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

摘要

ABSTRACT Fibrosis may be a key factor in sensorimotor dysfunction in patients with chronic overuseinduced musculoskeletal disorders. Using a clinically relevant rodent model, in which performance of a high demand handlepulling 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 SpragueDawley 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 (FG3019), or a control immunoglobulin G (IgG). Control rats were untreated or received FG3019, IgG, or vehicle (saline) injections. Mean task reach rate and grasp force were higher in 3week HRHF + FG3019 rats, compared with untreated HRHF rats. Grip strength declined while forepaw mechanical sensitivity increased in untreated HRHF rats, compared with controls; changes improved by FG3019 treatment. The HRHF task increased collagen in multiple tissues (flexor digitorum muscles, nerves, and forepaw dermis), which was reduced with FG3019 treatment. FG3019 treatment also reduced HRHFinduced increases in CCN2 and transforming growth factor ?in muscles. In tendons, FG3019 reduced HRHFinduced increases in CCN2, epitendon thickening, and cell proliferation. Our findings indicate that CCN2 is critical to the progression of chronic overuseinduced multitissue fibrosis and functional declines. FG3019 treatment may be a novel therapeutic strategy for overuseinduced musculoskeletal disorders. ?2019 The Authors.Journal of Orthopaedic Research ?published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:20042018, 2019