Runx2 Expression in Smooth Muscle Cells Is Required for Arterial Medial Calcification in Mice
| Autor: | Mu-En Lin, Elizabeth M. Leaf, Mei Y. Speer, Theodore M. Chen, Cecilia M. Giachelli |
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| Rok vydání: | 2015 |
| Předmět: |
Male
musculoskeletal diseases Pathology medicine.medical_specialty Transgene Myocytes Smooth Muscle Cell Core Binding Factor Alpha 1 Subunit Mice Transgenic Biology Phosphates Pathology and Forensic Medicine Mice Osteogenesis medicine Animals Humans Myocyte Vitamin D Vascular Calcification Fibroblast Sequence Deletion Calcium metabolism Bone Development Regular Article musculoskeletal system Phenotype Cell biology RUNX2 Disease Models Animal medicine.anatomical_structure Alkaline phosphatase Calcium Female |
| Zdroj: | The American Journal of Pathology. 185:1958-1969 |
| ISSN: | 0002-9440 |
| Popis: | Arterial medial calcification (AMC) is a hallmark of aging, diabetes, and chronic kidney disease. Smooth muscle cell (SMC) transition to an osteogenic phenotype is a common feature of AMC, and is preceded by expression of runt-related transcription factor 2 (Runx2), a master regulator of bone development. Whether SMC-specific Runx2 expression is required for osteogenic phenotype change and AMC remains unknown. We therefore created an improved targeting construct to generate mice with floxed Runx2 alleles (Runx2(f/f)) that do not produce truncated Runx2 proteins after Cre recombination, thereby preventing potential off-target effects. SMC-specific deletion using SM22-recombinase transgenic allele mice (Runx2(ΔSM)) led to viable mice with normal bone and arterial morphology. After vitamin D overload, arterial SMCs in Runx2(f/f) mice expressed Runx2, underwent osteogenic phenotype change, and developed severe AMC. In contrast, vitamin D-treated Runx2(ΔSM) mice had no Runx2 in blood vessels, maintained SMC phenotype, and did not develop AMC. Runx2 deletion did not affect serum calcium, phosphate, fibroblast growth factor-23, or alkaline phosphatase levels. In vitro, Runx2(f/f) SMCs calcified to a much greater extent than those derived from Runx2(ΔSM) mice. These data indicate a critical role of Runx2 in SMC osteogenic phenotype change and mineral deposition in a mouse model of AMC, suggesting that Runx2 and downstream osteogenic pathways in SMCs may be useful therapeutic targets for treating or preventing AMC in high-risk patients. |
| Databáze: | OpenAIRE |
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