SUMMARY Transforming growth factor-β (TGFβ) regulates the expression of genes supporting breast cancer cell in bone but little is known about prostate cancer bone metastases and TGFβ. Our study reveals that the TGFBR1 inhibitor SD208 effectively reduces prostate cancer bone metastases. TGFβ upregulates in prostate cancer cells a set of genes associated with cancer aggressiveness and bone metastases, and the most upregulated gene was PMEPA1. In patients, PMEPA1 expression decreased in metastatic prostate cancer and low Pmepa1 correlated with decreased metastasis-free survival. Only membrane-anchored isoforms of PMEPA1 interacted with R-SMADs and ubiquitin ligases, blocking TGFβ signaling independently of the proteasome. Interrupting this negative feedback loop by PMEPA1 knockdown increased prometastatic gene expression and bone metastases in a mouse prostate cancer model.

The regulation of osteoclasts is vital for maintaining balance in bone remodeling (i.e., bone resorption by osteoclasts and bone formation by osteoblasts) and is thus important in the treatment of bone disease. Boneresorbing osteoclasts are derived from hematopoietic cells of the monocyte/macrophage lineage, and they differentiate into multinucleated cells through multiple processes (1). Osteoclast formation and activity are regulated by local factors and by stromal and osteoblast cells in the bone environment (2).

Increased fracture risk is commonly reported in cancer patients receiving radiotherapy, particularly at sites within the field of treatment. The direct and systemic effects of ionizing radiation on bone at a therapeutic dose are not well characterized in clinically relevant animal models. Using twenty-week male C57Bl/6 mice, effects of irradiation (right hindlimb; 2 Gy) on bone volume and microarchitecture were evaluated prospectively by microcomputed tomography and histomorphometry and compared to contralateral-shielded bone (left hindlimb) and non-irradiated control bone. One-week post-irradiation, trabecular bone volume declined in irradiated tibiae (−22%; p<0.0001) and femora (−14%; p=0.0586) and microarchitectural parameters were compromised. Trabecular bone volume declined in contralateral tibiae (−17%; p=0.003), and no loss was detected at the femur. Osteoclast number, apoptotic osteocyte number and marrow adiposity were increased in irradiated bone relative to contralateral and non-irradiated bone, while osteoblast number was unchanged. Despite no change in osteoblast number one-week post-irradiation, dynamic bone formation indices revealed a reduction in mineralized bone surface and a concomitant increase in unmineralized osteoid surface area in irradiated bone relative to contralateral and non-irradiated control bone. Further, dose- and time-dependent calvarial culture and in vitro assays confirmed that calvarial osteoblasts and osteoblast-like MC3T3 cells were relatively radioresistant, while calvarial osteocyte and osteocyte-like MLO-Y4 cell apoptosis was induced as early as 48h post-irradiation (4 Gy). In osteoclastogenesis assays, radiation exposure (8 Gy) stimulated murine macrophage RAW264.7 cell differentiation and co-culture of irradiated RAW264.7 cells with MLO-Y4 or murine bone marrow cells enhanced this effect. These studies highlight the multi-faceted nature of radiation-induced bone loss by demonstrating direct and systemic effects on bone and its many cell types using clinically relevant doses and have important implications for bone health in patients treated with radiation therapy.

This study examined the rate of suicide attempts and relevant variables and identified risk factors for suicide attempts among Korean adolescents. A cross-sectional study was performed using an anonymous, self-report questionnaire. A total of 2,100 Korean adolescents, including 1,321 student adolescents and 779 delinquent adolescents, were selected using a proportional stratified random sampling method for this study. The results showed the rate of suicide attempts to be 11.6%, with delinquent adolescents reporting a higher rate of suicide attempts than student adolescents. Adolescent suicide attempts indicated higher levels of dysfunctional family dynamics and maladaptive personalities. In addition, adolescents who attempted suicide expressed a significantly lower level of life satisfaction and less effective coping strategies compared with those adolescents who had not attempted suicide. Logistic regression analysis revealed that five predictive risk factors appeared to be statistically significant: coping strategy, parental child-rearing pattern, depression, parent-child relationship, and psychosomatic symptoms, in this order at p < 0.05.