Abstract
ABSTRACTFibrosis may be a key factor in sensorimotor dysfunction in patients with chronic overuse‐induced musculoskeletal disorders. Using a clinically relevant rodent model, in which performance of a high demand handle‐pulling task induces tissue fibrosis and sensorimotor declines, we pharmacologically blocked cellular communication network factor 2 (CCN2; connective tissue growth factor) with the goal of reducing the progression of these changes. Young adult, female Sprague–Dawley rats were shaped to learn to pull at high force levels (10 min/day, 5 weeks), before performing a high repetition high force (HRHF) task for 3 weeks (2 h/day, 3 days/week). HRHF rats were untreated, or treated in task weeks 2 and 3 with a monoclonal antibody that blocks CCN2 (FG‐3019), or a control immunoglobulin G (IgG). Control rats were untreated or received FG‐3019, IgG, or vehicle (saline) injections. Mean task reach rate and grasp force were higher in 3‐week HRHF + FG‐3019 rats, compared with untreated HRHF rats. Grip strength declined while forepaw mechanical sensitivity increased in untreated HRHF rats, compared with controls; changes improved by FG‐3019 treatment. The HRHF task increased collagen in multiple tissues (flexor digitorum muscles, nerves, and forepaw dermis), which was reduced with FG‐3019 treatment. FG‐3019 treatment also reduced HRHF‐induced increases in CCN2 and transforming growth factor β in muscles. In tendons, FG‐3019 reduced HRHF‐induced increases in CCN2, epitendon thickening, and cell proliferation. Our findings indicate that CCN2 is critical to the progression of chronic overuse‐induced multi‐tissue fibrosis and functional declines. FG‐3019 treatment may be a novel therapeutic strategy for overuse‐induced musculoskeletal disorders. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:2004–2018, 2019
Highlights
Cellular communication network factor 2 (CCN2; CTGF) is a secreted matricellular protein with four modular domains that independently interact with different molecules, such as collagen and proteoglycans in the extracellular matrix.[4]
These declines persisted in 3‐week high repetition high force (HRHF) and HRHF + human immunoglobulin G (hIgG) rats, yet improved in HRHF + FG‐3019 rats (Fig. 2B)
We previously reported muscle, tendon, and median nerve fibrosis, characterized by increased tissue levels of collagen type 1, CCN2, and TGFβ1 in rats performing the HRHF lever‐pulling task for 6–18 weeks.[8,17,22,23]
Summary
Cellular communication network factor 2 (CCN2; CTGF) is a secreted matricellular protein with four modular domains that independently interact with different molecules, such as collagen and proteoglycans in the extracellular matrix.[4]. We have a clinically relevant rodent model of chronic overuse in which rats perform an operant reaching, grasping and lever‐pulling task for food reward.[16] Performance of this task at high repetition high force (HRHF) levels for 3–18 weeks induces progressive musculotendinous and nerve fibrosis and sensorimotor declines,[8,17,18,19] similar to responses seen in patients with upper extremity overuse‐induced musculoskeletal disorders.[1] Use of ibuprofen or anti‐tumor necrosis factor ɑ drug reduced tissue inflammation in this model.[17,18] they did not fully ameliorate task‐induced functional declines, or return tissue fibrogenic proteins to control levels in HRHF rats. An initial 5‐week shaping period in which rats learn to pull at high force levels induces elevated levels of extracellular and fibrogenic proteins [TGFβ1]), relative to control rats.[17,19] we sought here to determine if a monoclonal antibody that binds human and rodent CCN2 would reduce progression of tissue fibrosis and sensorimotor declines induced early in our operant rat model of overuse‐induced musculoskeletal disorders
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