LY3023414 inhibits both osteogenesis and osteoclastogenesis through the PI3K/Akt/GSK3 signalling pathway

Aims LY3023414 is a novel oral phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitor designed for advanced cancers, for which a phase II clinical study was completed in March 2020; however, little is known about its effect on bone modelling/remodelling. In this study, we aimed to explore the function of LY3023414 in bone modelling/remodelling. Methods The function of LY3023414 was explored in the context of osteogenesis (bone formation by osteoblasts) and osteoclastogenesis (osteoclast formation and bone resorption). Murine preosteoblast MC3T3-E1 cell line and murine bone marrow-derived macrophage cells (BMMs) were subjected to different treatments. An MTS cell proliferation assay was used to examine the cytotoxicity. Thereafter, different induction conditions were applied, such as MCSF and RANKL for osteoclastogenesis and osteogenic media for osteogenesis. Specific staining, a bone resorption assay, and quantitative real-time polymerase chain reaction (qRT-PCR) were subsequently used to evaluate the effect of LY3023414. Moreover, small interfering RNA (siRNA) was applied to knockdown Akt1 or Akt2 for further validation. Lastly, western blot was used to examine the exact mechanism of action. Results LY3023414 attenuated PI3K/protein kinase B (Akt)/GSK3-dependent activation of β-catenin and nuclear factor-activated T cell 1 (NFATc1) during osteogenesis and osteoclastogenesis, respectively. LY3023414 mainly inhibited osteoclast formation instead of mature osteoclast function. Moreover, it suppressed osteogenesis both in the early stage of differentiation and late stage of calcification. Similarly, gene knockdown of Akt isoforms by siRNA downregulated osteogenic and osteoclastogenic processes, indicating that Akt1 and Akt2 acted synergistically. Conclusion LY3023414 can suppress osteogenesis and osteoclastogenesis through inhibition of the PI3K/Akt/GSK3 signalling pathway, which highlights the potential benefits and side effects of LY3023414 for future clinical applications. Cite this article: Bone Joint Res 2021;10(4):237–249.

Root Membrane Technique-An Insight

There are different treatment options in modern dentistry for the replacement of lost dentition. Of these the most upcoming and acceptable treatment option is Dental implants. The common problem usually with immediate implant placement in the anterior region is the post-operative soft tissue contour as a part of the bone modelling during healing. Hurzeler et al in 2010 introduced a new technique called the “socket shield technique”. This technique has been used as an alternative treatment modality for immediate implant placement in the aesthetic zone.This review articles provides a detailed information regarding the clinical concept of Root membrane technique.

Computational Analysis of Resistance to Alveolar Bone Resorption of Osseointegrated Implant

Dental implant failure started with a resorption on alveolar crest. Resorption occurred if the stress is greater than the strength threshold (ultimate strength). Bones carrying mechanical loads adapt their strength to the load applied on it by bone modelling or remodelling; by apposition or destruction depends on internal stress level distributed on the bones. This research was conducted using FEM on a CBCT image of model which were implanted and converted into computerized 3D finite element digital model. The model was given material properties, fixed support, and being simulated on occlusal loads of 87 N and friction loads of 29 N for 0,7 seconds.Maximum princip al loads on alveolar bone of implant model was 41 Mpa and still below the ultimate strength (69 MPa). Based on the stress level above, it may be concluded that alveolar bone on implant model has good resistance towards resorption.