Western University, London, Ontario, Canada.
Arthritis Rheumatol. 2014 Oct;66(10):2816-27. doi: 10.1002/art.38758.
Mitogen-inducible gene 6 (MIG-6) regulates epidermal growth factor receptor (EGFR) signaling in synovial joint tissues. Whole-body knockout of the Mig6 gene in mice has been shown to induce osteoarthritis and joint degeneration. To evaluate the role of chondrocytes in this process, Mig6 was conditionally deleted from Col2a1-expressing cell types in the cartilage of mice.
Bone and cartilage in the synovial joints of cartilage-specific Mig6-deleted (knockout [KO]) mice and control littermates were compared. Histologic staining and immunohistochemical analyses were used to evaluate joint pathology as well as the expression of key extracellular matrix and regulatory proteins. Calcified tissue in synovial joints was assessed by micro-computed tomography (micro-CT) and whole-skeleton staining.
Formation of long bones was found to be normal in KO animals. Cartilage thickness and proteoglycan staining of articular cartilage in the knee joints of 12-week-old KO mice were increased as compared to controls, with higher cellularity throughout the tissue. Radiopaque chondro-osseous nodules appeared in the knees of KO animals by 12 weeks of age and progressed to calcified bone-like tissue by 36 weeks of age. Nodules were also observed in the spine of 36-week-old animals. Erosion of bone at ligament entheses was evident by 12 weeks of age, by both histologic and micro-CT assessment.
MIG-6 expression in chondrocytes is important for the maintenance of cartilage and joint homeostasis. Dysregulation of EGFR signaling in chondrocytes results in anabolic activity in cartilage, but erosion of ligament entheses and the formation of ectopic chondro-osseous nodules severely disturb joint physiology.
有丝分裂原诱导基因 6（MIG-6）调节滑膜关节组织中的表皮生长因子受体（EGFR）信号。已证明在小鼠中全身敲除 Mig6 基因会诱导骨关节炎和关节退化。为了评估软骨细胞在这一过程中的作用，在小鼠软骨中条件性删除 Col2a1 表达细胞类型中的 Mig6 基因。
比较滑膜关节中软骨特异性 Mig6 缺失（敲除 [KO]）小鼠和对照同窝仔鼠的骨和软骨。组织学染色和免疫组织化学分析用于评估关节病理学以及关键细胞外基质和调节蛋白的表达。通过微计算机断层扫描（micro-CT）和全骨骼染色评估滑膜关节中的钙化组织。
发现 KO 动物的长骨形成正常。与对照组相比，12 周龄 KO 小鼠膝关节软骨的厚度和蛋白聚糖染色增加，整个组织的细胞密度更高。12 周龄时 KO 动物的膝关节出现不透射线的软骨骨结节，36 周龄时进展为钙化骨样组织。36 周龄动物的脊柱也观察到结节。12 周龄时，通过组织学和 micro-CT 评估，韧带附着处的骨侵蚀明显。
软骨细胞中 MIG-6 的表达对于维持软骨和关节内稳态很重要。软骨细胞中 EGFR 信号的失调导致软骨的合成代谢活性，但韧带附着处的侵蚀和异位软骨骨结节的形成严重扰乱关节生理学。
