Sdc4, also known as Syndecan 4, is a cell surface heparan sulfate proteoglycan. It is implicated in regulating various cellular functions such as cytoskeleton regulation, cell adhesion, and cell migration. It is involved in multiple signaling pathways, like the MAPK signaling pathway, and has been associated with the PI3K/AKT pathway where it can downregulate AKT1 gene expression [2,4]. Sdc4 is of great biological importance as it impacts diverse physiological and pathological processes. Genetic models, such as knockout mouse models, have been crucial for studying its functions.

In Sdc4 global knockout (KO) mice, vertebral trabecular and cortical bone mass was severely reduced, and biomechanical properties of vertebrae were altered. These changes were likely due to elevated osteoclastic activity. Also, there were subtle phenotypic changes in the intervertebral disc, with reduced mature collagen crosslinks and increased chondroitin sulfate levels in specific disc compartments. Transcriptomic analysis of the nucleus pulposus tissue in KO mice showed dysregulation in heparan sulfate GAG degradation, mitochondria metabolism, autophagy, and protein processing pathways [1]. In pancreatic cancer cells, knocking out SDC4 markedly impaired macropinocytosis, colony formation, as well as xenograft tumor initiation and growth [2]. In osteosarcoma, a positive feedback loop was observed between SDC4 and TGF-β signaling, where knockdown of ZFP36L1 promoted cell migration by activating TGF-β signaling and increasing SDC4 expression [3].

In conclusion, Sdc4 is essential for maintaining vertebral bone and extracellular matrix homeostasis in the intervertebral disc. It also plays significant roles in cancer-influencing tumor cell behaviors such as macropinocytosis, colony formation, and metastasis. Gene knockout mouse models have been instrumental in uncovering these functions, providing valuable insights into diseases like osteoporosis-related spine conditions and various cancers [1,2,3].

References:

1. Sao, Kimheak, Risbud, Makarand V. 2024. Sdc4 deletion perturbs intervertebral disc matrix homeostasis and promotes early osteopenia in the aging mouse spine. In Matrix biology : journal of the International Society for Matrix Biology, 131, 46-61. doi:10.1016/j.matbio.2024.05.006. https://pubmed.ncbi.nlm.nih.gov/38806135/

2. Cui, Can, Pan, Yuting, Zhang, Chengqian, Zhou, Xianglian, Qu, Yi. 2022. Eltrombopag binds SDC4 directly and enhances MAPK signaling and macropinocytosis in cancer cells. In American journal of cancer research, 12, 2697-2710. doi:. https://pubmed.ncbi.nlm.nih.gov/35812066/

3. Ma, Mengjun, Zhuang, Jiahao, Li, Hongyu, Wu, Yanfeng, Shen, Huiyong. 2023. Low expression of ZFP36L1 in osteosarcoma promotes lung metastasis by inhibiting the SDC4-TGF-β signaling feedback loop. In Oncogene, 43, 47-60. doi:10.1038/s41388-023-02880-7. https://pubmed.ncbi.nlm.nih.gov/37935976/

4. Vuorinen, Sofia I, Okolicsanyi, Rachel K, Gyimesi, Martina, Griffiths, Lyn R, Haupt, Larisa M. 2022. SDC4-rs1981429 and ATM-rs228590 may provide early biomarkers of breast cancer risk. In Journal of cancer research and clinical oncology, 149, 4563-4578. doi:10.1007/s00432-022-04236-2. https://pubmed.ncbi.nlm.nih.gov/36152082/