Miller R E, Tran P B, Ishihara S, Larkin J, Malfait A M
Department of Internal Medicine, Division of Rheumatology, Rush University Medical Center, 1611 W. Harrison St, Suite 510, Chicago, IL 60612, USA; Department of Biochemistry, Rush University Medical Center, 1611 W. Harrison St, Suite 510, Chicago, IL 60612, USA.
Department of Internal Medicine, Division of Rheumatology, Rush University Medical Center, 1611 W. Harrison St, Suite 510, Chicago, IL 60612, USA.
Osteoarthritis Cartilage. 2016 Feb;24(2):299-306. doi: 10.1016/j.joca.2015.09.005. Epub 2015 Sep 26.
The primary goal of this study was to test the disease-modifying effect of blocking a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5 with a neutralizing monoclonal antibody (mAb) starting 4 weeks after destabilization of the medial meniscus (DMM) in the mouse. We also investigated whether ADAMTS-5 blockade reversed mechanical allodynia and decreased monocyte chemoattractant protein (MCP)-1 production by dorsal root ganglia (DRG) cells.
Ten-week old male C57BL/6 mice underwent DMM surgery and were either left untreated or treated with anti-ADAMTS-5 mAb or IgG2c isotype control mAb starting 4 weeks after surgery. Knees were collected for histopathology 4 or 12 weeks later. Mechanical allodynia was monitored biweekly in the ipsilateral hind paw through 16 weeks. DRG were collected and cultured 8 weeks after DMM for analysis of MCP-1 production.
By 4 weeks after DMM, mild cartilage degeneration was evident in the medial compartment, small osteophytes were present, and subchondral bone sclerosis was established. By 16 weeks after surgery, significant cartilage deterioration was apparent on the medial tibial plateaux and medial femoral condyles, osteophyte size had increased, and subchondral bone sclerosis was maintained. Treatment with ADAMTS-5 mAb from week 4 to 16 after surgery slowed cartilage degeneration and osteophyte growth but did not affect subchondral bone sclerosis. Moreover, ADAMTS-5 blockade resulted in temporary reversal of mechanical allodynia, which correlated with decreased MCP-1 production by cultured DRG cells.
This study suggests therapeutic efficacy of an ADAMTS-5 mAb in the DMM model, when therapy starts early in disease.
本研究的主要目标是在小鼠内侧半月板不稳定（DMM）4周后，用一种中和性单克隆抗体（mAb）测试阻断含血小板反应蛋白基序的解聚素和金属蛋白酶（ADAMTS）-5对疾病的修饰作用。我们还研究了ADAMTS-5阻断是否能逆转机械性异常疼痛，并降低背根神经节（DRG）细胞产生的单核细胞趋化蛋白（MCP）-1。
10周龄雄性C57BL/6小鼠接受DMM手术，术后4周开始，要么不接受治疗，要么用抗ADAMTS-5 mAb或IgG2c同型对照mAb治疗。4周或12周后收集膝关节进行组织病理学检查。在同侧后爪每两周监测一次机械性异常疼痛，持续16周。DMM术后8周收集DRG并进行培养，以分析MCP-1的产生。
DMM术后4周，内侧关节间隙出现轻度软骨退变，有小骨赘形成，软骨下骨硬化。术后16周，胫骨内侧平台和股骨内侧髁出现明显的软骨恶化，骨赘大小增加，软骨下骨硬化持续存在。术后第4周开始至第16周用ADAMTS-5 mAb治疗可减缓软骨退变和骨赘生长，但不影响软骨下骨硬化。此外，ADAMTS-5阻断导致机械性异常疼痛暂时逆转，这与培养的DRG细胞产生的MCP-1减少相关。
本研究表明，当在疾病早期开始治疗时，ADAMTS-5 mAb在DMM模型中具有治疗效果。
