TNF-α antibodies and osteoprotegerin decrease systemic bone loss associated with inflammation through distinct mechanisms in collagen-induced arthritis
TNF-α antibodies and osteoprotegerin decrease systemic bone loss associated with inflammation through distinct mechanisms in collagen-induced arthritis
复制标题
在胶原诱导性关节炎中，肿瘤坏死因子-α（TNF-α）抗体和骨保护素通过不同机制减轻与炎症相关的全身性骨质流失。
DOI：
10.1016/j.bone.2004.07.004
复制
发表时间：
2004-11-01
期刊：
影响因子：
4.1
通讯作者：
Cohen-Solal, ME
中科院分区：
文献类型：
--
作者：
Saidenberg-Kermanac'h, N;Corrado, A;Cohen-Solal, ME
简介：类风湿性关节炎（RA）与局灶性和全身性骨质流失相关，涉及RANKL和TNF-alpha等细胞因子。RANK-L促进局灶性和全身性骨质疏松，而骨保护素（OPG）抑制骨吸收。尽管抗TNF-α抗体（抗TNF-α Ab）可减少关节炎症和骨侵蚀，但其对骨丢失的影响尚不清楚。本研究的目的是评价OPG和抗TNF-α Ab单独或联合应用对胶原诱导的关节炎（CIA）（一种RA模型）炎症和骨重建的影响。方法：DBA/1小鼠（n = 28）用牛II型胶原免疫，并用OPG-Fc或抗TNF-α Ab或两者，或生理盐水处理。一组小鼠（n = 7）未被免疫（幼稚组）。在基线和处死时测量尿脱氧吡啶啉（D-pyr）和全身骨矿物质密度（BMD）。在股骨干骺端评价组织形态学参数。结果：抗TNF-α抗体，而不是OPG，降低临床关节炎评分（P < 0.02 vs.生理盐水）和炎症组织学评分。CIA小鼠从基线到处死的BMD变化（DeltaBMD）显著小于未处理小鼠。与生理盐水相比，OPG和抗TNF-α Ab显著增加了DeltaBMD，OPG的作用更大（P < 0.003）。OPG组DeltaD-pyr降低65%，抗TNF-α Ab组降低13%。与生理盐水相比，OPG可增加骨小梁体积（BV/TV）（P < 0.02），减少骨小梁分离（P < 0.02），降低骨形成率（BFR）（P < 0.01）。抗TNF-α Ab在骨体积或骨小梁分离方面没有产生显著变化，但骨小梁厚度增加（P < 0.02，与盐水相比）至接近于未处理小鼠的值，表明骨形成得以保留。OPG和抗TNF-α抗体没有添加剂的影响被发现。结论：全身OPG和抗TNF-α抗体治疗通过不同的机制，包括降低骨吸收和保存骨形成防止CIA小鼠骨丢失。结合这两种药物可能有助于预防炎症性疾病中的骨质流失。(C)2004年爱思唯尔公司All rights reserved.
Introduction: Rheumatoid arthritis (RA) is associated with focal and systemic bone loss involving cytokines such as RANKL and TNF-alpha. RANK-L promotes focal and systemic osteoporosis, whereas osteoprotegerin (OPG) inhibits bone resorption. Although anti-TNF-alpha antibodies (anti-TNF-alpha Ab) decrease joint inflammation and bone erosions, their effects on bone loss are unknown. The aim of this study was to evaluate the effects of OPG and anti-TNF-alpha Ab, separately or in combination, on inflammation and bone remodeling in collagen-induced arthritis (CIA), a model of RA. Methods: DBA/1 mice (n = 28) were immunized with bovine type II collagen and treated with OPG-Fc or anti-TNF-a Ab or both, or saline. One group of mice (n = 7) was not immunized (naive group). Urinary deoxypyridinoline (D-pyr) and whole-body bone mineral density (BMD) were measured at baseline and at sacrifice. Histomorphometric parameters were evaluated at the femoral metaphysis. Results: Anti-TNF-alpha Ab, but not OPG, decreased the clinical arthritis score (P < 0.02 vs. saline) and the histological score of inflammation. The BMD change from baseline to sacrifice (DeltaBMD) was significantly smaller in CIA mice than naive mice. OPG and anti-TNF-alpha Ab significantly increased DeltaBMD versus saline, and the effect was greater with OPG (P < 0.003). DeltaD-pyr decreased by 65% with OPG and 13% with anti-TNF-alpha Ab. Compared with saline, OPG increased trabecular bone volume (BV/TV) (P < 0.02), decreased trabecular separation (P < 0.02), and decreased the bone formation rate (BFR) (P < 0.01). Anti-TNF-alpha Ab produced no significant changes in bone volume or trabecular separation but increased trabecular thickness (P < 0.02 vs. saline) to a value close to that in naive mice, suggesting preservation of bone formation. No additive effects of OPG and anti-TNF-alpha Ab were found. Conclusions: Systemic OPG and anti-TNF-alpha Ab therapy prevented bone loss in CIA mice through distinct mechanisms involving decreased bone resorption and preserved bone formation. Combining these two agents might help to prevent bone loss in inflammatory diseases. (C) 2004 Elsevier Inc. All rights reserved.