Gorth Deborah J, Mauck Robert L, Chiaro Joseph A, Mohanraj Bhavana, Hebela Nader M, Dodge George R, Elliott Dawn M, Smith Lachlan J
Arthritis Res Ther. 2012 Aug 3;14(4):R179. doi: 10.1186/ar3932.
Inflammation plays a key role in the progression of intervertebral disc degeneration, a condition strongly implicated as a cause of lower back pain. The objective of this study was to investigate the therapeutic potential of poly(lactic-co-glycolic acid) (PLGA) microspheres loaded with interleukin-1 receptor antagonist (IL-1ra) for sustained attenuation of interleukin-1 beta (IL-1β) mediated degradative changes in the nucleus pulposus (NP), using an in vitro model.
IL-1ra was encapsulated in PLGA microspheres and release kinetics were determined over 35 days. NP agarose constructs were cultured to functional maturity and treated with combinations of IL-1β and media conditioned with IL-1ra released from microspheres at intervals for up to 20 days. Construct mechanical properties, glycosaminoglycan content, nitrite production and mRNA expression of catabolic mediators were compared to properties for untreated constructs using unpaired Student's t-tests.
IL-1ra release kinetics were characterized by an initial burst release reducing to a linear release over the first 10 days. IL-1ra released from microspheres attenuated the degradative effects of IL-1β as defined by mechanical properties, glycosaminoglycans (GAG) content, nitric oxide production and mRNA expression of inflammatory mediators for 7 days, and continued to limit functional degradation for up to 20 days.
In this study, we successfully demonstrated that IL-1ra microspheres can attenuate the degradative effects of IL-1β on the NP for extended periods. This therapeutic strategy may be appropriate for treating early-stage, cytokine-mediated disc degeneration. Ongoing studies are focusing on testing IL-1ra microspheres in an in vivo model of disc degeneration, as a prelude to clinical translation.
炎症在椎间盘退变的进展中起关键作用，椎间盘退变是导致下腰痛的一个重要原因。本研究的目的是使用体外模型，研究负载白细胞介素-1受体拮抗剂（IL-1ra）的聚乳酸-乙醇酸共聚物（PLGA）微球对白细胞介素-1β（IL-1β）介导的髓核（NP）降解变化的持续抑制作用的治疗潜力。
将IL-1ra包裹在PLGA微球中，并在35天内测定其释放动力学。将NP琼脂糖构建体培养至功能成熟，并每隔一段时间用IL-1β和从微球释放的IL-1ra条件培养基组合处理长达20天。使用未配对的学生t检验，将构建体的力学性能、糖胺聚糖含量、亚硝酸盐产生和分解代谢介质的mRNA表达与未处理构建体的性能进行比较。
IL-1ra的释放动力学特征是最初的爆发式释放，在最初10天内降至线性释放。从微球释放的IL-1ra在7天内减弱了IL-1β的降解作用，这由力学性能、糖胺聚糖（GAG）含量、一氧化氮产生和炎症介质的mRNA表达来定义，并在长达20天内持续限制功能降解。
在本研究中，我们成功证明IL-1ra微球可长期减弱IL-1β对NP的降解作用。这种治疗策略可能适用于治疗早期细胞因子介导的椎间盘退变。正在进行的研究集中在椎间盘退变的体内模型中测试IL-1ra微球，作为临床转化的前奏。
