Department of Life Science and Bioinformatics, Biotech Hub, Assam University, Silchar, Assam, India.
Department of Life Science and Bioinformatics, Biotech Hub, Assam University, Silchar, Assam, India.
Pharmacol Rep. 2019 Jun;71(3):399-408. doi: 10.1016/j.pharep.2019.01.007. Epub 2019 Jan 15.
Discoidin domain receptor2 (DDR2), a cell membrane tyrosine kinase on chondrocytes surface plays main role in cell-ECM interaction during the progressive degeneration of articular cartilage in osteoarthritis. The degraded component of ECM, type II collagen upon DDR2 binding provokes synthesis of matrix metalloproteinases (MMPs), responsible for severe destruction of joint tissues. DDR2 knockout has been investigated to decline the expression of MMP-1 and 13. Previously, various molecules were effective in preclinical level against different targets in OA, but found to be collapsed in clinical trial due to insufficient target specificity and clinical toxicity. Review emphasizes the role of DDR2 in the degeneration of cartilage in osteoarthritis (OA) and its blocking by DDR2 antagonist attenuates the disease severity. DDR2 in chondrocytes contributes paramount role in degradation of cartilage at early stage of osteoarthritis via collagen 2 binding through the felicitation of TGF-β signaling molecule and other triggering factors. DDR2 involvement in regulation of matrix metalloproteinase (MMP), cross talking interaction in maintenance of ECM-chondrocytes, bone developments, interference RNA and designing the DDR2 antagonists have been critically investigated. The exploration may conclude that the DDR2 could be the novel pharmacological target to prevent the progression of osteoarthritis at early stage because of over expression of DDR2 and MMP which further promotes severe cartilage degeneration. Owing to pharmacological specificity of DDR2 in OA as drug target, it is to be hypothesized that development of safe molecules as DDR2 antagonist could be the good option in the treatment of OA with promising landmark.
Discoidin domain receptor2 (DDR2)，一种位于软骨细胞表面的细胞膜酪氨酸激酶，在骨关节炎中关节软骨进行性退变过程中，在细胞-细胞外基质相互作用中起主要作用。细胞外基质的降解成分，与 DDR2 结合后会引发基质金属蛋白酶 (MMPs)的合成，导致关节组织的严重破坏。DDR2 敲除已被研究用于降低 MMP-1 和 MMP-13 的表达。先前，针对 OA 的不同靶点，各种分子在临床前水平都有一定的效果，但由于缺乏足够的靶向特异性和临床毒性，在临床试验中失败。综述强调了 DDR2 在骨关节炎 (OA) 软骨退变中的作用，以及 DDR2 拮抗剂的阻断作用可减轻疾病的严重程度。DDR2 在软骨细胞中通过与 II 型胶原结合，通过促进 TGF-β 信号分子和其他触发因子，在 OA 的早期阶段对软骨降解起着至关重要的作用。DDR2 在调节基质金属蛋白酶 (MMP)、维持细胞外基质-软骨细胞、骨骼发育、干扰 RNA 和设计 DDR2 拮抗剂方面的作用已受到严格研究。研究可能得出结论，由于 DDR2 和 MMP 的过度表达进一步促进了严重的软骨退化，因此 DDR2 可能成为预防早期骨关节炎进展的新的药理学靶点。由于 DDR2 在 OA 中的药理学特异性作为药物靶点，可以假设开发安全的 DDR2 拮抗剂分子可能是治疗 OA 的一个很好的选择，具有有前景的里程碑。
