Huebner J L, Kraus V B
Department of Medicine, Division of Rheumatology, Duke University Medical Center, Durham, NC 27710, USA.
Osteoarthritis Cartilage. 2006 Sep;14(9):923-30. doi: 10.1016/j.joca.2006.03.007. Epub 2006 May 5.
To identify biochemical markers of osteoarthritis (OA) in the guinea pig, we characterized four biomarkers and 17 cytokines for age- and strain-related differences.
Two guinea pig strains were examined in this study: (1) the Hartley (OA-prone) and (2) Strain 13 (OA-resistant). Levels of synovial fluid keratan sulfate (KS) and cartilage oligomeric matrix protein (COMP), as well as levels of serum C2C, CPII, and a panel of cytokines and chemokines were quantified in both guinea pig strains. These included: IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-17, G-CSF, GM-CSF, IFN-gamma, KC, MIP-1 alpha, RANTES, and TNF-alpha.
Synovial fluid concentrations of KS and COMP increased coincident with histological OA and correlated positively with the severity of histological damage in both strains. Synovial fluid concentrations of these biomarkers were elevated in the knees of the Hartley compared to the Strain 13 animals, as early as 2 months of age. From as early as 4 months of age, the levels of serum C2C/CPII, representing the ratio of type II collagen degradation and synthesis, were elevated in the OA-prone Hartley compared with Strain 13 animals. Also, at 12 months of age, strain-related differences were apparent for 11 of the 16 cytokines and chemokines. Using multiple linear regression, serum IL-6 and TNF-alpha concentrations were each strongly associated with strain, weight, and their interaction (r2 = 0.80, P = 0.0002 for IL-6; r2 = 0.55, P = 0.02 for TNF-alpha).
Biomarkers derived from synovial fluid are reflective of histological severity in the spontaneous model of OA in the guinea pig. The synovial fluid biomarker profiles indicated accelerated cartilage matrix turnover in the Hartley strain as early as 2 months of age, prior to evidence of histological damage. The Hartley strain also exemplified an imbalance in type II collagen metabolism and a serum cytokine/chemokine profile indicative of a pro-inflammatory state. These findings elucidate additional disease-related features in the guinea pig that have relevance to OA in humans.
为了确定豚鼠骨关节炎（OA）的生化标志物，我们对四种生物标志物和17种细胞因子进行了年龄和品系相关差异的特征分析。
本研究检测了两种豚鼠品系：（1）哈特利（易患OA）和（2）13号品系（抗OA）。对两种豚鼠品系的滑液硫酸角质素（KS）和软骨寡聚基质蛋白（COMP）水平，以及血清C2C、CPII水平，还有一组细胞因子和趋化因子水平进行了定量分析。这些包括：白细胞介素-1α、白细胞介素-1β、白细胞介素-2、白细胞介素-3、白细胞介素-4、白细胞介素-5、白细胞介素-6、白细胞介素-10、白细胞介素-12p40、白细胞介素-12p70、白细胞介素-17、粒细胞集落刺激因子、粒细胞-巨噬细胞集落刺激因子、干扰素-γ、KC、巨噬细胞炎性蛋白-1α、调节激活正常T细胞表达和分泌因子，以及肿瘤坏死因子-α。
KS和COMP的滑液浓度随组织学OA的出现而增加，且与两种品系组织学损伤的严重程度呈正相关。早在2月龄时，与13号品系动物相比，哈特利品系豚鼠膝关节滑液中这些生物标志物的浓度就升高了。早在4月龄时，与13号品系动物相比，代表II型胶原降解与合成比例的血清C2C/CPII水平在易患OA的哈特利品系中升高。此外，在12月龄时，16种细胞因子和趋化因子中的11种存在品系相关差异。使用多元线性回归分析，血清白细胞介素-6和肿瘤坏死因子-α浓度均与品系、体重及其相互作用密切相关（白细胞介素-6：r2 = 0.80，P = 0.0002；肿瘤坏死因子-α：r2 = 0.55，P = 0.02）。
来自滑液的生物标志物反映了豚鼠OA自发模型中的组织学严重程度。滑液生物标志物谱表明，早在2月龄、在组织学损伤证据出现之前，哈特利品系的软骨基质周转就加速了。哈特利品系还体现了II型胶原代谢失衡以及血清细胞因子/趋化因子谱表明存在促炎状态。这些发现阐明了豚鼠中与人类OA相关的其他疾病相关特征。
