Hessle Lovisa, Stordalen Gunhild A, Wenglén Christina, Petzold Christiane, Tanner Elizabeth K, Brorson Sverre-Henning, Baekkevold Espen S, Önnerfjord Patrik, Reinholt Finn P, Heinegård Dick
Sections of Molecular Skeletal Biology and Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
PLoS One. 2013 Jun 3;8(6):e63080. doi: 10.1371/journal.pone.0063080. Print 2014.
Chondroadherin, a leucine rich repeat extracellular matrix protein with functions in cell to matrix interactions, binds cells via their α2β1 integrin as well as via cell surface proteoglycans, providing for different sets of signals to the cell. Additionally, the protein acts as an anchor to the matrix by binding tightly to collagens type I and II as well as type VI. We generated mice with inactivated chondroadherin gene to provide integrated studies of the role of the protein. The null mice presented distinct phenotypes with affected cartilage as well as bone. At 3-6 weeks of age the epiphyseal growth plate was widened most pronounced in the proliferative zone. The proteome of the femoral head articular cartilage at 4 months of age showed some distinct differences, with increased deposition of cartilage intermediate layer protein 1 and fibronectin in the chondroadherin deficient mice, more pronounced in the female. Other proteins show decreased levels in the deficient mice, particularly pronounced for matrilin-1, thrombospondin-1 and notably the members of the α1-antitrypsin family of proteinase inhibitors as well as for a member of the bone morphogenetic protein growth factor family. Thus, cartilage homeostasis is distinctly altered. The bone phenotype was expressed in several ways. The number of bone sialoprotein mRNA expressing cells in the proximal tibial metaphysic was decreased and the osteoid surface was increased possibly indicating a change in mineral metabolism. Micro-CT revealed lower cortical thickness and increased structure model index, i.e. the amount of plates and rods composing the bone trabeculas. The structural changes were paralleled by loss of function, where the null mice showed lower femoral neck failure load and tibial strength during mechanical testing at 4 months of age. The skeletal phenotype points at a role for chondroadherin in both bone and cartilage homeostasis, however, without leading to altered longitudinal growth.
软骨黏附蛋白是一种富含亮氨酸重复序列的细胞外基质蛋白，在细胞与基质相互作用中发挥作用，它通过细胞的α2β1整合素以及细胞表面蛋白聚糖与细胞结合，为细胞提供不同的信号组。此外，该蛋白通过紧密结合Ⅰ型、Ⅱ型和Ⅵ型胶原，作为基质的锚定物。我们构建了软骨黏附蛋白基因失活的小鼠，以全面研究该蛋白的作用。基因敲除小鼠呈现出明显的表型，软骨和骨骼均受影响。在3 - 6周龄时，骺生长板在增殖区增宽最为明显。4月龄时股骨头关节软骨的蛋白质组显示出一些明显差异，软骨黏附蛋白缺陷小鼠中软骨中间层蛋白1和纤连蛋白的沉积增加，在雌性小鼠中更明显。其他蛋白质在缺陷小鼠中的水平降低，特别是基质蛋白-1、血小板反应蛋白-1，尤其是蛋白酶抑制剂α1 -抗胰蛋白酶家族的成员以及骨形态发生蛋白生长因子家族的一个成员。因此，软骨内环境稳态明显改变。骨骼表型以多种方式表现出来。胫骨近端干骺端表达骨唾液蛋白mRNA的细胞数量减少，类骨质表面增加，这可能表明矿物质代谢发生了变化。显微CT显示皮质厚度降低，结构模型指数增加，即构成骨小梁的板层和骨棒数量增加。这些结构变化伴随着功能丧失，在4月龄的力学测试中，基因敲除小鼠的股骨颈破坏载荷和胫骨强度较低。骨骼表型表明软骨黏附蛋白在骨骼和软骨内环境稳态中均起作用，然而，并未导致纵向生长改变。
