Increased type II collagen degradation and very early focal cartilage degeneration is associated with upregulation of chondrocyte differentiation related genes in early human articular cartilage lesions.
Increased type II collagen degradation and very early focal cartilage degeneration is associated with upregulation of chondrocyte differentiation related genes in early human articular cartilage lesions.
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发表时间：
2005-05
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通讯作者：
E. Tchetina;Ginette Squires;A. Poole
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作者：
E. Tchetina;Ginette Squires;A. Poole
目的骨关节炎（OA）的关节软骨变性包括细胞外基质（ECM）的过度降解和软骨细胞分化（肥大）。我们确定了早期局灶性oa样关节软骨病变患者髌骨-股骨髁软骨中胶原酶裂解程度、软骨退变和分化相关基因表达之间的相互关系。方法解剖时取3例供体的早期局灶性病变的关节软骨标本和相邻的正常软骨标本，从与髌骨连接的股骨髁表面切下全深度切片。切片切片后进行Mankin分级，ELISA检测II型胶原的胶原酶裂解，RT-PCR检测基因表达。结果早期局灶性软骨变性与II型胶原的胶原酶裂解增加有关。胶原酶金属蛋白酶-1 （MMP-1）、MMP-14 （MT1-MMP）和聚集酶ADAMTS-5（一种具有血栓反应蛋白基序的崩解素和金属蛋白酶）（但不包括ADAMTS-4）；细胞因子白介素1 / β和肿瘤坏死因子α (tnf - α)；软骨细胞终末分化相关基因COL10A1、MMP-13、MMP-9、印度刺猬；caspase 3在病变附近经常上调。与生长板软骨细胞增殖相关的生长因子，即成纤维细胞生长因子-2、甲状旁腺激素相关蛋白、转化生长因子(TGF)- β 1/2以及基质分子COL2A1和aggrecan在病变附近和远处表达。在所有基因中，只有caspase 3和ADAMTS-5的表达与这些早期病变有关。胶原酶活性的升高与COL10A1、caspase 3、il -1 α / β、MMP-1和ADAMTS-5表达的频繁升高以及Sox-9 （sry型高流动性组盒转录因子-9）、tgf - β 1、tgf - β 2、tnf - α和聚集蛋白的表达降低有关。其他基因对胶原酶活性的变化无明显差异。结论膝关节软骨早期局灶性退变伴胶原酶活性和软骨细胞终末分化及基质降解相关基因表达上调。因此，软骨细胞分化可能与骨性关节炎等软骨退变的早期发展密切相关。
OBJECTIVE Articular cartilage degeneration in osteoarthritis (OA) involves excessive degradation of extracellular matrix (ECM) and chondrocyte differentiation (hypertrophy). We determined the interrelationship between the extent of collagen cleavage by collagenase, cartilage degeneration, and differentiation related gene expression in patella-femoral condylar cartilages of patients bearing very early focal OA-like articular cartilage lesions. METHODS Articular cartilage specimens with very early focal lesions and adjacent normal cartilage from 3 donors were removed at autopsy as full-depth slices cut from the femoral condyle surface that articulates with patella. Slices were divided into sections and used for Mankin grading, examination of collagenase cleavage of type II collagen by ELISA, and gene expression by RT-PCR. RESULTS Early focal cartilage degeneration was associated with increased collagenase cleavage of type II collagen. The collagenases metalloproteinase-1 (MMP-1), MMP-14 (MT1-MMP), and aggrecanase ADAMTS-5 (a disintegrin and metalloprotease with thrombospondin motifs) (but not ADAMTS-4); cytokines interleukin 1alpha/beta and tumor necrosis factor-alpha (TNF-alpha); chondrocyte terminal differentiation-related genes COL10A1, MMP-13, MMP-9, Indian hedgehog; and caspase 3 were often upregulated in the vicinity of the lesion. Growth factors associated with growth plate chondrocyte proliferation, namely fibroblast growth factor-2, parathyroid hormone related protein, transforming growth factor (TGF)-beta1/2, as well as the matrix molecules COL2A1 and aggrecan were expressed adjacent to and remote from the lesion. Of all genes only caspase 3 and ADAMTS-5 expression was exclusively seen in association with these early lesions. Elevation of collagenase activity was associated with a frequent elevation of expression of COL10A1, caspase 3, IL-1alpha/beta, MMP-1, and ADAMTS-5, and a decreased expression of Sox-9 (SRY-type high-mobility-group box transcription factor-9), TGF-beta1, TGF-beta2, TNF-alpha, and aggrecan. Other genes showed no observable difference with changes in collagenase activity. CONCLUSION Very early focal degeneration in knee articular cartilage is accompanied by upregulation of collagenase activity and expression of genes associated with chondrocyte terminal differentiation and matrix degradation. Thus chondrocyte differentiation may be closely related to the very early development of cartilage degeneration such as occurs in OA.