ADAMTS4, also known as aggrecanase-1, is a crucial extracellular matrix (ECM)-remodeling enzyme belonging to the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family. It plays a significant role in ECM formation, homeostasis, and remodeling, participating in various biological processes [1,2,4]. ADAMTS4 can cleave specific proteoglycans like versican and NG2, and is involved in pathways related to inflammation, cell differentiation, and cancer progression [2,3,4].

In severe respiratory viral infections, damage-responsive lung fibroblasts produce ADAMTS4, which along with inflammatory cytokines, modifies the lung microenvironment, leading to immune cell infiltration at the expense of lung function, and its levels in the lower respiratory tract are associated with influenza virus infection severity [1]. In the amnion, ADAMTS4 is essential for versican cleavage at parturition, and its induction can lead to preterm birth [2]. Genetic ablation of Adamts4 in mice impedes NG2 proteolysis in oligodendrocyte precursor cells, impairing oligodendrocyte differentiation and axonal myelination, as well as myelin repair in demyelinating conditions [3]. In lung cancer, knockdown of ADAMTS4 inhibits cancer cell proliferation, migration, and HUVEC tubule formation, while overexpression promotes these processes by stabilizing c-Myc and activating the MAPK signaling pathway [4].

In conclusion, ADAMTS4 is vital for ECM-related functions and is involved in multiple disease conditions. Mouse models with Adamts4 gene knockout or knockdown have revealed its role in severe respiratory infections, preterm birth, demyelinating diseases, and cancer progression. Understanding ADAMTS4 can provide potential therapeutic targets for these diseases.

References:

1. Boyd, David F, Allen, E Kaitlynn, Randolph, Adrienne G, Crawford, Jeremy Chase, Thomas, Paul G. 2020. Exuberant fibroblast activity compromises lung function via ADAMTS4. In Nature, 587, 466-471. doi:10.1038/s41586-020-2877-5. https://pubmed.ncbi.nlm.nih.gov/33116313/

2. Li, Meng-Die, Lu, Jiang-Wen, Zhang, Fan, Wang, Wang-Sheng, Sun, Kang. 2024. ADAMTS4 is a crucial proteolytic enzyme for versican cleavage in the amnion at parturition. In Communications biology, 7, 301. doi:10.1038/s42003-024-06007-w. https://pubmed.ncbi.nlm.nih.gov/38461223/

3. Jiang, Chunxia, Qiu, Wanwan, Yang, Yingying, Zhao, Xiaofeng, Qiu, Mengsheng. 2023. ADAMTS4 Enhances Oligodendrocyte Differentiation and Remyelination by Cleaving NG2 Proteoglycan and Attenuating PDGFRα Signaling. In The Journal of neuroscience : the official journal of the Society for Neuroscience, 43, 4405-4417. doi:10.1523/JNEUROSCI.2146-22.2023. https://pubmed.ncbi.nlm.nih.gov/37188512/

4. Zhai, Wei, Yang, Wensheng, Ge, Jing, Luo, Shiya, Pu, Xingxiang. 2024. ADAMTS4 exacerbates lung cancer progression via regulating c-Myc protein stability and activating MAPK signaling pathway. In Biology direct, 19, 94. doi:10.1186/s13062-024-00512-y. https://pubmed.ncbi.nlm.nih.gov/39415271/