Stolina Marina, Adamu Stephen, Ominsky Mike, Dwyer Denise, Asuncion Frank, Geng Zhaopo, Middleton Scot, Brown Heather, Pretorius Jim, Schett Georg, Bolon Brad, Feige Ulrich, Zack Debra, Kostenuik Paul J
Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, California 91320, USA.
J Bone Miner Res. 2005 Oct;20(10):1756-65. doi: 10.1359/JBMR.050601. Epub 2005 Jun 6.
RANKL is an essential mediator of bone erosions, but the role of RANKL in systemic bone loss had not been studied in arthritis. RANKL protein was increased in rat joint extracts and serum at the earliest stages of arthritis. Osteoprotegerin (OPG) treatment reversed local and systemic bone loss, suggesting that RANKL is both a marker and mediator of bone loss in arthritis.
RANKL is well established as an essential mediator of bone erosions in inflammatory arthritis, but the role of RANKL in systemic bone loss in arthritis had not been studied. We hypothesized that serum RANKL could serve as both a mediator and as a novel biomarker for local and systemic bone loss in arthritis. We challenged this hypothesis in two established rat models of inflammatory arthritis. We sought to determine whether serum RANKL was elevated early in disease progression and whether RANKL suppression could prevent both local and systemic bone loss in these models.
Detailed time-course studies were conducted in animals with collagen-induced (CIA) or adjuvant-induced (AIA) arthritis to evaluate the onset and progression of inflammation (paw swelling), bone erosions, osteoclast numbers, and RANKL protein levels in arthritic joints and in serum. Additional CIA and AIA rats (n=8/group) received placebo (PBS) or recombinant OPG (3 mg/kg three times weekly) for 10 days beginning 4 days after disease onset (first macroscopic evidence of hind paw erythema and edema) to assess the role of RANKL in local and systemic bone loss.
RANKL protein was significantly elevated in the joints and serum of CIA and AIA rats within 1-2 days of disease onset. Increased RANKL levels were associated with local (hind paw) and systemic (vertebral) osteopenia in both models. The RANKL inhibitor OPG prevented local and systemic osteopenia in both models of established disease.
RANKL protein is significantly increased both locally and systemically during the earliest stages of inflammatory arthritis in rats, suggesting that serum RANKL might have prognostic value for bone erosions and systemic osteopenia in this condition. RANKL inhibition through OPG prevented local and systemic bone loss in these arthritis models, suggesting that RANKL inhibition is a promising new approach for treating bone loss in arthritis.
核因子κB受体活化因子配体（RANKL）是骨侵蚀的关键介质，但RANKL在关节炎全身骨质流失中的作用尚未得到研究。在关节炎的最早阶段，大鼠关节提取物和血清中的RANKL蛋白增加。骨保护素（OPG）治疗可逆转局部和全身骨质流失，这表明RANKL既是关节炎骨质流失的标志物，也是其介质。
RANKL已被确认为炎症性关节炎中骨侵蚀的关键介质，但RANKL在关节炎全身骨质流失中的作用尚未得到研究。我们假设血清RANKL可能既是关节炎局部和全身骨质流失的介质，也是一种新型生物标志物。我们在两种已建立的大鼠炎症性关节炎模型中对这一假设进行了验证。我们试图确定血清RANKL在疾病进展早期是否升高，以及RANKL抑制是否能预防这些模型中的局部和全身骨质流失。
对胶原诱导性（CIA）或佐剂诱导性（AIA）关节炎动物进行详细的时间进程研究，以评估炎症（爪肿胀）、骨侵蚀、破骨细胞数量以及关节炎关节和血清中RANKL蛋白水平的发生和进展。另外的CIA和AIA大鼠（每组n = 8）在疾病发作后4天（后爪红斑和水肿的首个宏观证据）开始接受安慰剂（PBS）或重组OPG（3mg/kg，每周三次）治疗10天，以评估RANKL在局部和全身骨质流失中的作用。
在疾病发作后1 - 2天内，CIA和AIA大鼠的关节和血清中的RANKL蛋白显著升高。在两种模型中，RANKL水平升高均与局部（后爪）和全身（椎体）骨质减少相关。RANKL抑制剂OPG可预防两种已确诊疾病模型中的局部和全身骨质减少。
在大鼠炎症性关节炎的最早阶段，RANKL蛋白在局部和全身均显著增加，这表明血清RANKL可能对这种情况下的骨侵蚀和全身骨质减少具有预后价值。通过OPG抑制RANKL可预防这些关节炎模型中的局部和全身骨质流失，这表明抑制RANKL是治疗关节炎骨质流失的一种有前景的新方法。
