Delayed tooth movement in Runx2+/− mice associated with mTORC2 in stretch-induced bone formation
| Autor: | Takashi Yamashiro, Irma Thesleff, Teruko Takano-Yamamoto, Nagato Tamamura, Tomo Aonuma, Tomohiro Fukunaga, Nobuo Takeshita, Yuichi Sakai, Shohei Shigemi |
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| Přispěvatelé: | Institute of Biotechnology |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
musculoskeletal diseases Stromal cell lcsh:Diseases of the musculoskeletal system Mechanical stress Endocrinology Diabetes and Metabolism 030209 endocrinology & metabolism mTORC2 Article Bone remodeling 03 medical and health sciences 0302 clinical medicine stomatognathic system medicine Orthopedics and Sports Medicine Protein kinase B PI3K/AKT/mTOR pathway biology Chemistry musculoskeletal neural and ocular physiology Osteoblast Experimental tooth movement 1184 Genetics developmental biology physiology musculoskeletal system Runx2+/− mice 313 Dentistry Cell biology RUNX2 medicine.anatomical_structure Osteocalcin biology.protein 030101 anatomy & morphology BMSCs lcsh:RC925-935 |
| Zdroj: | Bone Reports, Vol 12, Iss, Pp 100285-(2020) Bone Reports |
| ISSN: | 2352-1872 |
| Popis: | Runt-related transcription factor 2 (Runx2) is an essential transcription factor for osteoblast differentiation, and is activated by mechanical stress to promote osteoblast function. Cleidocranial dysplasia (CCD) is caused by mutations of RUNX2, and CCD patients exhibit malocclusion and often need orthodontic treatment. However, treatment is difficult because of impaired tooth movement, the reason of which has not been clarified. We examined the amount of experimental tooth movement in Runx2+/− mice, the animal model of CCD, and investigated bone formation on the tension side of experimental tooth movement in vivo. Continuous stretch was conducted to bone marrow stromal cells (BMSCs) as an in vitro model of the tension side of tooth movement. Compared to wild-type littermates the Runx2+/− mice exhibited delayed experimental tooth movement, and osteoid formation and osteocalcin (OSC) mRNA expression were impaired in osteoblasts on the tension side of tooth movement. Runx2 heterozygous deficiency delayed stretch-induced increase of DNA content in BMSCs, and also delayed and reduced stretch-induced alkaline phosphatase (ALP) activity, OSC mRNA expression, and calcium content of BMSCs in osteogenic medium. Furthermore Runx2+/− mice exhibited delayed and suppressed expression of mammalian target of rapamycin (mTOR) and rapamycin-insensitive companion of mTOR (Rictor), essential factors of mTORC2, which is regulated by Runx2 to phosphorylate Akt to regulate cell proliferation and differentiation, in osteoblasts on the tension side of tooth movement in vivo and in vitro. Loss of half Runx2 gene dosage inhibited stretch-induced PI3K dependent mTORC2/Akt activity to promote BMSCs proliferation. Furthermore, Runx2+/− BMSCs in osteogenic medium exhibited delayed and suppressed stretch-induced expression of mTOR and Rictor. mTORC2 regulated stretch-elevated Runx2 and ALP mRNA expression in BMSCs in osteogenic medium. We conclude that Runx2+/− mice present a useful model of CCD patients for elucidation of the molecular mechanisms in bone remodeling during tooth movement, and that Runx2 plays a role in stretch-induced proliferation and osteogenesis in BMSCs via mTORC2 activation. Highlights • Experimental tooth movement is delayed in Runx2+/− mice compared with wild-type mice. • Runx2 plays a role in stretch-induced proliferation and differentiation of BMSCs via mTORC2 activation. • Runx2+/− mice are useful model to clarify the mechanical stress-induced bone remodeling in CCD patients. |
| Databáze: | OpenAIRE |
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