Homeobox protein MSX‐1 inhibits expression of bone morphogenetic protein 2, bone morphogenetic protein 4, and lymphoid enhancer‐binding factor 1 via Wnt/β‐catenin signaling to prevent differentiation of dental mesenchymal cells during the late bell stage

Homeobox protein MSX‐1 (hereafter referred to as MSX‐1) is essential for early tooth‐germ development. Tooth‐germ development is arrested at bud stage in Msx1 knockout mice, which prompted us to study the functions of MSX‐1 beyond this stage. Here, we investigated the roles of MSX‐1 during late bell stage. Mesenchymal cells of the mandibular first molar were isolated from mice at embryonic day (E)17.5 and cultured in vitro. We determined the expression levels of β‐catenin, bone morphogenetic protein 2 (Bmp2), Bmp4, and lymphoid enhancer‐binding factor 1 (Lef1) after knockdown or overexpression of Msx1. Our findings suggest that knockdown of Msx1 promoted expression of Bmp2, Bmp4, and Lef1, resulting in elevated differentiation of odontoblasts, which was rescued by blocking the expression of these genes. In contrast, overexpression of Msx1 decreased the expression of Bmp2, Bmp4, and Lef1, leading to a reduction in odontoblast differentiation. The regulation of Bmp2, Bmp4, and Lef1 by Msx1 was mediated by the Wnt/β‐catenin signaling pathway. Additionally, knockdown of Msx1 impaired cell proliferation and slowed S‐phase progression, while overexpression of Msx1 also impaired cell proliferation and prolonged G1‐phase progression. We therefore conclude that MSX‐1 maintains cell proliferation by regulating transition of cells from G1‐phase to S‐phase and prevents odontoblast differentiation by inhibiting expression of Bmp2, Bmp4, and Lef1 at the late bell stage via the Wnt/β‐catenin signaling pathway.     

A prospective,randomized pilot study on the safety and efficacy of recombinant human growth and differentiation factor‐5 coated onto β‐tricalcium phosphate for sinus lift augmentation

Objectives: The aim of this prospective, randomized clinical trial was to investigate the potential of recombinant human growth and differentiation factor‐5 (rhGDF‐5) coated onto β‐tricalcium phosphate (β‐TCP) (rhGDF‐5/β‐TCP) to support bone formation after sinus lift augmentation. Material and methods: In total, 31 patients participated in this multicenter clinical trial. They required a two‐stage unilateral maxillary sinus floor augmentation (residual bone height <5 mm). According to a parallel‐group design, the patients were randomized to three treatment groups: (a) augmentation with rhGDF‐5/β‐TCP and a 3‐month healing period, (b) augmentation with rhGDF‐5/β‐TCP and a 4‐month healing period and (c) medical device β‐TCP mixed with autologous bone and a 4‐month healing period. The primary study objective was the area of newly formed bone within the augmented area as assessed by histomorphometric evaluation of trephine bur biopsies. Results: The osseous regeneration was similar in each treatment group; the amount of newly formed bone ranged between 28% (± 15.5%) and 31.8% (± 17.9%). Detailed analysis of histological data will be published elsewhere. As secondary efficacy variables, the augmentation height at the surgery site was measured by radiography. The largest augmentation was radiologically achieved in the rhGDF‐5/β‐TCP – 3‐month and the rhGDF‐5/β‐TCP – 4‐month treatment groups. As safety parameters, adverse events were recorded and anti‐drug antibody levels were evaluated. Most of the adverse events were judged as unrelated to the study medication. Four out of 47 (8.5%) implants failed in patients treated with rhGDF‐5/β‐TCP, a result that is in agreement with the general implant failure rate of 5–15%. Transiently very low amounts of anti‐rhGDF‐5 antibodies were detected in some patients who received rhGDF‐5, which was not related to the bone formation outcome. Conclusion: rhGDF‐5/β‐TCP was found to be effective and safe as the control treatment with autologous bone mixed β‐TCP in sinus floor augmentation. Thus, further investigation regarding efficacy and safety will be carried out in larger patient populations. To cite this article:
Koch FP, Becker J, Terheyden H, Capsius B, Wagner W, on behalf of the research group of this multicenter clinical trial. A prospective, randomized pilot study on the safety and efficacy of recombinant human growth and differentiation factor‐5 coated onto β‐tricalcium phosphate for sinus lift augmentation.
Clin. Oral Impl. Res. 21 , 2010; 1301–1308.
doi: 10.1111/j.1600‐0501.2010.01949.x