Rgs12, the largest protein in the RGS protein family, is a key regulator involved in multiple biological processes. It plays a crucial role in inflammation, bone remodeling, and is associated with pathways like Hippo, NF-κB, and G-protein signaling. Genetic models, such as KO/CKO mouse models, have been essential in uncovering its functions [1-10].

In various disease models, Rgs12 shows distinct roles. In the ligature-induced periodontitis model, ablation of Rgs12 in Mx1+ hematopoietic cells blocked bone loss, inhibited osteoclast formation and inflammatory cytokine production [1]. In an orthotopic xenograft mouse model of osteosarcoma, depletion of Rgs12 promoted tumor progression and lung metastasis, with Rgs12 identified as a tumor suppressor via inhibiting YAP-TEAD1-Ezrin signaling [2]. In the collagen-induced arthritis model, deletion of Rgs12 in myeloid lineage or globally inhibited the development of arthritis [3]. For oral cancer, Rgs12 knockout mice showed more aggressive tumors, and Rgs12 was found to regulate PTEN phosphorylation and SUMOylation to repress cancer [4]. In osteoarthritis models, Rgs12 deficiency in macrophages prevented ubiquitination-related inflammation and cartilage damage [5]. In oral squamous cell carcinoma, Rgs12 knockout in macrophages led to decreased M1 TAMs and increased cancer cell proliferation [6]. In Rgs12 mouse mutants, there was deafness due to defective organization of stereocilia in sensory hair cells [7]. In chondrocyte-lineage Rgs12-deficient mice, there were issues in skeletal development due to defective mitochondrial function [8]. In the inflammatory arthritis model, Rgs12 knockout inhibited angiogenesis and disease development [9]. In African American prostate cancer models, Rgs12 was identified as a tumor-suppressor gene [10].

In conclusion, Rgs12 is a multifunctional gene involved in inflammation, bone remodeling, and tumorigenesis. KO/CKO mouse models have been instrumental in revealing its role in periodontitis, osteosarcoma, inflammatory arthritis, oral cancer, osteoarthritis, sensory hair cell function, skeletal development, and prostate cancer, providing insights into potential therapeutic targets for these diseases.

References:

1. Yuan, G, Fu, C, Yang, S T, Hajishengallis, G, Yang, S. 2021. RGS12 Drives Macrophage Activation and Osteoclastogenesis in Periodontitis. In Journal of dental research, 101, 448-457. doi:10.1177/00220345211045303. https://pubmed.ncbi.nlm.nih.gov/34796776/

2. Li, Yang, Liu, Min, Yang, Shuting, Karin Eisinger-Mathason, T S, Yang, Shuying. 2021. RGS12 is a novel tumor suppressor in osteosarcoma that inhibits YAP-TEAD1-Ezrin signaling. In Oncogene, 40, 2553-2566. doi:10.1038/s41388-020-01599-z. https://pubmed.ncbi.nlm.nih.gov/33686240/

3. Yuan, Gongsheng, Yang, Shuting, Ng, Andrew, Xing, Lianping, Yang, Shuying. 2020. RGS12 Is a Novel Critical NF-κB Activator in Inflammatory Arthritis. In iScience, 23, 101172. doi:10.1016/j.isci.2020.101172. https://pubmed.ncbi.nlm.nih.gov/32512384/

4. Fu, C, Yuan, G, Yang, S T, Zhang, D, Yang, S. 2020. RGS12 Represses Oral Cancer via the Phosphorylation and SUMOylation of PTEN. In Journal of dental research, 100, 522-531. doi:10.1177/0022034520972095. https://pubmed.ncbi.nlm.nih.gov/33198557/

5. Yuan, Gongsheng, Yang, Shuting, Yang, Shuying. 2021. Macrophage RGS12 contributes to osteoarthritis pathogenesis through enhancing the ubiquitination. In Genes & diseases, 9, 1357-1367. doi:10.1016/j.gendis.2021.08.005. https://pubmed.ncbi.nlm.nih.gov/35873013/

6. Yuan, Gongsheng, Yang, Shuting, Yang, Shuying. 2023. RGS12 represses oral squamous cell carcinoma by driving M1 polarization of tumor-associated macrophages via controlling ciliary MYCBP2/KIF2A signaling. In International journal of oral science, 15, 11. doi:10.1038/s41368-023-00216-5. https://pubmed.ncbi.nlm.nih.gov/36797232/

7. Akturk, Anil, Day, Matthew, Tarchini, Basile. 2022. RGS12 polarizes the GPSM2-GNAI complex to organize and elongate stereocilia in sensory hair cells. In Science advances, 8, eabq2826. doi:10.1126/sciadv.abq2826. https://pubmed.ncbi.nlm.nih.gov/36260679/

8. Yuan, Gongsheng, Yang, Shuting, Liu, Min, Yang, Shuying. 2020. RGS12 is required for the maintenance of mitochondrial function during skeletal development. In Cell discovery, 6, 59. doi:10.1038/s41421-020-00190-w. https://pubmed.ncbi.nlm.nih.gov/32922858/

9. Yuan, Gongsheng, Yang, Shu-Ting, Yang, Shuying. 2022. Endothelial RGS12 governs angiogenesis in inflammatory arthritis by controlling cilia formation and elongation via MYCBP2 signaling. In Cell insight, 1, 100055. doi:10.1016/j.cellin.2022.100055. https://pubmed.ncbi.nlm.nih.gov/37193553/

10. Wang, Yongquan, Wang, Jianghua, Zhang, Li, Creighton, Chad J, Ittmann, Michael. 2017. RGS12 Is a Novel Tumor-Suppressor Gene in African American Prostate Cancer That Represses AKT and MNX1 Expression. In Cancer research, 77, 4247-4257. doi:10.1158/0008-5472.CAN-17-0669. https://pubmed.ncbi.nlm.nih.gov/28611045/