Sambamurthy Nisha, Nguyen Vu, Smalley Ryan, Xiao Rui, Hankenson Kurt, Gan Justin, Miller Rachel E, Malfait Anne-Marie, Dodge George R, Scanzello Carla R
Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz Department of Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
Division of Rheumatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
J Orthop Res. 2018 Mar;36(3):864-875. doi: 10.1002/jor.23671. Epub 2017 Aug 29.
Elevated chemokine receptor Ccr7 is observed in knee osteoarthritis (OA) and associated with severity of symptoms. In this study, we confirmed that CCR7 protein expression is elevated in synovial tissue from OA patients by immunohistochemical staining. We then investigated whether Ccr7 deficiency impacted structural and functional joint degeneration utilizing a murine model of OA. OA-like disease was induced in male C57BL/6 and Ccr7-deficient (Ccr7 ) mice by destabilization of the medial meniscus (DMM). Functional deficits were measured by computer integrated monitoring of spontaneous activity every 4 weeks after DMM surgery up 16 weeks. Joint degeneration was evaluated at 6 and 19 weeks post-surgery by histopathology, and subchondral bone changes analyzed by microCT. Results showed reduction in locomotor activities in DMM-operated C57BL/6 mice by 8 weeks, while activity decreases in Ccr7 mice were delayed until 16 weeks. Histopathologic evaluation showed minimal protection from early cartilage degeneration (p = 0.06) and osteophytosis (p = 0.04) in Ccr7 mice 6 weeks post-DMM compared to C57BL/6 controls, but not at 19 weeks. However, subchondral bone mineral density (p = 0.03) and histologic sclerosis (p = 0.02) increased in response to surgery in C57BL/6 mice at 6 weeks, while Ccr7 mice were protected from these changes. Our results are the first to demonstrate a role for Ccr7 in early development of functional deficits and subchondral bone changes in the DMM model. Understanding the mechanism of Ccr7 receptor signaling in the initiation of joint pathology and disability will inform the development of innovative therapies to slow symptomatic OA development after injury. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. J Orthop Res 36:864-875, 2018.
趋化因子受体Ccr7在膝骨关节炎（OA）中表达升高，并与症状严重程度相关。在本研究中，我们通过免疫组化染色证实OA患者滑膜组织中CCR7蛋白表达升高。然后，我们利用OA小鼠模型研究Ccr7缺陷是否会影响关节结构和功能的退变。通过内侧半月板失稳（DMM）诱导雄性C57BL/6和Ccr7缺陷（Ccr7-/-）小鼠出现类OA疾病。DMM手术后每4周通过计算机综合监测自发活动来测量功能缺陷，持续16周。术后6周和19周通过组织病理学评估关节退变，并通过显微CT分析软骨下骨变化。结果显示，DMM手术的C57BL/6小鼠在8周时运动活动减少，而Ccr7-/-小鼠的活动减少则延迟至16周。组织病理学评估显示，与C57BL/6对照组相比，DMM术后6周Ccr7-/-小鼠对早期软骨退变（p = 0.06）和骨赘形成（p = 0.04）有轻微保护作用，但在19周时没有。然而，C57BL/6小鼠在术后6周时，软骨下骨矿物质密度（p = 0.03）和组织学硬化（p = 0.02）因手术而增加，而Ccr7-/-小鼠则免受这些变化的影响。我们的结果首次证明Ccr7在DMM模型中功能缺陷和软骨下骨变化的早期发展中起作用。了解Ccr7受体信号在关节病理和残疾发生中的机制，将为开发创新疗法以减缓损伤后症状性OA的发展提供依据。发表于2017年。本文是美国政府工作成果，在美国属于公共领域。《矫形外科学研究》36:864 - 875, 2018。
