Gefitinib for Epidermal Growth Factor Receptor Activated Osteoarthritis Subpopulation Treatment.
Gefitinib for Epidermal Growth Factor Receptor Activated Osteoarthritis Subpopulation Treatment.
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吉非替尼用于表皮生长因子受体激活的骨关节炎亚群治疗。
DOI：
10.1016/j.ebiom.2018.06.002
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发表时间：
2018-06
期刊：
影响因子：
11.1
通讯作者：
Ouyang H
中科院分区：
文献类型：
--
作者：
Sun H;Wu Y;Pan Z;Yu D;Chen P;Zhang X;Wu H;Zhang X;An C;Chen Y;Qin T;Lei X;Yuan C;Zhang S;Zou W;Ouyang H
骨关节炎（OA）是老年人身体残疾的主要原因，目前还没有有效的药物能够有效地恢复软骨基质合成和降解之间的平衡。OA患者的亚群分类也不准确，阻碍了个性化精准医疗的发展。在本研究中，我们发现OA患者的一个亚群表现出高水平的表皮生长因子受体（EGFR）激活。Col2a1-creERT2;Egfrf/f小鼠，发现EGFR的激活，通过EGFR磷酸化（pEGFR）表示，导致关节破坏。令人兴奋的是，抑制EGFR抑制软骨基质变性，促进软骨再生。美国食品和药物管理局（FDA）批准的药物吉非替尼在小鼠模型和临床病例报告中均能有效抑制OA关节EGFR功能，恢复软骨结构和功能。总的来说，我们的研究结果提出了EGFR激活OA亚群的概念，并阐明了EGFR信号在调节软骨稳态中的机制。吉非替尼可能是治疗OA亚群的一种有希望的疾病改善药物。有一个骨关节炎患者亚群具有高激活水平的EGFR （pEGFRhigh）。吉非替尼可同时促进ECM合成并抑制pEGFRhigh骨性关节炎软骨的进一步降解。吉非替尼关节内控释可能是pEGFRhigh OA治疗的一种治疗策略。EGFR激活通过抑制自噬来调节OA的发展。骨关节炎（OA）是世界上最常见的肌肉骨骼疾病之一，但大多数诊所的治疗方法都是“一刀切”的。我们发现并不是所有的OA患者都是一样的，特别是在这个病例中，有一组人的EGFR激活水平很高，EGFR是软骨细胞中的一种功能性蛋白质。发现抗癌药物吉非替尼在EGFR激活的OA中具有保护关节软骨免受破坏的多种功能。因此，我们的研究强调了OA亚群的概念，并提出了一种新的OA治疗策略。
Osteoarthritis (OA) is a leading cause of physical disability among aging populations, with no available drugs able to efficiently restore the balance between cartilage matrix synthesis and degradation. Also, OA has not been accurately classified into subpopulations, hindering the development toward personalized precision medicine. In the present study, we identified a subpopulation of OA patients displaying high activation level of epidermal growth factor receptor (EGFR). With Col2a1-creERT2; Egfrf/f mice, it was found that the activation of EGFR, indicated by EGFR phosphorylation (pEGFR), led to the destruction of joints. Excitingly, EGFR inhibition prohibited cartilage matrix degeneration and promoted cartilage regeneration. The Food and Drug Administration (FDA)-approved drug gefitinib could efficiently inhibit EGFR functions in OA joints and restore cartilage structure and function in the mouse model as well as the clinical case report. Overall, our findings suggested the concept of the EGFR activated OA subpopulation and illustrated the mechanism of EGFR signaling in regulating cartilage homeostasis. Gefitinib could be a promising disease-modifying drug for this OA subpopulation treatment. There is a subpopulation of osteoarthritic patients with high activation level of EGFR (pEGFRhigh). Gefitinib can simultaneously promote ECM synthesis and inhibit further degradation in pEGFRhigh osteoarthritic cartilage. Intra-articular controlled-release of gefitinib could be a therapeutic strategy for pEGFRhigh OA treatment. EGFR activation regulates OA development through inhibition of autophagy. Osteoarthritis (OA) is one of the most prevalent musculoskeletal disorder worldwide, but most treatments in clinics are designed as a “one-size-fits-all-approach”. We found that not all OA patients are the same, and specifically in this case, there is a group of people with high activation level of EGFR, a functional protein in the cells of cartilage. The anti-cancer drug gefitinib was discovered to have multiple functions in protecting articular cartilage from destruction in EGFR activated OA. Our research therefore highlighted the OA subpopulation concept and suggested a novel OA therapeutic strategy.
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影响因子：
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作者：
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通讯作者：
Lotz, Martin
影响因子：
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通讯作者：
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