Blocking CCN2 Reduces Progression of Sensorimotor Declines and Fibrosis in a Rat Model of Chronic Repetitive Overuse

Fibrosis 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