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抗RANKL治疗可抑制侵蚀性关节破坏并减轻炎症，但对迟发型超敏反应性关节炎（DTHA）模型中的骨形成没有影响。

Anti-RANKL treatment inhibits erosive joint destruction and lowers inflammation but has no effect on bone formation in the delayed-type hypersensitivity arthritis (DTHA) model.

作者信息

Atkinson Sara Marie, Bleil Janine, Maier René, Kühl Anja A, Thorn Mette, Serikawa Kyle, Fox Brian, Kruse Kim, Haase Claus, Skov Søren, Nansen Anneline, Syrbe Uta

机构信息

Global Research, Novo Nordisk A/S, 2760, Måløv, Denmark.

Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, C, Denmark.

出版信息

Arthritis Res Ther. 2016 Jan 23;18:28. doi: 10.1186/s13075-016-0931-3.

DOI:10.1186/s13075-016-0931-3
PMID:26801240
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4724155/
Abstract

BACKGROUND

The aims of the present study were to determine the relationship between bone destruction and bone formation in the delayed-type hypersensitivity arthritis (DTHA) model and to evaluate the effect of receptor activator of nuclear factor κB ligand (RANKL) blockade on severity of arthritis, bone destruction, and bone formation.

METHODS

DTHA was induced in C57BL/6 mice. Inflammation, erosive joint damage, and new bone formation were semiquantitatively scored by histology. Osteoclast activity was assessed in vivo, and messenger RNA (mRNA) expression of mediators of bone destruction and bone formation were analyzed by mRNA deep sequencing. Serum concentrations of tartrate-resistant acid phosphatase 5b, carboxy-terminal telopeptide I (CTX-I), matrix metalloproteinase 3 (MMP3), and serum amyloid P component (SAP) were determined by enzyme-linked immunosorbent assay. Anti-RANKL monoclonal antibody treatment was initiated at the time of immunization.

RESULTS

Bone destruction (MMP3 serum levels, cathepsin B activity, and RANKL mRNA) peaked at day 3 after arthritis induction, followed by a peak in cartilage destruction and bone erosion on day 5 after arthritis induction. Periarticular bone formation was observed from day 10. Induction of new bone formation indicated by enhanced Runx2, collagen X, osteocalcin, MMP2, MMP9, and MMP13 mRNA expression was observed only between days 8 and 11. Anti-RANKL treatment resulted in a modest reduction in paw and ankle swelling and a reduction of serum levels of SAP, MMP3, and CTX-I. Destruction of the subchondral bone was significantly reduced, while no effect on bone formation was seen.

CONCLUSIONS

Anti-RANKL treatment prevents joint destruction but does not prevent new bone formation in the DTHA model. Thus, although occurring sequentially during the course of DTHA, bone destruction and bone formation are apparently not linked in this model.

摘要

背景

本研究的目的是确定迟发型超敏反应性关节炎（DTHA）模型中骨破坏与骨形成之间的关系，并评估核因子κB受体激活剂配体（RANKL）阻断对关节炎严重程度、骨破坏和骨形成的影响。

方法

在C57BL/6小鼠中诱导DTHA。通过组织学对炎症、侵蚀性关节损伤和新骨形成进行半定量评分。在体内评估破骨细胞活性，并通过mRNA深度测序分析骨破坏和骨形成介质的信使核糖核酸（mRNA）表达。通过酶联免疫吸附测定法测定血清抗酒石酸酸性磷酸酶5b、羧基末端肽I（CTX-I）、基质金属蛋白酶3（MMP3）和血清淀粉样P成分（SAP）的浓度。在免疫时开始抗RANKL单克隆抗体治疗。

结果

骨破坏（MMP3血清水平、组织蛋白酶B活性和RANKL mRNA）在关节炎诱导后第3天达到峰值，随后在关节炎诱导后第5天软骨破坏和骨侵蚀达到峰值。从第10天开始观察到关节周围骨形成。仅在第8天至第11天观察到由Runx2、胶原蛋白X、骨钙素、MMP2、MMP9和MMP13 mRNA表达增强所表明的新骨形成诱导。抗RANKL治疗导致爪和踝关节肿胀适度减轻，血清SAP、MMP3和CTX-I水平降低。软骨下骨的破坏显著减少，而对骨形成未见影响。

结论

抗RANKL治疗可预防DTHA模型中的关节破坏，但不能预防新骨形成。因此，尽管在DTHA病程中骨破坏和骨形成是相继发生的，但在该模型中它们显然没有联系。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b63/4724155/b3a62a6253bd/13075_2016_931_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b63/4724155/56e3c6075e8b/13075_2016_931_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b63/4724155/9067e73f9bc7/13075_2016_931_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b63/4724155/21773b9ad98c/13075_2016_931_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b63/4724155/5367937a1bf6/13075_2016_931_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b63/4724155/b38e69fe4555/13075_2016_931_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b63/4724155/b3a62a6253bd/13075_2016_931_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b63/4724155/56e3c6075e8b/13075_2016_931_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b63/4724155/9067e73f9bc7/13075_2016_931_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b63/4724155/21773b9ad98c/13075_2016_931_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b63/4724155/5367937a1bf6/13075_2016_931_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b63/4724155/b38e69fe4555/13075_2016_931_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b63/4724155/b3a62a6253bd/13075_2016_931_Fig6_HTML.jpg

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