Xu L, Flahiff C M, Waldman B A, Wu D, Olsen B R, Setton L A, Li Y
Harvard Medical School, Boston, Massachusetts, USA.
Arthritis Rheum. 2003 Sep;48(9):2509-18. doi: 10.1002/art.11233.
To investigate whether heterozygosity for a loss-of-function mutation in the gene encoding the alpha1 chain of type XI collagen (Col11a1) in mice (chondrodysplasia, cho) causes osteoarthritis (OA), and to understand the biochemical and biomechanical effects of this mutation on articular cartilage in knee and temporomandibular (TM) joints.
Articular cartilage from the knee and TM joints of mice heterozygous for cho (cho/+) and their wild-type littermates (+/+) was examined. The morphologic properties of cartilage were evaluated, and collagen fibrils were examined by transmission electron microscopy. Immunohistochemical staining was performed to examine the protein expression levels of matrix metalloproteinase 3 (MMP-3) and MMP-13 in knee joints. In 6-month-old animals, fixed-charge density was determined using a semiquantitative histochemical method, and tensile stiffness was determined using an osmotic loading technique.
The diameter of collagen fibrils in articular cartilage of knee joints from heterozygous cho/+ mice was increased relative to that in control cartilage, and histologic analysis showed OA-like degenerative changes in knee and TM joints, starting at age 3 months. The changes became more severe with aging. At 3 months, protein expression for MMP-3 was increased in knee joints from cho/+ mice. At 6 months, protein expression for MMP-13 was higher in knee joints from cho/+ mice than in joints from their wild-type littermates, and negative fixed-charge density was significantly decreased. Moreover, tensile stiffness in articular cartilage of knee joints from cho/+ mice was moderately reduced and was inversely correlated with the increase in articular cartilage degeneration.
Heterozygosity for a loss-of-function mutation in Col11a1 results in the development of OA in the knee and TM joints of cho/+ mice. Morphologic and biochemical evidence of OA appears to precede significant mechanical changes, suggesting that the cho mutation leads to OA through a mechanism that does not initially involve mechanical factors.
研究小鼠中编码XI型胶原α1链（Col11a1）的基因功能丧失性突变的杂合性（软骨发育不良，cho）是否会导致骨关节炎（OA），并了解该突变对膝关节和颞下颌关节（TM）软骨的生化和生物力学影响。
检查cho杂合子（cho/+）小鼠及其野生型同窝小鼠（+/+）膝关节和TM关节的关节软骨。评估软骨的形态学特性，并通过透射电子显微镜检查胶原纤维。进行免疫组织化学染色以检查膝关节中基质金属蛋白酶3（MMP-3）和MMP-13的蛋白表达水平。在6个月大的动物中，使用半定量组织化学方法测定固定电荷密度，并使用渗透加载技术测定拉伸刚度。
与对照软骨相比，杂合cho/+小鼠膝关节关节软骨中胶原纤维的直径增加，组织学分析显示膝关节和TM关节在3个月大时开始出现类似OA的退行性变化。随着年龄增长，这些变化变得更加严重。在3个月时，cho/+小鼠膝关节中MMP-3的蛋白表达增加。在6个月时，cho/+小鼠膝关节中MMP-13的蛋白表达高于其野生型同窝小鼠的关节，并且负固定电荷密度显著降低。此外，cho/+小鼠膝关节关节软骨的拉伸刚度适度降低，并且与关节软骨退变的增加呈负相关。
Col11a1功能丧失性突变的杂合性导致cho/+小鼠膝关节和TM关节发生OA。OA的形态学和生化证据似乎先于明显的力学变化，这表明cho突变通过一种最初不涉及力学因素的机制导致OA。
