Anabolic phenotype in cartilage-specific mitogen-inducible gene-6 knockout mice is independent of transforming growth factor-α.
Anabolic phenotype in cartilage-specific mitogen-inducible gene-6 knockout mice is independent of transforming growth factor-α.
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DOI：
10.1016/j.ocarto.2023.100387
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发表时间：
2023-09
期刊：
影响因子：
--
通讯作者：
Beier, Frank
中科院分区：
文献类型：
--
作者：
Hadzic, Ermina;To, Bethia;Pest, Michael A.;Qin, Ling;Beier, Frank
关键词：
骨关节炎 (OA) 是一种全关节疾病，目前尚无可用的疾病治疗方法。表皮生长因子受体 (EGFR) 信号通路在软骨/骨发育中发挥重要作用，其配体转化生长因子-α (TGFα) 在 OA 中表达上调。相比之下，丝裂原诱导基因 6 (Mig6) 是 EGFR 的负调节因子，软骨特异性 Mig-6 缺失会导致对软骨的合成代谢影响和软骨骨结节 (CON) 的形成。我们的目的是通过抑制软骨特异性 Mig6 缺陷小鼠中 TGFα 的产生来减弱 EGFR 信号传导，以测试这是否会阻止 CON 的形成。我们通过将软骨特异性 Mig-6fl/flCol2a1-Cre+/- 和全身 Tgfa± 小鼠杂交来产生双敲除小鼠，以产生实验和对照野生型小鼠。膝关节和肘关节切片用于检查关节软骨厚度、细胞密度和破骨细胞的存在。此外，还完成了免疫组织化学分析磷酸化 EGFR 和 SOX9。 Mig-6 缺陷小鼠在第 12 周时肘关节和膝关节均表现出软骨增厚和 CON，这与 TGFα 配体的存在无关。同样，Mig6-cKO/Tgfa-KO 和 Mig6-cKO 小鼠的关节软骨细胞密度增加，但 Tgfa-KO 小鼠的关节软骨细胞密度没有增加，并且 SOX9 和磷酸化 EGFR 染色增加。关节软骨显示出增加的厚度/细胞密度和 CON 形成，与 TGFα 的存在无关，表明 Mig6 缺陷小鼠的合成代谢表型与 TGFα/EGFR 结合无关。合成代谢表型可能是由于另一种 EGFR 配体激活或其他非 EGFR 特异性机制所致。需要更多的研究来阐明导致合成代谢作用的确切途径。
Osteoarthritis (OA) is a whole joint disorder with no disease modifying treatment currently available. The Epidermal Growth Factor Receptor (EGFR) signaling pathway plays an important role in cartilage/bone development and its ligand transforming growth factor-α (TGFα) is upregulated in OA. In contrast, Mitogen-inducible gene 6 (Mig6) is a negative regulator of EGFR, and cartilage-specific Mig-6 deletion results in anabolic effects on cartilage and formation of chondro-osseus nodules (CON). We aimed to attenuate EGFR signaling by inhibiting TGFα production in cartilage-specific Mig6 deficient mice, to test whether this would prevent the formation of CONs. We generated double knockout mice by crossing cartilage-specific Mig-6fl/flCol2a1-Cre+/− and whole-body Tgfa± mice to generate experimental and control wild-type mice. Knee and elbow sections were used to examine articular cartilage thickness, cell density, and osteoclast presence. Additionally, immunohistochemistry was completed to analyze phospho-EGFR and SOX9. Mig-6 deficient mice display cartilage thickening and CONs at 12 weeks in both the elbow and knee joints, which is independent of TGFα ligand presence. Similarly, articular cartilage cell density is increased in Mig6-cKO/Tgfa-KO and Mig6-cKOmice, but not Tgfa-KO mice, and displays increased SOX9 and phospho-EGFR staining. The articular cartilage displays increased thickness/cell density and CON formation independent of the presence of TGFα, suggesting the anabolic phenotype in the Mig6-deficient mice is independent of TGFα/EGFR binding. The anabolic phenotype may be due to an alternative EGFR ligand activation, or other non-EGFR specific mechanism. More research is required to elucidate the exact pathway responsible for the anabolic effects.
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