Blocking CCN2 Reduces Established Bone Loss Induced by Prolonged Intense Loading by Increasing Osteoblast Activity in Rats

We have an operant model of reaching and grasping in which detrimental bone remodeling is observed rather than beneficial adaptation when rats perform a high‐repetition, high‐force (HRHF) task long term. Here, adult female Sprague–Dawley rats performed an intense HRHF task for 18 weeks, which we have shown induces radial trabecular bone osteopenia. One cohort was euthanized at this point (to assay the bone changes post task; HRHF‐Untreated). Two other cohorts were placed on 6 weeks of rest while being simultaneously treated with either an anti‐CCN2 (FG‐3019, 40 mg/kg body weight, ip; twice per week; HRHF‐Rest/anti‐CCN2), or a control IgG (HRHF‐Rest/IgG), with the purpose of determining which might improve the trabecular bone decline. Results were compared with food‐restricted control rats (FRC). MicroCT analysis of distal metaphysis of radii showed decreased trabecular bone volume fraction (BV/TV) and thickness in HRHF‐Untreated rats compared with FRCs; responses improved with HRHF‐Rest/anti‐CCN2. Rest/IgG also improved trabecular thickness but not BV/TV. Histomorphometry showed that rest with either treatment improved osteoid volume and task‐induced increases in osteoclasts. Only the HRHF‐Rest/anti‐CCN2 treatment improved osteoblast numbers, osteoid width, mineralization, and bone formation rate compared with HRHF‐Untreated rats (as well as the latter three attributes compared with HRHF‐Rest/IgG rats). Serum ELISA results were in support, showing increased osteocalcin and decreased CTX‐1 in HRHF‐Rest/anti‐CCN2 rats compared with both HRHF‐Untreated and HRHF‐Rest/IgG rats. These results are highly encouraging for use of anti‐CCN2 for therapeutic treatment of bone loss, such as that induced by chronic overuse. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.