肿瘤坏死因子-α抗体和骨保护素通过不同机制减少胶原诱导性关节炎中与炎症相关的全身性骨质流失。

TNF-alpha antibodies and osteoprotegerin decrease systemic bone loss associated with inflammation through distinct mechanisms in collagen-induced arthritis.

作者信息

Saidenberg-Kermanac'h N, Corrado A, Lemeiter D, deVernejoul M C, Boissier M C, Cohen-Solal M E

机构信息

UPRES EA-3408 and Department of Rheumatology, Avicenne Hospital (AP-HP), Claude Bernard Foundation, Bobigny Medical School, Paris 13 University, Paris, France.

出版信息

Bone. 2004 Nov;35(5):1200-7. doi: 10.1016/j.bone.2004.07.004.

DOI:10.1016/j.bone.2004.07.004

PMID:15542046

Abstract

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-alpha 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.

摘要

引言

类风湿性关节炎（RA）与包括核因子κB受体活化因子配体（RANKL）和肿瘤坏死因子-α（TNF-α）等细胞因子介导的局部和全身性骨质流失有关。RANK-L可促进局部和全身性骨质疏松，而骨保护素（OPG）则抑制骨吸收。尽管抗TNF-α抗体（抗TNF-α Ab）可减轻关节炎症和骨侵蚀，但其对骨质流失的影响尚不清楚。本研究旨在评估OPG和抗TNF-α Ab单独或联合应用对胶原诱导性关节炎（CIA，一种RA模型）炎症和骨重塑的影响。

方法

将28只DBA/1小鼠用牛II型胶原免疫，并分别用OPG-Fc或抗TNF-α Ab或两者联合处理，或给予生理盐水。一组小鼠（n = 7）未免疫（未处理组）。在基线和处死时测量尿脱氧吡啶啉（D-吡啶）和全身骨密度（BMD）。在股骨近端干骺端评估组织形态计量学参数。

结果

抗TNF-α Ab可降低临床关节炎评分（与生理盐水组相比，P < 0.02）和炎症组织学评分，但OPG无此作用。与未处理组相比，CIA小鼠从基线到处死时的BMD变化（ΔBMD）明显较小。与生理盐水组相比，OPG和抗TNF-α Ab均可显著增加ΔBMD，且OPG的作用更大（P < 0.003）。OPG使ΔD-吡啶降低65%，抗TNF-α Ab使其降低13%。与生理盐水组相比，OPG增加了骨小梁体积（BV/TV）（P < 0.02），减小了骨小梁间距（P < 0.02），并降低了骨形成率（BFR）（P < 0.01）。抗TNF-α Ab对骨体积或骨小梁间距无显著影响，但增加了骨小梁厚度（与生理盐水组相比，P < 0.02），使其值接近未处理组小鼠，提示骨形成得以保留。未发现OPG和抗TNF-α Ab有相加作用。