The Current and Future Therapies of Bone Regeneration to Repair Bone Defects

Bone defects often result from tumor resection, congenital malformation, trauma, fractures, surgery, or periodontitis in dentistry. Although dental implants serve as an effective treatment to recover mouth function from tooth defects, many patients do not have the adequate bone volume to build an implant. The gold standard for the reconstruction of large bone defects is the use of autogenous bone grafts. While autogenous bone graft is the most effective clinical method, surgical stress to the part of the bone being extracted and the quantity of extractable bone limit this method. Recently mesenchymal stem cell-based therapies have the potential to provide an effective treatment of osseous defects. In this paper, we discuss both the current therapy for bone regeneration and the perspectives in the field of stem cell-based regenerative medicine, addressing the sources of stem cells and growth factors used to induce bone regeneration effectively and reproducibly

Helix-Loop-Helix Proteins Regulate Pre-TCR and TCR Signaling through Modulation of Rel/NF-κB Activities

AbstractE2A and HEB are basic helix-loop-helix transcription factors essential for T cell development. Complete inhibition of their activities through transgenic overexpression of their inhibitors Id1 and Tal1 leads to a dramatic loss of thymocytes. Here, we suggest that bHLH proteins play important roles in establishing thresholds for pre-TCR and TCR signaling. Inhibition of their function allows double-negative cells to differentiate without a functional pre-TCR, while anti-CD3 stimulation downregulates bHLH activities. We also find that the transcription factor NF-κB becomes activated in transgenic thymocytes. Further activation of NF-κB exacerbates the loss of thymocytes, whereas inhibition of NF-κB leads to the rescue of double-positive thymocytes. Therefore, we propose that E2A and HEB negatively regulate pre-TCR and TCR signaling and their removal causes hyperactivation and apoptosis of thymocytes

RAF1-MEK/ERK pathway-dependent ARL4C expression promotes ameloblastoma cell proliferation and osteoclast formation

Ameloblastoma is an odontogenic neoplasm characterized by slow intraosseous growth with progressive jaw resorption. Recent reports have revealed that ameloblastoma harbours an oncogenic BRAFV600E mutation with mitogen-activated protein kinase (MAPK) pathway activation and described cases of ameloblastoma harbouring a BRAFV600E mutation in which patients were successfully treated with a BRAF inhibitor. Therefore, the MAPK pathway may be involved in the development of ameloblastoma; however, the precise mechanism by which it induces ameloblastoma is unclear. The expression of ADP-ribosylation factor (ARF)-like 4c (ARL4C), induced by a combination of the EGF-MAPK pathway and Wnt/beta-catenin signalling, has been shown to induce epithelial morphogenesis. It was also reported that the overexpression of ARL4C, due to alterations in the EGF/RAS-MAPK pathway and Wnt/beta-catenin signalling, promotes tumourigenesis. However, the roles of ARL4C in ameloblastoma are unknown. We investigated the involvement of ARL4C in the development of ameloblastoma. In immunohistochemical analyses of tissue specimens obtained from 38 ameloblastoma patients, ARL4C was hardly detected in non-tumour regions but tumours frequently showed strong expression of ARL4C, along with the expression of both BRAFV600E and RAF1 (also known as C-RAF). Loss-of-function experiments using inhibitors or siRNAs revealed that ARL4C elevation depended on the RAF1-MEK/ERK pathway in ameloblastoma cells. It was also shown that the RAF1-ARL4C and BRAFV600E-MEK/ERK pathways promoted cell proliferation independently. ARL4C-depleted tumour cells (generated by knockdown or knockout) exhibited decreased proliferation and migration capabilities. Finally, when ameloblastoma cells were co-cultured with mouse bone marrow cells and primary osteoblasts, ameloblastoma cells induced osteoclast formation. ARL4C elevation in ameloblastoma further promoted its formation capabilities through the increased RANKL expression of mouse bone marrow cells and/or primary osteoblasts. These results suggest that the RAF1-MEK/ERK-ARL4C axis, which may function in cooperation with the BRAFV600E-MEK/ERK pathway, promotes ameloblastoma development. (c) 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

