Chia Shi-Lu, Sawaji Yasunobu, Burleigh Annika, McLean Celia, Inglis Julia, Saklatvala Jeremy, Vincent Tonia
Imperial College London, London, UK.
Arthritis Rheum. 2009 Jul;60(7):2019-27. doi: 10.1002/art.24654.
We have previously identified in articular cartilage an abundant pool of the heparin-binding growth factor, fibroblast growth factor 2 (FGF-2), which is bound to the pericellular matrix heparan sulfate proteoglycan, perlecan. This pool of FGF-2 activates chondrocytes upon tissue loading and is released following mechanical injury. In vitro, FGF-2 suppresses interleukin-1-driven aggrecanase activity in human cartilage explants, suggesting a chondroprotective role in vivo. We undertook this study to investigate the in vivo role of FGF-2 in murine cartilage.
Basal characteristics of the articular cartilage of Fgf2(-/-) and Fgf2(+/+) mice were determined by histomorphometry, nanoindentation, and quantitative reverse transcriptase-polymerase chain reaction. The articular cartilage was graded histologically in aged mice as well as in mice in which osteoarthritis (OA) had been induced by surgical destabilization of the medial meniscus. RNA was extracted from the joints of Fgf2(-/-) and Fgf2(+/+) mice following surgery and quantitatively assessed for key regulatory molecules. The effect of subcutaneous administration of recombinant FGF-2 on OA progression was assessed in Fgf2(-/-) mice.
Fgf2(-/-) mice were morphologically indistinguishable from wild-type (WT) animals up to age 12 weeks; the cartilage thickness and proteoglycan staining were equivalent, as was the mechanical integrity of the matrix. However, Fgf2(-/-) mice exhibited accelerated spontaneous and surgically induced OA. Surgically induced OA in Fgf2(-/-) mice was suppressed to levels in WT mice by subcutaneous administration of recombinant FGF-2. Increased disease in Fgf2(-/-) mice was associated with increased expression of messenger RNA of Adamts5, the key murine aggrecanase.
These data identify FGF-2 as a novel endogenous chondroprotective agent in articular cartilage.
我们之前在关节软骨中发现了大量与细胞周围基质硫酸乙酰肝素蛋白聚糖（基底膜聚糖）结合的肝素结合生长因子，即成纤维细胞生长因子2（FGF-2）。这一FGF-2库在组织负荷时激活软骨细胞，并在机械损伤后释放。在体外，FGF-2可抑制白细胞介素-1驱动的人软骨外植体中的聚集蛋白聚糖酶活性，提示其在体内具有软骨保护作用。我们开展本研究以探究FGF-2在小鼠软骨中的体内作用。
通过组织形态计量学、纳米压痕和定量逆转录聚合酶链反应来确定Fgf2(-/-)和Fgf2(+/+)小鼠关节软骨的基础特征。对老年小鼠以及通过内侧半月板手术失稳诱导骨关节炎（OA）的小鼠的关节软骨进行组织学分级。手术后从Fgf2(-/-)和Fgf2(+/+)小鼠的关节中提取RNA，并对关键调节分子进行定量评估。评估皮下注射重组FGF-2对Fgf2(-/-)小鼠OA进展的影响。
在12周龄之前，Fgf2(-/-)小鼠在形态上与野生型（WT）动物没有区别；软骨厚度和蛋白聚糖染色相同，基质的机械完整性也相同。然而，Fgf2(-/-)小鼠表现出自发性和手术诱导性OA加速。皮下注射重组FGF-2可将Fgf2(-/-)小鼠手术诱导的OA抑制至WT小鼠的水平。Fgf2(-/-)小鼠疾病加重与关键小鼠聚集蛋白聚糖酶Adamts5的信使核糖核酸表达增加有关。
这些数据表明FGF-2是关节软骨中一种新型的内源性软骨保护剂。
