Bone mass and turnover are maintained by the coordinated balance between bone formation by osteoblasts and bone resorption by osteoclasts, under regulation of many systemic and local factors. Phosphoinositide-dependent serine-threonine protein kinase Akt is one of the key players in the signaling of potent bone anabolic factors. This study initially showed that the disruption of Akt1, a major Akt in osteoblasts and osteoclasts, in mice led to low-turnover osteopenia through dysfunctions of both cells. Ex vivo cell culture analyses revealed that the osteoblast dysfunction was traced to the increased susceptibility to the mitochondria-dependent apoptosis and the decreased transcriptional activity of runt-related transcription factor 2 (Runx2), a master regulator of osteoblast differentiation. Notably, our findings revealed a novel role of Akt1/forkhead box class O (FoxO) 3a/Bim axis in the apoptosis of osteoblasts: Akt1 phosphorylates the transcription factor FoxO3a to prevent its nuclear localization, leading to impaired transactivation of its target gene Bim which was also shown to be a potent proapoptotic molecule in osteoblasts. The osteoclast dysfunction was attributed to the cell autonomous defects of differentiation and survival in osteoclasts and the decreased expression of receptor activator of nuclear factor-κB ligand (RANKL), a major determinant of osteoclastogenesis, in osteoblasts. Akt1 was established as a crucial regulator of osteoblasts and osteoclasts by promoting their differentiation and survival to maintain bone mass and turnover. The molecular network found in this study will provide a basis for rational therapeutic targets for bone disorders.

Chordomas are rare, malignant bone tumors of the skull-base and axial skeleton. Until recently, there was no consensus among experts regarding appropriate clinical management of chordoma, resulting in inconsistent care and suboptimal outcomes for many patients. To address this shortcoming, the European Society of Medical Oncology (ESMO) and the Chordoma Foundation, the global chordoma patient advocacy group, convened a multi-disciplinary group of chordoma specialists to define by consensus evidence-based best practices for the optimal approach to chordoma. In January 2015, the first recommendations of this group were published, covering the management of primary and metastatic chordomas. Additional evidence and further discussion were needed to develop recommendations about the management of local-regional failures. Thus, ESMO and CF convened a second consensus group meeting in November 2015 to address the treatment of locally relapsed chordoma. This meeting involved over 60 specialists from Europe, the United States and Japan with expertise in treatment of patients with chordoma. The consensus achieved during that meeting is the subject of the present publication and complements the recommendations of the first position paper.

Osteoclasts (OCs) undergo rapid apoptosis without trophic factors, such as macrophage colony‐stimulating factor (M‐CSF). Their apoptosis was associated with a rapid and sustained increase in the pro‐apoptotic BH3‐only Bcl‐2 family member Bim. This was caused by the reduced ubiquitylation and proteasomal degradation of Bim that is mediated by c‐Cbl. Although the number of OCs was increased in the skeletal tissues of bim−/− mice, the mice exhibited mild osteosclerosis due to reduced bone resorption. OCs differentiated from bone marrow cells of bim−/− animals showed a marked prolongation of survival in the absence of M‐CSF, compared with bim+/+ OCs, but the bone‐resorbing activity of bim−/− OCs was significantly reduced. Overexpression of a degradation‐resistant lysine‐free Bim mutant in bim−/− cells abrogated the anti‐apoptotic effect of M‐CSF, while wild‐type Bim did not. These results demonstrate that ubiquitylation‐dependent regulation of Bim levels is critical for controlling apoptosis and activation of OCs.

RANK and CD40 activate NF‐κB and MAPKs to similar levels via TRAF6. Even though overexpression of TRAF6 results in osteoclast formation, RANK but not CD40 promotes osteoclastogenesis. To understand the molecular basis for RANK‐specific activity in osteoclastogenesis, we created an osteoclast formation system driven by anti‐human CD40 antibody‐mediated stimulation of a chimeric receptor, h40/mRK, which consists of the extracellular domain of human CD40 and the transmembrane and cytoplasmic domains of mouse RANK. By introducing mutations into three TRAF6‐binding sites of RANK, we found that h40/mRK with a single TRAF6‐binding site efficiently induced Ca2+ oscillation and expression of NFATc1, a master switch in osteoclastogenesis, whereas CD40 carrying a single TRAF6‐binding site did not. However, expression of CD40 that was approximately 100 times greater than that of h40/mRK resulted in osteoclast formation, indicating that the RANK–TRAF6 signal is more potent than the CD40–TRAF6 signal in terms of NFATc1 activation and osteoclastogenesis. These results suggest that RANK may harbor a specific domain that amplifies TRAF6 signaling.

Objective To examine the incidence of vertebral osteomyelitis (VO) and the clinical features of VO focusing on risk factors for death using a Japanese nationwide administrative database. Design Retrospective observational study. Setting Hospitals adopting the Diagnosis Procedure Combination system during 2007–2010. Participants We identified 7118 patients who were diagnosed with VO (International Classification of Diseases, 10th Revision codes: A18.0, M46.4, M46.5, M46.8, M46.9, M48.9 and M49.3, checked with the detailed diagnoses in each case and all other codes indicating the presence of a specific infection) and hospitalised between July and December, 2007–2010, using the Japanese Diagnosis Procedure Combination database. Main outcome measures The annual incidence of VO was estimated. Logistic regression analysis was performed to analyse factors affecting in-hospital mortality in the VO patients. Dependent variables included patient characteristics (age, sex and comorbidities), procedures (haemodialysis and surgery) and hospital factors (type of hospital and hospital volume). Results Overall, 58.9% of eligible patients were men and the average age was 69.2 years. The estimated incidence of VO increased from 5.3/100 000 population per year in 2007 to 7.4/100 000 population per year in 2010. In-hospital mortality was 6%. There was a linear trend between higher rates of in-hospital mortality and greater age. A higher rate of in-hospital mortality was significantly associated with haemodialysis use (ORs, 10.56 (95% CI 8.12 to 13.74)), diabetes (2.37 (1.89 to 2.98)), liver cirrhosis (2.63 (1.49 to 4.63)), malignancy (2.68, (2.10 to 3.42)) and infective endocarditis (3.19 (1.80 to 5.65)). Conclusions Our study demonstrates an increasing incidence of VO, and defines risk factors for death with a nationwide database. Several comorbidities were significantly associated with higher rates of in-hospital death in VO patients.

In the past few years, the pro-apoptotic molecule Bim has attracted increasing attention as a plausible target for tumor therapy. A variety of normal and pathological systems regulated by Bim, dependent on cell type, apoptotic stimulation, and chemotherapeutic agents, have been documented. Bim promotes anoikis of many tumor cells, such as lung cancer, breast cancer, osteosarcoma, and melanoma. Various chemotherapeutic agents use Bim as a mediating executioner of cell death. Hence, Bim suppression supports metastasis and chemoresistance. Imatinib, gefitinib, bortezomib, and Bim protein itself are spotlighted as current and future Bim-targeting therapeutic agents. The potential benefits of Bim-targeted therapies are selectivity of treatment for tumor cells and reduction in tumor-associated phenomena such as chemoresistance and metastasis. Thus, Bim-targeting therapies may provide more effective and unique tumor management modalities in future. This review article discusses all these issues. [Mol Cancer Ther 2009;8(12):3173–80]