NF-κB Signaling Regulates Physiological and Pathological Chondrogenesis

The nuclear factor-κB (NF-κB) is a transcription factor that regulates the expression of genes that control cell proliferation and apoptosis, as well as genes that respond to inflammation and immune responses. There are two means of NF-κB activation: the classical pathway, which involves the degradation of the inhibitor of κBα (IκBα), and the alternative pathway, which involves the NF-κB-inducing kinase (NIK, also known as MAP3K14). The mouse growth plate consists of the resting zone, proliferative zone, prehypertrophic zone, and hypertrophic zone. The p65 (RelA), which plays a central role in the classical pathway, is expressed throughout the cartilage layer, from the resting zone to the hypertrophic zone. Inhibiting the classical NF-κB signaling pathway blocks growth hormone (GH) or insulin-like growth factor (IGF-1) signaling, suppresses cell proliferation, and suppresses bone morphogenetic protein 2 (BMP2) expression, thereby promoting apoptosis. Since the production of autoantibodies and inflammatory cytokines, such as tumor necrosis factor-α (TNFα), interleukin (IL)-1β, IL-6, and IL-17, are regulated by the classical pathways and are increased in rheumatoid arthritis (RA), NF-κB inhibitors are used to suppress inflammation and joint destruction in RA models. In osteoarthritis (OA) models, the strength of NF-κB-activation is found to regulate the facilitation or suppression of OA. On the other hand, RelB is involved in the alternative pathway, and is expressed in the periarticular zone during the embryonic period of development. The alternative pathway is involved in the generation of chondrocytes in the proliferative zone during physiological conditions, and in the development of RA and OA during pathological conditions. Thus, NF-κB is an important molecule that controls normal development and the pathological destruction of cartilage

Critical Roles of NF-κB Signaling Molecules in Bone Metabolism Revealed by Genetic Mutations in Osteopetrosis

The nuclear factor-κB (NF-κB) transcription factor family consists of five related proteins, RelA (p65), c-Rel, RelB, p50/p105 (NF-κB1), and p52/p100 (NF-κB2). These proteins are important not only for inflammation and the immune response but also for bone metabolism. Activation of NF-κB occurs via the classic and alternative pathways. Inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, activate the former, and cytokines involved in lymph node formation, such as receptor activator of NF-κB ligand (RANKL) and CD40L, activate the latter. p50 and p52 double-knockout mice revealed severe osteopetrosis due to the total lack of osteoclasts, which are specialized cells for bone resorption. This finding suggests that the activation of NF-κB is required for osteoclast differentiation. The NF-κB signaling pathway is controlled by various regulators, including NF-κB essential modulator (NEMO), which is encoded by the IKBKG gene. In recent years, mutant forms of the IKBKG gene have been reported as causative genes of osteopetrosis, lymphedema, hypohidrotic ectodermal dysplasia, and immunodeficiency (OL-EDA-ID). In addition, a mutation in the RELA gene, encoding RelA, has been reported for the first time in newborns with high neonatal bone mass. Osteopetrosis is characterized by a diffuse increase in bone mass, ranging from a lethal form observed in newborns to an asymptomatic form that appears in adulthood. This review describes the genetic mutations in NF-κB signaling molecules that have been identified in patients with osteopetrosis

破骨細胞様細胞の形成、活性化および延命効果に関与する因子の研究

緒言 第1章:塩基性線維芽細胞成長因子(basic fibroblast growth factor:bFGF)の破骨細胞様細胞形成および骨吸収におよぼす効果 第2章 マクロファージコロニー刺激因子(M-CSF)およびインターロイキン1α(IL-α)の破骨細胞様細胞におよぼす延命効果 結論Made available in DSpace on 2012-06-26T07:11:49Z (GMT). No. of bitstreams: 1 jimi.pdf: 9293513 bytes, checksum: 70cb89a50fb084a7373519a6468ccc34 (MD5) Previous issue date: 1995-03-2