Plod2, encoding lysyl hydroxylases 2, is a key enzyme mediating the formation of stabilized collagen cross-links. Collagen is the major protein of the extracellular matrix (ECM), and Plod2-regulated collagen organization is crucial for various biological processes. It has been associated with pathways like HIF-1α, TGF-β, and microRNA-26a/b regulation, and plays a significant role in cancer and musculoskeletal repair [1,5].

In cancer, loss-of-function studies have shown that depletion of PLOD2 reduces the proliferation and migration of clear cell renal cell carcinoma (ccRCC) cells both in vitro and in vivo. PLOD2 is transcriptionally activated by HIF1A in ccRCC, and it interacts with EGFR to activate the AKT signaling pathway, promoting ccRCC progression. In osteosarcoma, knockdown of PLOD2 antagonizes lung metastasis in mice. Also, in glioblastoma, PLOD2 knockdown inhibits tumor proliferation, invasion, and anchorage-independent growth. In colorectal cancer, overexpression of PLOD2 facilitates proliferation, invasion, and metastasis, and minoxidil, a PLOD2 inhibitor, suppresses these effects [2,3,4,6]. In the context of musculoskeletal repair, zeugopod mesenchymal cell-specific deletion of Hif1α (downstream of which lies the PLOD2/LOX pathway for collagen cross-linking) significantly mitigates heterotopic ossification (HO) in a mouse injury-induced HO model [5].

In conclusion, Plod2 is essential for collagen cross-linking and ECM organization. Model-based research, especially through gene knockout or knockdown in mouse models, has revealed its oncogenic role in multiple cancers, promoting tumor cell proliferation, migration, and metastasis. In musculoskeletal repair, it is involved in aberrant repair processes like HO. Understanding Plod2 through these models provides insights into disease mechanisms and potential therapeutic targets for cancer and musculoskeletal disorders.

References:

1. Du, Hongzhi, Pang, Mao, Hou, Xiaoying, Yuan, Shengtao, Sun, Li. 2017. PLOD2 in cancer research. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 90, 670-676. doi:10.1016/j.biopha.2017.04.023. https://pubmed.ncbi.nlm.nih.gov/28415047/

2. Liu, Tao, Xiang, Wan, Chen, Zhizhuang, Luo, Yongwen, Chen, Liang. 2023. Hypoxia-induced PLOD2 promotes clear cell renal cell carcinoma progression via modulating EGFR-dependent AKT pathway activation. In Cell death & disease, 14, 774. doi:10.1038/s41419-023-06298-7. https://pubmed.ncbi.nlm.nih.gov/38008826/

3. Trang, Nguyen Thi Nha, Lai, Chao-Yang, Tsai, Hsiao-Chi, Tzeng, Huey-En, Tang, Chih-Hsin. 2023. Apelin promotes osteosarcoma metastasis by upregulating PLOD2 expression via the Hippo signaling pathway and hsa_circ_0000004/miR-1303 axis. In International journal of biological sciences, 19, 412-425. doi:10.7150/ijbs.77688. https://pubmed.ncbi.nlm.nih.gov/36632453/

4. Kreße, Nina, Schröder, Hannah, Stein, Klaus-Peter, Sandalcioglu, Ibrahim Erol, Dumitru, Claudia Alexandra. 2022. PLOD2 Is a Prognostic Marker in Glioblastoma That Modulates the Immune Microenvironment and Tumor Progression. In International journal of molecular sciences, 23, . doi:10.3390/ijms23116037. https://pubmed.ncbi.nlm.nih.gov/35682709/

5. Kang, Heeseog, Strong, Amy L, Sun, Yuxiao, Tower, Robert J, Levi, Benjamin. 2024. The HIF-1α/PLOD2 axis integrates extracellular matrix organization and cell metabolism leading to aberrant musculoskeletal repair. In Bone research, 12, 17. doi:10.1038/s41413-024-00320-0. https://pubmed.ncbi.nlm.nih.gov/38472175/

6. Lan, Jiawen, Zhang, Sijing, Zheng, Lin, Zhou, Miao, Zhou, Jun. 2023. PLOD2 promotes colorectal cancer progression by stabilizing USP15 to activate the AKT/mTOR signaling pathway. In Cancer science, 114, 3190-3202. doi:10.1111/cas.15851. https://pubmed.ncbi.nlm.nih.gov/37227305/