Regulation of MDM2 E3 ligase-dependent vascular calcification by MSX1/2

• Published in: Experimental & molecular medicine 2021, 53(0), , pp.1-11
• Main Authors: Kwon, Duk-Hwa, Choe, Nakwon, Shin, Sera, Ryu, Juhee, Kim, Nacksung, Eom, Gwang Hyeon, Nam, Kwang-Il, Kim, Hyung Seok, Ahn, Youngkeun, Kim, Young-Kook, Park, Woo Jin, Mendrysa, Susan M., Kook, Hyun
• Format: Article
• Language: English
• Subjects: 13/51; 13/89; 14/19; 42/109; 42/44; 631/136/1425; 631/208/200; 64/110; 64/60; 82/1; Animal models; Animals; Biomarkers; Biomedical and Life Sciences; Biomedicine; Blood vessels; Calcification; Calcification (ectopic); Calcium (blood); Calcium - metabolism; Calcium phosphates; Cardiovascular diseases; Clinical trials; Coronary artery; Crystals; Disease Models, Animal; Disease Susceptibility; Gene Expression Regulation; Gene Knockdown Techniques; Histone deacetylase; Homeobox; Homeodomain Proteins - metabolism; Humans; Male; MDM2 protein; Medical Biochemistry; Metabolic syndrome; Mice; Mice, Knockout; Models, Biological; Molecular Medicine; Morbidity; MSX1 Transcription Factor - metabolism; Msx2 protein; Mutation; Patients; Promoter Regions, Genetic; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; Renal failure; Response Elements; Salts; Signal transduction; Stem Cells; Therapeutic applications; Transcription activation; Transgenic mice; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Vascular Calcification - etiology; Vascular Calcification - metabolism; Vascular Calcification - pathology; Vascular diseases; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-021-00708-6

Vascular calcification increases morbidity and mortality in patients with cardiovascular and renal diseases. Previously, we reported that histone deacetylase 1 prevents vascular calcification, whereas its E3 ligase, mouse double minute 2 homolog (MDM2), induces vascular calcification. In the present study, we identified the upstream regulator of MDM2. By utilizing cellular models and transgenic mice, we confirmed that E3 ligase activity is required for vascular calcification. By promoter analysis, we found that both msh homeobox 1 (Msx1) and msh homeobox 2 (Msx2) bound to the MDM2 promoter region, which resulted in transcriptional activation of MDM2. The expression levels of both Msx1 and Msx2 were increased in mouse models of vascular calcification and in calcified human coronary arteries. Msx1 and Msx2 potentiated vascular calcification in cellular and mouse models in an MDM2-dependent manner. Our results establish a novel role for MSX1/MSX2 in the transcriptional activation of MDM2 and the resultant increase in MDM2 E3 ligase activity during vascular calcification. Vascular disease: Driver of deposition of calcium salts identified The identification of a signaling pathway involved in triggering vascular calcification, the deposition of calcium phosphate crystals in blood vessels, could inform new therapeutic interventions for related cardiovascular complications. Vascular calcification causes significant complications in patients with metabolic syndrome, renal failure, or cardiovascular disease. In their previous work, Hyun Kook and Duk-Hwa Kwon at Chonnam National University Medical School, Jeollanamdo, Republic of Korea, and coworkers demonstrated that the E3 ligase activity of a protein called MDM2 induces calcification. Now, following further mouse trials, the team have identified an upstream signaling pathway involving several development proteins such as MSX1 and MSX2 which activate MDM2. The activation of this signaling axis leads to the degradation of a key protein that would otherwise prevent calcification. The results may provide a platform for novel therapies targeting the condition.