of the fibrosis. For our 2nd target, we chose interferon (IFN)-?, since it is an anti-fibrotic cytokine that regulates skeletal muscle recovery following acute injury of muscles. Exogenous IFN-? is known to promote skeletal muscle regeneration by inhibiting signaling of transforming growth factor beta 1 (TGFB1), a fibrotic stimulator. Although it has not been investigated as a therapy for chronic skeletal muscle damage, its anti-fibrotic and regenerative roles in skeletal muscle makes administration of exogenous IFN-? a potential therapy for muscle damage and fibrosis occurring with overuse-induced MSDs. Therefore, in Aim 2, we will determine if systemic administration of exogenous recombinant interferon-gamma (rIFN-?) reduce muscle fibrosis and improve muscle strength in rats that have performed a HRHF task for 18 weeks. We hypothesize that increasing exogenous IFN-? will enhance endogenous IFN-? levels, both of which will reduce TGFB1 signaling and muscle fibrosis, and enhance muscle regeneration and strength. Our 3rd target, Substance P, a nociceptive neuropeptide, and its main receptor neurokinin-1 receptor (NK-1R), are also increased in tendon and muscle tissues of animal models of tendinopathies and myositis, and in biopsied tendon tissues collected from patients undergoing surgical treatment for long-term fibrotic tendinopathies with pain. The Substance P-NK-1R pathway has been implicated as an inducer of collagen production in fibrotic tendinopathies, and was recently proposed as a therapeutic target for their treatment, although this hypothesis has yet to be tested. Therefore, in Aim 3A, we will determine if a specific NK-1R antagonist (L732138) reduce tissue fibrosis and sensorimotor declines in rats that have performed a HRHF task for 18 weeks. We hypothesize that blocking HRHF-induced increases in Substance P will reduce tendon, muscle and nerve fibrosis, as well as associated sensorimotor declines. Also, in Aim 3B, we will determine if Substance P mediated up-regulation of CTGF expression in fibroblasts is required to increase proliferation and collagen production in vitro. We hypothesize that Substance P acts directly to stimulate CTGF expression via the NK- 1R/ERK receptor/signaling pathway, and that CTGF plays an essential role in promoting Substance P -induced proliferation and extracellular matrix production in tendon and muscle fibroblasts. Pre-clinical clarification of fibrotic progression in MSDs is highly significant to pulic health and this field of research. There is currently no treatment for MSD-induced tissue fibrosis other than rest or surgery, which are not always successful. Our findings are expected to lead to novel therapeutic strategies for the clinical management of patients with upper extremity nerve and musculotendinous fibrosis. We are working with clinical colleagues to translate our findings to the treatment of patient populations. This work has strong potential for long-term, sustained impact on the field of preventative medicine and rehabilitative sciences.

Public Health Relevance

Musculoskeletal disorders (MSDs) occurring as a result of prolonged repetitive and forceful work tasks are a leading cause of long-term pain and physical disability, and include diagnoses such as median nerve compression, tendinopathies, myalgia and rotator cuff disorders. We propose testing novel drug interventions to treat chronic fibrotic conditions associated with upper extremity overuse-induced MSDs, which will be tested in a unique operant rat model of overuse-MSDs. This work will provide pre-clinical clarification of fibrotic progression in MSDs, a finding that is highly significant to public health and this field f research. Our findings are also expected to lead to novel therapeutic strategies for the clinical management of patients with upper extremity nerve and musculotendinous fibrosis, who are no longer responsive to traditional rehabilitation means (rest, ice, ibuprofen). This work has strong potential for long-term, sustained impact on the field of preventative medicine and rehabilitative sciences.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056019-09
Application #
9207423
Study Section
Musculoskeletal Rehabilitation Sciences Study Section (MRS)
Program Officer
Washabaugh, Charles H
Project Start
2008-02-01
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
9
Fiscal Year
2017
Total Cost
$433,881
Indirect Cost
$155,752
Name
Temple University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Bove, Geoffrey M; Harris, Michele Y; Zhao, Huaqing et al. (2016) Manual therapy as an effective treatment for fibrosis in a rat model of upper extremity overuse injury. J Neurol Sci 361:168-80
Frara, Nagat; Abdelmagid, Samir M; Tytell, Michael et al. (2016) Growth and repair factors, osteoactivin, matrix metalloproteinase and heat shock protein 72, increase with resolution of inflammation in musculotendinous tissues in a rat model of repetitive grasping. BMC Musculoskelet Disord 17:34
Frara, Nagat; Abdelmagid, Samir M; Sondag, Gregory R et al. (2016) Transgenic Expression of Osteoactivin/gpnmb Enhances Bone Formation In Vivo and Osteoprogenitor Differentiation Ex Vivo. J Cell Physiol 231:72-83
Ali, Sayed; Cunningham, Ryan; Amin, Mamta et al. (2015) The extensor carpi ulnaris pseudolesion: evaluation with microCT, histology, and MRI. Skeletal Radiol 44:1735-43
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Barbe, Mary F; Jain, Nisha X; Massicotte, Vicky S et al. (2015) Ergonomic task reduction prevents bone osteopenia in a rat model of upper extremity overuse. Ind Health 53:206-21
Fisher, Paul W; Zhao, Yingjie; Rico, Mario C et al. (2015) Increased CCN2, substance P and tissue fibrosis are associated with sensorimotor declines in a rat model of repetitive overuse injury. J Cell Commun Signal 9:37-54
Jain, N X; Barr-Gillespie, A E; Clark, B D et al. (2014) Bone loss from high repetitive high force loading is prevented by ibuprofen treatment. J Musculoskelet Neuronal Interact 14:78-94
Barbe, Mary F; Gallagher, Sean; Massicotte, Vicky S et al. (2013) The interaction of force and repetition on musculoskeletal and neural tissue responses and sensorimotor behavior in a rat model of work-related musculoskeletal disorders. BMC Musculoskelet Disord 14:303
Gao, Helen G L; Fisher, Paul W; Lambi, Alex G et al. (2013) Increased serum and musculotendinous fibrogenic proteins following persistent low-grade inflammation in a rat model of long-term upper extremity overuse. PLoS One 8:e71875

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