RANKL is a marker and mediator of local and systemic bone loss in two rat models of inflammatory arthritis
RANKL is a marker and mediator of local and systemic bone loss in two rat models of inflammatory arthritis
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DOI：
10.1359/jbmr.050601
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发表时间：
2005-10-01
影响因子：
6.2
通讯作者：
Kostenuik, PJ
中科院分区：
文献类型：
--
作者：
Stolina, M;Adamu, S;Kostenuik, PJ
RANKL是骨侵蚀的重要介质，但RANKL在关节炎中全身性骨丢失中的作用尚未研究。RANKL蛋白在大鼠关节提取物和血清中增加，在关节炎的最早阶段。骨保护素（OPG）治疗逆转局部和全身骨丢失，表明RANKL是一个标志物和介质的骨丢失在arthritis.Introduction：RANKL是公认的炎症性关节炎骨侵蚀的重要介质，但RANKL在关节炎全身骨丢失的作用还没有研究。我们假设血清RANKL可以作为关节炎局部和全身骨丢失的介质和新的生物标志物。我们在两个已建立的炎症性关节炎大鼠模型中挑战了这一假设。我们试图确定血清RANKL是否在疾病进展的早期升高，以及RANKL抑制是否可以防止这些模型中的局部和全身骨丢失。在患有胶原诱导（CIA）或促炎剂诱导（AIA）关节炎的动物中进行详细的时间过程研究，以评估炎症的发作和进展（爪肿胀）、骨侵蚀、破骨细胞数量和关节炎关节和血清中的RANKL蛋白水平。额外的CIA和AIA大鼠（n = 8/组）接受安慰剂（PBS）或重组OPG（3 mg/kg，每周三次），从发病后4天开始，持续1.0天（后爪红斑和水肿的第一个肉眼可见证据）以评估RANKL在局部和全身性骨丢失中的作用。CIA和AIA大鼠发病后1-2天关节和血清中RANKL蛋白显著升高。在两种模型中，RANKL水平升高与局部（后爪）和全身（椎骨）骨质减少相关。RANKL抑制剂OPG防止局部和全身性骨量减少在这两个模型建立diseases.Conclusions：RANKL蛋白显着增加，局部和全身在大鼠炎症性关节炎的最早阶段，这表明血清RANKL可能有骨侵蚀和全身性骨量减少在这种情况下的预后价值。在这些关节炎模型中，通过OPG抑制RANKL可预防局部和全身骨丢失，表明RANKL抑制是治疗关节炎骨丢失的一种有前景的新方法。
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.Introduction: 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.Materials and Methods: 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 1.0 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.Results: 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.Conclusions: 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.