Zhang Yihe, Jiang Bingjie, Zhang Pengyuan, Chiu Sung K, Lee Meng H
Department of Biological Sciences/Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, China.
Shanghai XP Biomed Ltd, Shanghai, China.
Bone Joint Res. 2022 Nov;11(11):763-776. doi: 10.1302/2046-3758.1111.BJR-2022-0147.R2.
Tissue inhibitors of metalloproteinases (TIMPs) are the endogenous inhibitors of the zinc-dependent matrix metalloproteinases (MMP) and A disintegrin and metalloproteinases (ADAM) involved in extracellular matrix modulation. The present study aims to develop the TIMPs as biologics for osteoclast-related disorders.
We examine the inhibitory effect of a high affinity, glycosyl-phosphatidylinositol-anchored TIMP variant named 'T1' on receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced osteoclast differentiation.
Osteoclast progenitor cells transduced with T1 failed to form tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts or exhibit bone-resorbing activity following treatment with RANKL. At the messenger RNA level, T1 strongly attenuated expression of key osteoclast marker genes that included , , osteoclast stimulatory transmembrane protein (), dendritic cell-specific transmembrane protein (), osteoclast-associated receptor () and ATPase H-transporting V0 subunit d2 () by blocking autoamplification of nuclear factor of activated T cells 1 (NFATc1), the osteoclastogenic transcription factor. T1 selectively extended p44/42 mitogen-activated protein kinase activation, an action that may have interrupted terminal differentiation of osteoclasts. Inhibition studies with broad-spectrum hydroxamate inhibitors confirmed that the anti-resorptive activity of T1 was not reliant on its metalloproteinase-inhibitory activity.
T1 disrupts the RANKL-NFATc1 signalling pathway, which leads to osteoclast dysfunction. As a novel candidate in the prevention of osteoclastogenesis, the TIMP could potentially be developed for the treatment of osteoclast-related disorders such as osteoporosis.Cite this article: 2022;11(11):763-776.
金属蛋白酶组织抑制剂（TIMPs）是参与细胞外基质调节的锌依赖性基质金属蛋白酶（MMP）和去整合素金属蛋白酶（ADAM）的内源性抑制剂。本研究旨在开发TIMPs作为治疗破骨细胞相关疾病的生物制剂。
我们检测了一种名为“T1”的高亲和力、糖基磷脂酰肌醇锚定的TIMP变体对核因子κB受体活化因子配体（RANKL）诱导的破骨细胞分化的抑制作用。
用T1转导的破骨细胞祖细胞在接受RANKL处理后，未能形成抗酒石酸酸性磷酸酶（TRAP）阳性破骨细胞，也未表现出骨吸收活性。在信使RNA水平上，T1通过阻断活化T细胞核因子1（NFATc1）（破骨细胞生成转录因子）的自动扩增，强烈减弱了关键破骨细胞标志物基因的表达，这些基因包括、、破骨细胞刺激跨膜蛋白（）、树突状细胞特异性跨膜蛋白（）、破骨细胞相关受体（）和ATP酶H转运V0亚基d2（）。T1选择性地延长了p44/42丝裂原活化蛋白激酶的激活，这一作用可能中断了破骨细胞的终末分化。用广谱异羟肟酸抑制剂进行的抑制研究证实，T1的抗吸收活性不依赖于其金属蛋白酶抑制活性。
T1破坏RANKL-NFATc1信号通路，导致破骨细胞功能障碍。作为预防破骨细胞生成的新型候选药物，TIMP有可能被开发用于治疗破骨细胞相关疾病，如骨质疏松症。引用本文：2022；11（11）：763-776。
