The endocannabinoid system has been postulated to help restrict cancer progression and maintain osteoblastic function during bone metastasis. Herein, the effects of cannabinoid receptor (CB) type 1 and 2 activation on breast cancer cell and osteoblast interaction were investigated by using ACEA and GW405833 as CB1 and CB2 agonists, respectively. Our results showed that breast cancer cell (MDA-MB-231)-derived conditioned media markedly decreased osteoblast-like UMR-106 cell viability. In contrast, media from MDA-MB-231 cells pre-treated with GW405833 improved UMR-106 cell viability. MDA-MB-231 cells were apparently more susceptible to both CB agonists than UMR-106 cells. Thereafter, we sought to answer the question as to how CB agonists reduced MDA-MB-231 cell virulence. Present data showed that co-activation of CB1 and CB2 exerted cytotoxic effects on MDA-MB-231 cells by increasing apoptotic cell death through suppression of the NF-κB signaling pathway in an ROS-independent mechanism. ACEA or GW405833 alone or in combination also inhibited MDA-MB-231 cell migration. Thus, it can be concluded that the endocannabinoid system is able to provide protection during breast cancer bone metastasis by interfering cancer and bone cell interaction as well as by the direct suppression of cancer cell growth and migration.

β-thalassemia is often associated with hyperglycemia, osteoporosis and increased fracture risk. However, the underlying mechanisms of the thalassemia-associated bone loss remain unclear. It might result from abnormal activities of osteoblasts and osteoclasts, and perhaps prolonged exposure to high extracellular glucose. Herein, we determined the rate of duodenal calcium transport in hemizygous β-globin knockout thalassemic (BKO) mice. Their bones were collected for primary osteoblast and osteoclast culture. We found that BKO mice had lower calcium absorption than their wild-type (WT) littermates. Osteoblasts from BKO mice showed aberrant expression of osteoblast-specific genes, e.g., Runx2, alkaline phosphatase and osteocalcin, which could be partially restored by 1,25(OH)2D3 treatment. However, the mRNA expression levels of RANK, calcitonin receptor (Calcr), c-Fos, NFATc1, cathepsin K and DMT1 were similar in both BKO and WT groups. Exposure to high extracellular glucose modestly but significantly affected the expression of osteoclast-specific markers in WT osteoclasts with no significant effect on osteoblast-specific genes in WT osteoblasts. Thus, high glucose alone was unable to convert WT bone cells to BKO-like bone cells. In conclusion, the impaired calcium absorption and mutation-related aberrant bone cell function rather than exposure to high blood glucose were likely to be the principal causes of thalassemic bone loss.

Thalassemia causes anemia, ineffective erythropoiesis, bone loss and iron accumulation in several tissues, e.g., liver, bone and heart, the last of which leads to lethal cardiomyopathy and arrhythmia. Although exercise reportedly improves bone density in thalassemic mice, exercise performance is compromised and might pose risk of cardiovascular accident in thalassemic patients. Therefore, we sought to explore whether mild-intensity physical activity (MPA) with 30–50% of maximal oxygen consumption was sufficient to benefit the heart and bone. Herein, male hemizygous β-globin knockout (BKO) mice and wild-type littermates were subjected to voluntary wheel running 1 h/day, 5 days/week for 3 months (MPA group) or kept sedentary (SDN; control). As determined by atomic absorption spectroscopy, BKO-MPA mice had less iron accumulation in heart and bone tissues compared with BKO-SDN mice. Meanwhile, the circulating level of fibroblast growth factor-23—a factor known to reduce serum iron and intestinal calcium absorption—was increased early in young BKO-MPA mice. Nevertheless, MPA did not affect duodenal calcium transport or body calcium retention. Although MPA restored the aberrant bone calcium-phosphorus ratio to normal range, it did not change vertebral calcium content or femoral mechanical properties. Microstructural porosity in tibia of BKO-MPA mice remained unaltered as determined by synchrotron radiation X-ray tomographic microscopy. In conclusion, MPA prevents cardiac and bone iron accumulation, which is beneficial to thalassemic patients with limited physical fitness or deteriorated cardiac performance. However, in contrast to moderate-intensity exercise, MPA does not improve bone mechanical properties or reduce bone porosity.