Semaphorin 4D Promotes Skeletal Metastasis in Breast Cancer.

Bone density is controlled by interactions between osteoclasts, which resorb bone, and osteoblasts, which deposit it. The semaphorins and their receptors, the plexins, originally shown to function in the immune system and to provide chemotactic cues for axon guidance, are now known to play a role in this process as well. Emerging data have identified Semaphorin 4D (Sema4D) as a product of osteoclasts acting through its receptor Plexin-B1 on osteoblasts to inhibit their function, tipping the balance of bone homeostasis in favor of resorption. Breast cancers and other epithelial malignancies overexpress Sema4D, so we theorized that tumor cells could be exploiting this pathway to establish lytic skeletal metastases. Here, we use measurements of osteoblast and osteoclast differentiation and function in vitro and a mouse model of skeletal metastasis to demonstrate that both soluble Sema4D and protein produced by the breast cancer cell line MDA-MB-231 inhibits differentiation of MC3T3 cells, an osteoblast cell line, and their ability to form mineralized tissues, while Sema4D-mediated induction of IL-8 and LIX/CXCL5, the murine homologue of IL-8, increases osteoclast numbers and activity. We also observe a decrease in the number of bone metastases in mice injected with MDA-MB-231 cells when Sema4D is silenced by RNA interference. These results are significant because treatments directed at suppression of skeletal metastases in bone-homing malignancies usually work by arresting bone remodeling, potentially leading to skeletal fragility, a significant problem in patient management. Targeting Sema4D in these cancers would not affect bone remodeling and therefore could elicit an improved therapeutic result without the debilitating side effects

Effect of mesenchymal stem cell transplantation on behavior and structural changes in myelin in experimental rat autoimmune encephalomyelitis

Purpose: To investigate the effect of bone marrow mesenchymal stem cell (BM-MSC) transplantation on behavior and structural changes in myelin of experimental autoimmune encephalomyelitis (EAE) in rats.Methods: Wistar rats were randomly assigned to normal control, EAE, placebo injection treatment, and MSCs treatment. EAE, placebo injection treatment and MSCs treatment groups were further divided into six groups, i.e., 1-day, 3-day, 7-day, 14-day, 21-day, and 28-day post-onset. Changes in the diseasestatus of the rats and structural changes in myelin at different time points were assessed with silver staining.Results: Behavioral changes peaked between 13 to 17 days post-immunization (71.90 % incidence), while disease symptoms peaked between 3 and 5 days after onset, were sustained for about 7 days, and then eased gradually thereafter. The highest therapeutic scores and the entire course of the disease in EAE and placebo treatment groups were not significantly different (p > 0.05). However, in MSC treatment group, these parameters were significantly lower than in the above two groups (p < 0.05). In EAE and placebo treatment groups, myelin sheath lesions were obvious from day 3 to 7 but on day 14, the number of myelin sheath fragments decreased significantly. Recovery at different time points was also better than those in EAE and placebo treatment groups.Conclusion: MSC transplantation shortens the course of EAE, and also reduces its severity. Thus, it has some prospects for use in the management of EAE.Keywords: Bone marrow mesenchymal stem cells, Autoimmune encephalomyelitis, Transplantation, Myeli