Mmp15, also known as MT2-MMP, is a member of the membrane-type (MT) MMPs subgroup of matrix metalloproteinases [1]. MMPs are zinc-containing endopeptidases capable of degrading extracellular matrix (ECM) proteins, and Mmp15 is involved in processes such as extracellular matrix remodeling, which is crucial for normal tissue development and homeostasis. It is associated with signaling pathways like JNK/Sp1-mediated transcription [2].

In endothelial-to-mesenchymal transformation and endocardial cushion development, Snai1 directly regulates Mmp15, as snai1 knockdown in mice led to decreased Mmp15 expression and hypocellular endocardial cushions, while Snai1 overexpression promoted Mmp15 expression, cell transformation, and mesenchymal cell migration [3]. In early postnatal mammary gland development in mice, although Mmp15 knockout mice can still generate intact ductal networks, transcriptome profiling shows it has a role in regulating mammary gland adipocyte differentiation, controlling the formation of thermogenic brown fat [4]. In medaka, gap junction blockers inhibited follicular Mmp15 expression and ovulation, indicating a role of Mmp15 in fish reproduction [5]. In Pkd1l1-deficient mice, which phenocopy syndromic biliary atresia, there was increased expression of Mmp15 along with other fibrosis and extracellular matrix remodeling genes [6]. In early-stage breast cancer, cytoplasmic expression of Mmp15 was an independent risk factor for nonsentinel lymph node metastasis, helping in the establishment of a prediction model [7].

In summary, Mmp15 is essential for extracellular matrix remodeling and plays significant roles in various biological processes including heart development, mammary gland development, fish reproduction, and is associated with diseases like biliary atresia and breast cancer. Gene knockout mouse models have been instrumental in revealing these functions, providing insights into the underlying mechanisms and potential therapeutic targets for related diseases.

References:

1. Pittayapruek, Pavida, Meephansan, Jitlada, Prapapan, Ornicha, Komine, Mayumi, Ohtsuki, Mamitaro. 2016. Role of Matrix Metalloproteinases in Photoaging and Photocarcinogenesis. In International journal of molecular sciences, 17, . doi:10.3390/ijms17060868. https://pubmed.ncbi.nlm.nih.gov/27271600/

2. Lin, Chia-Liang, Ying, Tsung-Ho, Yang, Shun-Fa, Chiou, Hui-Ling, Hsieh, Yi-Hsien. 2023. Magnolin targeting of the JNK/Sp1/MMP15 signaling axis suppresses cervical cancer microenvironment and metastasis via microbiota modulation. In Cancer letters, 583, 216584. doi:10.1016/j.canlet.2023.216584. https://pubmed.ncbi.nlm.nih.gov/38123014/

3. Tao, Ge, Levay, Agata K, Gridley, Thomas, Lincoln, Joy. 2011. Mmp15 is a direct target of Snai1 during endothelial to mesenchymal transformation and endocardial cushion development. In Developmental biology, 359, 209-21. doi:10.1016/j.ydbio.2011.08.022. https://pubmed.ncbi.nlm.nih.gov/21920357/

4. Feinberg, Tamar Y, Rowe, R Grant, Saunders, Thomas L, Weiss, Stephen J. 2016. Functional roles of MMP14 and MMP15 in early postnatal mammary gland development. In Development (Cambridge, England), 143, 3956-3968. doi:. https://pubmed.ncbi.nlm.nih.gov/27633994/

5. Hagiwara, Akane, Ogiwara, Katsueki, Sugama, Natsu, Yamashita, Masakane, Takahashi, Takayuki. 2019. Inhibition of medaka ovulation by gap junction blockers due to its disrupting effect on the transcriptional process of LH-induced Mmp15 expression. In General and comparative endocrinology, 288, 113373. doi:10.1016/j.ygcen.2019.113373. https://pubmed.ncbi.nlm.nih.gov/31874135/

6. Lim, Yi Zou, Zhu, Min, Wang, Yunguan, Zhu, Hao, Corbitt, Natasha. 2024. Pkd1l1-deficiency drives biliary atresia through ciliary dysfunction in biliary epithelial cells. In Journal of hepatology, 81, 62-75. doi:10.1016/j.jhep.2024.02.031. https://pubmed.ncbi.nlm.nih.gov/38460793/

7. Zeng, Xue, Li, Yubing, Sun, Chaonan, Zhang, Yanyu, Zhang, Na. 2022. A New Model for Predicting Nonsentinel Lymph Node Metastasis in Early-Stage Breast Cancer Using MMP15. In Journal of oncology, 2022, 8675705. doi:10.1155/2022/8675705. https://pubmed.ncbi.nlm.nih.gov/36035312/