ABSTRACT

Purpose/Aim: We recently found that blocking CCN2 signaling using a monoclonal antibody (FG-3019) may be a novel therapeutic strategy for reducing overuse-induced tissue fibrosis. Since CCN2 plays roles in osteoclastogenesis, and persistent performance of a high repetition high force (HRHF) lever pulling task results in a loss in trabecular bone volume in the radius, we examined here whether blocking CCN2 signaling would reduce the early catabolic effects of performing a HRHF task for 3 weeks.

Materials and Methods: Young adult, female, Sprague-Dawley rats were operantly shaped to learn to pull at high force levels, before performing the HRHF task for 3 weeks. HRHF task rats were then left untreated (HRHF Untreated), treated in task weeks 2 and 3 with a monoclonal antibody that antagonizes CCN2 (HRHF+FG-3019), or treated with an IgG (HRHF+IgG), while continuing to perform the task. Non-task control rats were left untreated.

Results: In metaphyseal trabeculae of the distal radius, HRHF Untreated and HRHF-IgG rats showed increased osteoblast numbers and other indices of bone formation, compared to controls, yet decreased trabecular bone volume, increased osteoclast numbers, and increased serum CTX-1 (a serum biomarker of bone resorption). HRHF+FG-3019 rats also showed increased osteoblast numbers and bone formation, but in contrast to HRHF Untreated and HRHF-IgG rats, showed higher trabecular bone volume, and reduced osteoclast numbers and serum CTX-1 levels (and statistically similar to Control levels).

Conclusions: HRHF loading increased bone formation in each task group, yet blocking CCN2 dampened trabecular bone catabolism by reducing osteoclast numbers and activity.

摘要

目的/目的：我们最近发现使用单克隆抗体 (FG-3019) 阻断 CCN2 信号可能是一种减少过度使用引起的组织纤维化的新治疗策略。由于 CCN2 在破骨细胞生成中发挥作用，并且持续执行高重复力 (HRHF) 杠杆拉动任务会导致桡骨小梁骨体积的损失，我们在这里检查了阻断 CCN2 信号是否会降低执行一个HRHF 任务 3 周。

材料和方法：在执行 HRHF 任务 3 周之前，将年轻的成年雌性 Sprague-Dawley 大鼠可操作地塑造成学习在高强度水平下拉动。然后让 HRHF 任务大鼠不接受治疗（HRHF 未治疗），在任务第 2 周和第 3 周用拮抗 CCN2 的单克隆抗体治疗（HRHF+FG-3019），或用 IgG（HRHF+IgG）治疗，同时继续执行任务。非任务对照大鼠不接受治疗。

结果：在桡骨远端干骺端小梁中，与对照组相比，未治疗的 HRHF 和 HRHF-IgG 大鼠显示出增加的成骨细胞数量和其他骨形成指标，但小梁骨体积减少，破骨细胞数量增加，血清 CTX-1（a骨吸收的血清生物标志物）。HRHF+FG-3019 大鼠也显示出成骨细胞数量和骨形成增加，但与 HRHF 未处理和 HRHF-IgG 大鼠相比，显示出更高的骨小梁体积，并降低破骨细胞数量和血清 CTX-1 水平（在统计上与对照水平相似）。

结论：HRHF 负荷增加了每个任务组的骨形成，但阻断 CCN2 通过减少破骨细胞数量和活性来抑制骨小梁分解代谢。